Overall cerebral small vessel disease burden is associated with outcome of acute ischemic stroke after mechanical thrombectomy

Abstract

Objectives

To investigate the association between the overall cerebral small vessel disease (CSVD) burden and the therapeutic outcome of mechanical thrombectomy (MT) in patients with acute anterior circulation large-vessel occlusion stroke.

Materials and Methods

Data of patients who achieved successful revascularization after MT for acute anterior circulation large-vessel occlusion stroke in the Ningbo Medical Center Lihuili Hospital between April 2017 and January 2022 were retrospectively analyzed. The overall CSVD burden was evaluated by total CSVD score based on MRI images. According to the 90-day modified Rankin Scale (mRS) score, the participants were divided into the Good outcome group (mRS score 0–2) and Poor outcome group (mRS score 3–6). Multivariate Logistic regression was applied to assess the relationship between the overal CSVD burdern and 90-day outcome.

Results

In total, 145 eligible patients were included and classified into the Good outcome group (n = 77, 62.3% males, mean age: 64.92 ± 13.67 years) and Poor outcome group (n = 68, 50% males, mean age: 69.76 ± 10.88 years). Symptomatic intracranial hemorrhage (OR = 2.788, 95%CI: 1.143–8.745, P = 0.048), poor preoperative collateral status (OR = 3.619, 95%CI: 1.670–7.844, P = 0.001), and high total CSVD score (score 2: OR = 3.800, 95%CI: 1.173 = 12.311, P = 0.026; score 3: OR = 7.529, 95%CI: 1.555–36.460, P = 0.012) were independently prognostic for poor 90-day outcome in patients receiving MT.

Conclusion

This study identified that the overall CSVD burden was independently associated with the prognosis of patients receiving MT for acute anterior circulation large-vessel occlusion stroke.

Keywords

Cerebral small vessel disease ischemic stroke mechanical thrombectomy prognosis

Introduction

The treatment for acute ischemic stroke (AIS) depends largely on the early-stage efficient restoration of blood perfusion and the salvage of ischemic penumbra. Presently, mechanical thrombectomy (MT) is applied as the standard treatment for acute anterior circulation large-vessel occlusion stroke (ACLVOS), and it is more effective than intravenous thrombolysis (IVT) in improving the success rate of revascularization. It contributes to a high rate of reperfusion (up to 90%) immediately after operation, but is associated with a low rate of good prognosis at 90 days (less than 50%).¹ Optimizing indications for MT can help identify the patients suitable for thrombectomy treatment and then increase the rate of good prognosis.

Cerebral small vessel disease (CSVD) represents a range of clinical, neuroimaging, and pathological features involved in the intracerebral small arteries and their distal branches, arterioles, capillaries, venules, and small veins of various causes. On imaging, it mainly manifests lacunar cerebral infarction, white matter hyperintensities (WMH), cerebral microbleeds (CMB), enlarged perivascular spaces (EPVS), and cerebral atrophy.² It has been established that CSVD has significant implications for the occurrence, development, and prognosis of AIS. Additionally, it might be attributed to the cerebral blood flow/perfusion abnormalities and blood-brain barrier (BBB) permeability alterations in pathophysiology.³

Increasing recent studies have suggested a certain relationship between CSVD and the outcome of thrombectomy, and the majority of them are concentrating on single CSVD imaging markers.⁴ Nevertheless, various CSVD features usually coexist and influence each other. In this context, combination of more than one imaging features of CSVD has been increasingly used in clinical practice,^5–6 and it is more significant to explore the association between the overall CSVD burden (measured by total CSVD score) and the therapeutic outcome of thrombectomy.⁷ To this end, the current retrospective case-control study aimed at probing into the association between the overall CSVD burden and 90-day outcome of MT in 145 patients with acute ACLVOS.

