Prolonged vs. Short-Term Infusion of Imipenem/Cilastatin for Multidrug-Resistant Gram-Negative Bacilli Severe Pneumonia: A Randomized Controlled Trial Evaluating Efficacy, Safety, and Cost-Effectiveness ()
1. Introduction
Multidrug-resistant Gram-negative bacilli (MDR-GNB) infections, particularly severe pneumonia, represent a critical global health threat due to escalating antibiotic resistance and limited therapeutic options. Mortality rates exceed 40% in critically ill patients, driven by delayed appropriate antimicrobial therapy and suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment with conventional dosing strategies. The Infectious Diseases Society of America (IDSA) reported that extended infusion is an ideal way to optimize beta-lactam antibiotic efficacy [1]. Imipenem/cilastatin, a carbapenem with potent activity against MDR-GNB, is a cornerstone of empirical and targeted therapy. Prolonged infusion of β-lactams optimizes the time-dependent pharmacodynamic target (ƒT > MIC), particularly for multidrug-resistant pathogens with elevated MICs [2] [3]. However, its efficacy is compromised when administered via short-term infusions (e.g., 30 minutes), as the time-dependent bactericidal activity of β-lactams requires prolonged drug concentrations above the pathogen’s minimum inhibitory concentration (MIC) [4].
Pharmacokinetic/pharmacodynamic (PK/PD) models demonstrate that prolonged infusions (3 - 4 hours) of carbapenems maximize ƒT > MIC, a critical determinant of bactericidal efficacy against Gram-negative pathogens with reduced susceptibility [5]-[7]. Observational studies suggest clinical benefits in critically ill populations [8] [9], yet randomized trials remain limited and inconclusive [10] [11]. Observational studies have reported improved clinical outcomes with prolonged infusion in sepsis and ventilator-associated pneumonia, yet robust evidence from randomized controlled trials (RCTs) remains scarce. Existing RCTs are limited by small sample sizes, heterogeneous populations, or lack of cost-effectiveness analyses, leaving clinicians uncertain about the practical benefits of this strategy.
To address these gaps, we conducted a PROBE (Prospective Randomized Open Blinded Endpoint) trial comparing prolonged (3-hour) versus short-term (30-minute) infusion of imipenem/cilastatin in patients with MDR-GNB severe pneumonia. Our primary hypothesis was that prolonged infusion would increase clinical response rates by optimizing PK/PD target attainment. Secondary objectives included evaluating microbial eradication kinetics, survival benefits, safety profiles, and incremental cost-effectiveness. This study aims to provide definitive evidence to guide antimicrobial stewardship in critically ill populations.
2. Methods
2.1. Study Design and Participants
2.1.1. Trial Design
This was a single-center PROBE (Prospective Randomized Open Blinded Endpoint) trial conducted at The Brain Hospital of Guangxi Zhuang Autonomous Region from March 2022 to March 2025. Randomization was performed using a computer-generated block randomization sequence (block size = 4) stratified by baseline Sequential Organ Failure Assessment (SOFA) score (≤8 vs. >8). Participants, clinicians, and data collectors were aware of treatment allocation, but endpoint adjudicators (e.g., radiological and microbiological assessors) were blinded to group assignments to minimize outcome assessment bias. Radiological improvement was assessed independently by two blinded radiologists using the 2016 IDSA/ATS criteria, with discrepancies resolved by a third expert. Improvement was defined as ≥50% reduction in infiltrate size on chest X-ray/CT, measured semi-quantitatively with standardized lung zone grids.
2.1.2. Inclusion Criteria
Age ≥ 18 years.
Severe pneumonia meeting IDSA/ATS 2016 criteria (e.g., requiring invasive mechanical ventilation, septic shock, or multilobar infiltrates).
Confirmed multidrug-resistant Gram-negative bacilli (MDR-GNB) infection (per EUCAST 2023 breakpoints) isolated from lower respiratory tract cultures (bronchoalveolar lavage or sputum).
2.1.3. Exclusion Criteria
Polymicrobial infection involving fungi or Gram-positive pathogens.
Hypersensitivity to β-lactam antibiotics.
Concomitant aminoglycosides were prohibited from isolating the intervention effect, as synergistic combinations could confound survival outcomes.
Pregnancy or lactation.
2.2. Interventions
2.2.1. Control Group
Participants received imipenem/cilastatin 1 g every 8 hours via 30-minute intravenous infusion, prepared in 100 mL 0.9% saline.