Methods

Research subjects

One hundred and forty-five patients who received MT for acute ACLVOS in the Ningbo Medical Center Lihuili Hospital between April 2017 and January 2022 were included in this retrospective cohort analysis. Inclusion criteria: (1) age ≥ 18 years old; (2) AIS confirmed by the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke 2018; (3) onset-to-puncture time < 6 h, and occlusion of M1 and M2 segments of the middle cerebral artery (MCA M1/M2) or the internal carotid artery (ICA) confirmed by preoperative cranial computed tomography angiography (CTA); or onset-to-puncture time ranging between 6–24 h, fulfilling the selection criteria of the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) trial⁸; (4) revascularization after MT, i.e., modified thrombolysis in cerebral infarction (mTICI) grade 2b/3；(5) cranial magnetic resonance imaging (MRI), obtained before or after (within 72h) Endovascular therapy (EVT), with imaging of high enough quality for CSVD assessment. Exclusion criteria: (1) a history of cerebral stroke with a premorbid mRS score > 2; (2) cranial MRI data were not available; (3) complicated by bilateral cerebral infarction; (4) incomplete 90-day follow-up data.

MT treatment

Patients who had an onset within 4.5 h were assigned to undergo IVT plus MT, while patients who had contraindications for IVT or had an onset >4.5 h were managed by MT alone. MT was performed using a Solitaire stent (Medtronic, Inc., USA) combined with an intermediate catheter. Balloon dilation, stent angioplasty, and intra-arterial thrombolysis were applied as salvage techniques.

Imaging assessment

Cranial MRI images, including T1WI, T2WI, Diffusion-Weighted Imaging (DWI), Apparent Diffusion Coefficient (ADC), and FLAIR images, were obtained from all participants. Two trained neurologists blinded to clinical data independently assessed the images, on the basis of the Standards for Reporting Vascular changes on nEuroimaging (STRIVE).⁹ The severity of WMH was evaluated with the Fazekas scale. The lacuna presents as a circle or oval cavity filled with cerebrospinal fluid (CSF) signals in the basal ganglia, internal capsule, or semioval center. It is hypointense on T1WI but hyperintense on T2WI, and shows ring-like peripheral hyperintense signals with central hypointense signals (3–5 mm in diameter) on FLAIR. EPVS majorly refers to the fluid-filled space where the fluids travel with the blood vessels in the basal ganglia or semioval center. Consistent with CSF signals, the EPVS shows a linear shape when the fluids travel parallel to the blood vessels while a circle or oval shape when the fluids travel perpendicular to the blood vessels. It is hypointense on T1WI and FLAIR, but is hyperintense on T2WI (< 3 mm in diameter).

A point was counted for each of the following imaging features (Figure 1): (1) ≥ 1 lacuna, (2) Fazekas score ≥ 2 for deep WMH and (or) Fazekas score = 3 for paraventricular WMH, and (3) moderate-to-severe EPVS in the basal ganglia (grade 2–4). CMB was not evaluable due to the absence of T2* -weighted gradient-recalled echo (GRE), susceptibility weighted imaging (SWI) or enhanced T2* -weighted angiography (ESWAN).¹⁰ The total CSVD scores were calculated as 0–3 by summing the points mentioned above. Such truncated total CSVD scores were used in some previous studies because of various limitations.^5,11

Collateral status was evaluated with digital subtraction angiography (DSA) images on the basis of the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) Collateral Flow Grading System ¹²: grade 0–2, poor collaterals; grade 3–4, good collaterals.

Clinical assessment

Patient outcome was assessed via a 90-day mRS scoring system: score 0–2, good outcome; score 3–6, poor outcome. Based on the European Cooperative Acute Stroke Study II (ECASSII) ,¹³ symptomatic intracranial hemorrhage (sICH) is defined by presence of intracranial hemorrhage on head CT that leads to neurological deterioration and increase in NIHSS score ≥ 4 points.

Clinical information

Baseline characteristics of the participants were collected, including sex, age, admission systolic/diastolic blood pressure (SBP/DBP), previous history (hypertension, diabetes, and atrial fibrillation), laboratory data (fasting plasm glucose [FPG], creatinine, low-density lipoprotein cholesterol [LDL-C]), admission NIHSS score, admission ASPECT score, occlusion site (ICA, or MCA M1/M2), TOAST subtype, onset-to-revascularization time (ORT), received IVT rate, postoperative 90-day mRS score, incidence of sICH, etc.

Statistical analysis

SPSS 25.0 was applied to fulfill data analysis. Upon normal distribution, measurement data in mean ± standard deviation (x ± s) were compared by a two-sample independent t test or an analysis of variance. For measurement data twithout normal distribution, median with first (Q1) and third (Q3) quartiles (M [Q1, Q3]) was calculated, and Mann-Whitney U test or kruskal-wallis test was applied for comparisons. Enumeration data were represented by rate or percentage and compared via χ2 test or Fisher exact probability test Multivariate Logistic regression model was used based on the variables with statistical significance in prognosis in univariate analysis to explore the relationship between the total CSVD imaging score and the 90-day prognosis after MT. Furthermore, multicollinearity was tested using variance inflation factor(VIF), with a VIF≥5 indicating the presence of multicollinearity. In order to fix multicollinearity, WMH, LI, PVS and total CSVD imaging score were tested independently from each other in the different Multivariate Logistic regression models.

Results

Baseline characteristics

Totally, 241 patients with acute LVOS were initially enrolled, including 189 ACLVOS patients with successful revascularization. With the exclusion of 44 patients without MRI data or complete clinical data, 145 patients were eventually included in this study. CSVD was scored 0 point in 40 patients (27.6%), 1 point in 53 patients (36.6%), 2 points in 35 patients (24.1%), and 3 points in 17 patients (11.7%). Comparatively, patients with total CSVD score 0 were much younger (mean age) and had a lower admission NIHSS score (median) than patients with total CSVD score 1–3 (60.2 vs. 68.70, 72.4, 68.23 years; 14 vs. 16, 18, 25; P < 0.05). Compared with the patients having CSVD score 0, patients with CSVD score 2 had significantly lower admission ASPECT scores (8[8, 9] vs. 9[9, 10]; P < 0.05). In terms of the rate of poor 90-day outcome, it was significantly higher upon CSVD score 2–3 than that upon CSVD score 0–1 (77.1%, 88.2% vs. 25%, 32.1%; P < 0.05). Moreover, the ORT was statistically different among the four groups (P = 0.018 in kruskal-wallis test), but it marginally varied among the four groups after Bonferroni adjustment. No significant differences were demonstrated among the four groups regarding the sex, received IVT rate, proportions of patients having hypertension, diabetes or atrial fibrillation, admission SBP/DBP, FPG level, creatinine level, LDL-C level, occlusion site, TOAST subtype, collaterals, and incidence of sICH. See Table 1 for more details.

Table 1.

Baseline characteristics of patients undergoing mechanical thrombectomy stratified by CSVD burden measured by total CSVD score.

Characteristics	CSVD score 0(n = 40)	CSVD score 1(n = 53)	CSVD score 2(n = 35)	CSVD score 3(n = 17)	P-Value
Age(years)	60.2 ± 13.97	68.70 ± 11.72	72.4 ± 10.53	68.23 ± 12.63	<0.001*
Male sex	25(62.5%)	32(60.4%)	18(51.4%)	7(41.2%)	0.407
Admission SBP (mmHg)	148.12 ± 21.79	151.06 ± 22.80	153.51 ± 25.94	149.06 ± 22.40	0.778
Admission DBP (mmHg)	83.95 ± 12.41	86.79 ± 13.12	86.23 ± 15.34	85.41 ± 11.53	0.776
Admission NIHSS	14(10, 17)	16(11.5, 22.5)	18(15, 20)	25(17.5, 26)	<0.001*
Received IVT	29(72.5%)	30(56.6%)	20(57.1%)	11(64.7%)	0.402
ASPECT score	9(9, 10)	8(8, 8)	8(8, 9)	8(8, 9)	0.005*
TOAST subtype					0.573
LAA	14(35%)	15(28.3%)	14(40%)	6(35.5%)
Cardioembolism	20(50%)	30(56.6%)	20(57.1%)	8(47.1%)
Others	6(15%)	8(15.1%)	1(2.8%)	3(17.6%)
Risk factors
Hypertension	16(40%)	32(60.4%)	20(57.1%)	7(41.2%)	0.175
Diabetes	5(12.5%)	7(13.2%)	8(22.9%)	3(17.6%)	0.584
Atrial Fibrillation	20(50%)	30(56.6%)	20(57.1%)	8(47.1%)	0.769
Laboratory data
Glucose mmol/L	6.32 ± 2.53	7.27 ± 2.76	7.65 ± 3.07	8.88 ± 4.88	0.076
Creatinine umol/L	64.94 ± 13.67	71.59 ± 18.64	72.07 ± 21.41	69.02 ± 24.68	0.310
LDL-C mmol/L	2.73 ± 1.06	2.58 ± 0.95	2.56 ± 0.75	2.99 ± 1.32	0.573
Occlusion site					0.103
ICA	10(25%)	9(17%)	12(34.3%)	9(52.9%)
MCA M1	18(45%)	31(58.5%)	16(45.7%)	6(35.3%)
MCA M2	12(30%)	13(24.5%)	7(20%)	2(11.8%)
ORT min	280.5(240, 408.8)	379(273.5, 468.5)	360(303, 440)	415(272.5, 533)	0.018*
Good collaterals	27(67.5%)	28(52.8%)	17(48.6%)	7(41.2%)	0.212
sICH	2(5%)	3(5.66%)	6(17.1%)	4(23.5%)	0.060
Poor outcome	10(25%)	17(32.1%)	21(77.1%)	15(88.2%)	<0.001*