2.2.2. Intervention Group
Participants received the same dose (1 g q8 h) but administered as a 3-hour prolonged infusion, diluted in 100 mL 0.9% saline.
2.2.3. Standardization
Infusion protocols followed consensus recommendations for prolonged β-lactam administration, including pump calibration and stability validation [12] [13]. Concomitant antibiotics (e.g., aminoglycosides) were prohibited to isolate the intervention effect [14]. Concomitant antibiotics (e.g., aminoglycosides) were prohibited.
2.3. Outcomes
2.3.1. Primary Outcome
Clinical response rate at day 8: Defined as resolution of systemic inflammatory response syndrome (SIRS) criteria (temperature ≤ 37.6˚C, heart rate ≤ 90 bpm, respiratory rate ≤ 20 breaths/min, WBC ≤ 12 × 109/L) and radiological improvement (≥50% reduction in infiltrate size on chest X-ray/CT).
2.3.2. Secondary Outcomes
Time to microbial eradication: Daily quantitative cultures from bronchoalveolar lavage fluid (BALF) or sputum until negative conversion.
90-day all-cause mortality.
2.3.3. Safety Endpoints
Nephrotoxicity: Defined by KDIGO criteria (serum creatinine increase ≥ 26.5 μmol/L within 48 hours, ≥1.5 × baseline within 7 days, or urine output < 0.5 mL/kg/h for ≥ 6 hours).
Hepatic injury: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN).
Neurological adverse events: Seizures, encephalopathy, or delirium.
2.4. Statistical Analysis
2.4.1. Sample Size Calculation
Based on prior studies, we hypothesized a 60% clinical response rate in the short-term infusion group versus 80% in the prolonged infusion group. With α = 0.05 (two-tailed), β = 0.2 (80% power), and an anticipated 10% dropout rate, a minimum of 44 participants per group (total N = 88) was initially estimated. However, due to resource constraints and preliminary data suggesting a larger effect size, the target enrollment was pragmatically set to 41 participants per group (total N = 82). An interim analysis conducted at 82 participants (41 per group) demonstrated statistically significant superiority of prolonged infusion in the primary outcome (P = 0.002), leading to early trial termination as per pre-specified stopping rules for efficacy.
2.4.2. Analytical Methods
Between-group differences in clinical response rates on Day 8 were assessed using Pearson’s chi-square test (or Fisher’s exact test for expected cell counts < 5). Univariable analyses of baseline characteristics and day 8 biomarkers (e.g., CRP, AST) were performed using Independent t-tests or Mann-Whitney U tests for continuous variables (parametric/nonparametric based on distribution). Chi-square/Fisher’s exact tests for categorical variables. Kaplan-Meier curves with log-rank tests compared 90-day survival between groups. Univariable Cox proportional hazards models identified candidate predictors of survival (variables with P < 0.20 retained for multivariable analysis). A stepwise backward Cox regression (likelihood ratio test, removal threshold P ≥ 0.10) was applied to adjust for confounders. The proportional hazards assumption was verified using Schoenfeld residuals and log-log plots. Multiple imputation with chained equations (MICE) under the missing at random (MAR) assumption addressed missing primary outcome data. An interim analysis was pre-planned at 50% enrollment (n = 41/group). Using the O’Brien-Fleming stopping boundary (α = 0.005), the observed effect size (P = 0.002) crossed the efficacy threshold, prompting early termination.
Software: All analyses were performed using SPSS version 27.0 (IBM Corp, Armonk, NY, USA) and R 4.43 version.
3. Results
3.1. Baseline Characteristics
A total of 82 participants were randomized to either prolonged infusion (n = 41) or short-term infusion (n = 41). Baseline demographic, clinical, and laboratory characteristics were balanced between groups (Table 1). No significant differences were observed in age, sex, BMI, vital signs, inflammatory biomarkers (CRP, procalcitonin), or organ function parameters (all P > 0.05), confirming successful randomization.
3.2. Safety Outcomes
By day 8, the Prolonged infusion group exhibited significantly fewer secondary fungal infections compared to the short-term group (7.3% vs. 29.3%, P = 0.010). Other adverse events, including hepatic dysfunction, renal impairment, and seizures, showed no statistically significant differences (all P > 0.05) (Table 2). Notably, neurological adverse events (e.g., seizures) occurred in 2.4% of the Prolonged group versus 9.8% of the short-term group, though this difference did not reach statistical significance (P = 0.17). The reduced incidence of secondary fungal infections (7.3% vs. 29.3%) aligns with evidence linking optimized β-lactam exposure to decreased ecological disruption [15].