* P<0.05.

Values are mean (SD) or median (IQR) or number (%).

CSVD: cerebral small vessel disease; NIHSS: the National Institutes of Health Stroke Scale; SBP: systolic blood pressure; DBP: diastolic blood pressure; IVT: intravenous thrombolysis; ASPECT: Alberta Stroke Program Early CT; LAA: Large artery atherosclerosis; LDL-C: low-density lipoprotein cholesterol; ICA: internal carotid artery; MCA: middle cerebral artery; ORT: onset-to-revascularization time; sICH: symptomatic intracranial hemorrhage.

Univariate analysis of patient 90-day outcome

Of the 145 patients, 77 patients (53.1%) had a good outcome (Good outcome group) while 68 patients (46.9%) had a poor outcome (Poor outcome group). Patients who had a high total CSVD score were prone to have a poor outcome (Figure 2). In the univariate model, a poor outcome were associated with an older age (69.76 ± 10.88 vs. 64.92 ± 13.67 years), higher admission NIHSS score (18[15, 23.75] vs. 15[10, 20]), lower admission ASPECT score (8[8, 9] vs. 9[8, 9]), poorer collaterals (38.2% vs. 68.8% good collaterals), and a higher incidence of sICH (17.6% vs. 2.6%), as compared to a good outcome (all P < 0.05). Moreover, the differences in the total CSVD score and every single imaging features were distinctly different between the two group (P < 0.05). See Table 2 for more details.

Table 2.

Univariate analysis of influencing factors for functional outcome at 90 days.

Variables	Good outcome(n = 77)mRS (0–2)	Poor outcome(n = 68)mRS (3–6)	P-Value
Age(years)	64.92 ± 13.67	69.76 ± 10.88	0.021*
Male sex	48 (62.3%)	34 (50%)	0.135
Admission SBP (mmHg)	151.52 ± 23.28	149.57 ± 23.08	0.615
Admission DBP (mmHg)	85.60 ± 13.80	85.84 ± 12.70	0.913
Admission NIHSS	15 (10, 20)	18 (15, 23.75)	0.001*
Received IVT	50 (64.9%)	40 (58.8%)	0.449
ASPECT score	9 (8, 9)	8 (8, 9)	0.037*
TOAST subtype			0.468
LAA	25 (32.5%)	24 (35.3%)
Cardioembolism	40 (51.9%)	38 (55.9%)
Others	12 (15.6%)	6 (8.8%)
Risk factors
Hypertension	38 (49.4%)	37 (54.4%)	0.543
Diabetes	12 (15.6%)	11 (16.2%)	0.922
Atrial Fibrillation	40 (51.9%)	38 (55.9%)	0.312
Laboratory data
Glucose mmol/L	7.02 ± 2.81	7.60 ± 3.51	0.276
Creatinine umol/L	69.53 ± 19.04	69.61 ± 19.10	0.980
LDL-C mmol/L	2.72 ± 1.02	2.61 ± 0.95	0.494
Occlusion site			0.882
ICA	20 (26%)	20 (29.4%)
MCA M1	39 (50.6%)	32 (47.1%)
MCA M2	18 (23.4%)	16 (23.5%)
ORT min	330 (247, 465)	367 (282.8, 443)	0.262
Good collaterals	53 (68.8%)	26 (38.2%)	<0.001*
sICH	2 (2.6%)	12 (17.6%)	0.002*
CSVD score			<0.001*
0	30 (39%)	10 (14.7%)
1	36 (46.8%)	17 (25%)
2	9 (11.7%)	26 (38.2%)
3	2 (2.6%)	15 (22.1%)
Radiological features
WMH	24 (31.2%)	47 (69.1%)	<0.001*
LI	25 (32.5%)	47 (69.1%)	<0.001*
PVS	10 (13%)	20 (29.4%)	0.015*

* P<0.05.

Values are mean (SD) or median (IQR) or number (%).

CSVD: cerebral small vessel disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; NIHSS: the National Institutes of Health Stroke Scale; IVT: intravenous thrombolysis; ASPECT: Alberta Stroke Program Early CT; LAA: Large artery atherosclerosis; LDL-C: low-density lipoprotein cholesterol; ICA: internal carotid artery; MCA: middle cerebral artery; ORT: onset-to-revascularization time; sICH: symptomatic intracranial hemorrhage; WMH: white matter hyperintensities; LI: lacunes infarction; PVS: perivascular spaces.

Multivariate logistic regression analysis of patient 90-day outcome

sICH (OR = 2.788, 95%CI:1.143–8.745, P = 0.048), poor preoperative collaterals (OR = 3.619, 95%CI:1.670–7.844, P = 0.001), and high total CSVD score were independently prognostic for poor 90-day outcome of MT. As stratified by the total CSVD score, the risk of having a poor outcome when total CSVD score = 2 and 3 was approximately 4 times (OR = 3.800, 95%CI: 1.173–12.311, P = 0.026) and 7.5 times (OR = 7.529, 95%CI: 1.555–36.460, P = 0.012) higher than that in the context of total CSVD score = 0, respectively. No profound difference between patients with total CSVD score = 1 and 0 in terms of the risk of having a poor outcome. See Table 3 for more details. The presence of WMH or LI was significantly related to poor 90-day outcome of MT after adjusting for confounders in their respective multivariate regression models. However, there was no association between the presence of PVS and poor 90-day outcome of MT. See Supplemental Table S1-S3 for more details.

Table 3.

Multivariate logistic regression analysis for poor outcome predictors at 3 months (mRS score 3–6).

Variables	Multivariate adjusted OR	95%CI	P-Value
Age(years)	1.007	0.974–1.040	0.691
Admission NIHSS	1.044	0.977–1.115	0.202
ASPECT score	0.951	0.519–1.741	0.870
Poor collaterals	3.619	1.670–7.844	0.001*
sICH	2.788	1.143–8.745	0.048*
CSVD score
0	/	/
1	1.380	0.491–3.876	0.541
2	3.800	1.173–12.311	0.026*
3	7.529	1.555–36.460	0.012*

* P<0.05.

NIHSS: the National Institutes of Health Stroke Scale; ASPECT: Alberta Stroke Program Early CT; sICH: symptomatic intracranial hemorrhage; CSVD: cerebral small vessel disease.

Discussion

The present study preliminarily revealed the prognostic significance of patient age, admission NIHSS score, admission ASPECT score, collateral status, sICH, and total CSVD score for 90-day outcome of MT in patients with acute ACLVOS. Further multivariate analysis demonstrated the total CSVD score was independently prognostic for the poor outcome of MT in this population.

There were some studies investigating the relationship between CSVD and outcome of MT, but most of them were concentrating on single CSVD imaging features.^14–16 For example, a systemic retrospective study revealed that the poor 90-day outcome of MT was associated with severe leukoaraiosis and CMB but independent of the lacuna.⁴ Consistently, our study also noted that the severe WMH was correlated to the poor 90-day outcome of MT in Multivariate logistic regression analysis. However, the lacune was also identified as a prognostic factor in our study. We speculated that this might be due to the application of CT and the different exclusion criteria in previous studies (without excluding patients having bilateral cerebral stroke), while both the two factors can significantly affect the assessment of the lacuna.¹⁷ To our knowledge, the relationship between the EPVS and the outcome of MT has not been reported yet by now. This study, for the first time, suggested that the EPVS was not associated with the poor 90-day outcome of MT.

Various single CSVD imaging features exert different effects on the pathophysiologic basis of cerebrovascular diseases, and each features generally coexist and influence each other.¹⁸ The overall CSVD burden is highly reflective of the general condition of CSVD and thus has gained more attention in some relevant studies.¹⁹ Multiple previous studies proved that high total CSVD score was independently prognostic for poor prognosis of patients receiving IVT.^20–21 While for patients undergoing MT, relatively few studies on the total CSVD score have been performed, and the outcomes are different. It was believed that CSVD affected collateral status to reduce the rate of good prognosis after revascularization. On this basis, two studies were devised to explore the linkage between the total CSVD score and the collateral status before MT with inconsistent results.^5,22 However, prognosis of the patients was not covered in that two studies. Here, preoperative collateral status was demonstrated as independent of the total CSVD score. There was only one study⁶ investigating the role of the overall CSVD burden in MT outcome. Inconsistent with our study, that study reported that moderate-to-severe overall CSVD burden exhibited no distinct effect on the poor prognosis of ACLVOS patients receiving MT. Besides, the study suggested that the preoperative collateral status and postoperative revascularization, other than BBB dysfunction or vascular microcirculation disorders, were more influential in patients receiving MT, as compared to the patients undergoing thrombolysis. In contrast, all participants in our study achieved revascularization (mTICI grade 2b/3), excluding the possible confounders derived from failure of thrombectomy. Moreover, the multivariate analysis after adjustment for factors such as collateral compensation indicated that high total CSVD score was independently prognostic for poor 90-day outcome of MT. It has been established that CSVD increases BBB permeability, resulting in leakage of the intravascular components to perivascular spaces. In this way, there is an increased risk of developing hemorrhagic transformation in patients with cerebral infarction, especially in those receiving thrombolysis, and developing local inflammatory reactions in brain tissue.²³ The subsequent platelet activation and hypercoagulaion of the blood affect the reperfusion in brain tissue, leading to failure of effective tissue reperfusion even after revascularization.²⁴

This study faces some limitations. First, this is a retrospective study involving a small number of participants from a single center, and selection bias is inevitable. Second, this study adopted MRI for CSVD assessment, which was not applicable in some patients due to their severe medical conditions or other causes, resulting in exclusion of these patients in relevant analysis and thus causing bias. As far as we know, MRI is the nondisplaceable assessment method for CSVD, especially for EPVS and CMB which cannot be evaluated by CT or other imaging techniques. Third, CMB was not evaluable in this study due to the absence of T2*W GRE, SWI or ESWAN images, and thus truncated total CSVD score was used. There are some studies which believe that lack of certain single feature can overestimate or underestimate the effect of total CSVD score, although truncated total CSVD score was analyzed in some research.⁵ Fourth, the MRI used to assess CSVD were conducted before or after (within 72 h) EVT in different patients. However, chronic CSVD imaging makers were not likely to change rapidly within 72h after stroke. Finally, some factors that may affect patient prognosis are not included in this study, such as the infarct volume before and after MT.

Conclusion

This study identified that the overall CSVD burden was independently correlated to the prognosis of patients receiving MT for acute ACLVOS. In spite of the lack of sufficient evidence supporting that the total CSVD score can change treatment strategies of patients with LVOS, it alone or combined with some previously reported prognostic factors may be valuable tools to predict the prognosis of MT in further larger-scale, multi-center randomized controlled trials.

Supplemental Material

sj-docx-1-ine-10.1177_15910199221138140 - Supplemental material for Overall cerebral small vessel disease burden is associated with outcome of acute ischemic stroke after mechanical thrombectomy

Supplemental material, sj-docx-1-ine-10.1177_15910199221138140 for Overall cerebral small vessel disease burden is associated with outcome of acute ischemic stroke after mechanical thrombectomy by Rumeng Fan, Jiehua Gan, Feng Chen, Chensheng Le and Yong Chen in Interventional Neuroradiology

Footnotes

Compliance with declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article

Ethical standards

The study was approved by the ethics committees of the Ningbo Medical Center Lihuili Hospital without need for informed consent.

ORCID iD

Rumeng Fan

Supplemental material

Supplemental material for this article is available online.

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