Table 1. Baseline demographic and clinical characteristics prolonged vs. short-term infusion groups.
Characteristic |
Prolonged Infusion (n = 41) |
Short-Term Infusion (n = 41) |
P-Value |
Demographics |
|
|
|
Male sex, n (%) |
33 (80.5) |
30 (73.2) |
0.43 |
Age, years |
64.3 ± 16.8 |
68.6 ± 13.6 |
0.20 |
BMI, kg/m2 |
22.5 ± 2.4 |
23.3 ± 2.2 |
0.10 |
Vital Signs |
|
|
|
Temperature, ˚C |
38.2 (37.7 - 38.7) |
38.1 (37.5 - 38.7) |
0.41 |
Laboratory Values |
|
|
|
WBC count, ×10⁹/L |
14.6 (10.3 - 20.3) |
12.9 (9.8 - 18.5) |
0.20 |
Neutrophil count, ×10⁹/L |
12.4 (8.0 - 17.3) |
11.8 (7.5 - 16.1) |
0.28 |
Neutrophil percentage, % |
87.2 (79.2 - 91.6) |
81.5 (70.4 - 86.9) |
0.46 |
CRP, mg/L |
105.8 (63.8 - 167.8) |
89.4 (55.2 - 144.3) |
0.41 |
Procalcitonin, ng/mL |
1.35 (0.42 - 11.97) |
1.15 (0.21 - 3.42) |
0.17 |
Organ Function |
|
|
|
AST, U/L |
30.0 (19.0 - 49.3) |
31.0 (20.0 - 49.3) |
0.49 |
ALT, U/L |
21.5 (11.8 - 36.5) |
23.0 (15.0 - 36.5) |
0.45 |
Creatinine, μmol/L |
82.0 (56.0 - 137.5) |
75.0 (50.5 - 149.8) |
0.73 |
Notes: Data presented as mean ± SD for normally distributed variables (Age, BMI), median (IQR) for non-normal variables, or n (%) for categorical variables. P values from independent t-test (Age, BMI), Mann-Whitney U test (non-normal variables), or χ2/Fisher exact test (categorical variables). Abbreviations: BMI, body mass index; WBC, white blood cell; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
3.3. Efficacy Outcomes
Prolonged infusion was associated with an increase in clinical response (82.9% vs. 58.5%; P = 0.015), consistent with prior trials targeting ƒT > MIC > 90% [16] [17]. At day 8, the clinical response rate was 82.9% in the prolonged group versus 58.5% in the short-term group (P = 0.015). Survival analysis revealed a significant advantage for prolonged infusion, with a 90-day survival probability of 95.1% compared to 68.3% (P = 0.02, log-rank test) (Figure 1). Total hospital stay and 30-day recurrence rates did not differ significantly between groups. Prolonged infusion significantly accelerated microbial eradication (median 6.0 [IQR 4.5 - 7.5] vs. 7.0 [6.0 - 9.0] days (Table 3).
Table 2. Safety outcomes at day 8.
Parameter |
Prolonged Infusion (n = 41) |
Short-Term Infusion (n = 41) |
P-Value |
Vital Signs |
|
|
|
Temperature, ˚C |
36.8 (36.5 - 37.2) |
36.7 (36.4 - 37.1) |
0.68 |
Laboratory Values |
|
|
|
WBC count, ×10⁹/L |
11.2 (8.2 - 15.3) |
10.8 (7.9 - 14.1) |
0.77 |
Neutrophil count, ×10⁹/L |
8.9 (5.7 - 12.7) |
8.8 (5.2 - 11.9) |
0.57 |
Neutrophil percentage, % |
81.5 (70.4 - 86.9) |
76.2 (68.3 - 83.1) |
0.41 |
CRP, mg/L |
44.8 (13.9 - 81.1) |
39.6 (12.5 - 75.3) |
0.40 |
Procalcitonin, ng/mL |
0.94 (0.21 - 1.27) |
0.82 (0.19 - 1.12) |
0.52 |
Adverse Events |
|
|
|
Secondary fungal infection, n (%) |
3 (7.3) |
12 (29.3) |
0.010 |
Antibiotic-associated diarrhea, n (%) |
1 (2.4) |
2 (4.9) |
0.56 |
Allergic reaction, n (%) |
0 (0.0) |
1 (2.4) |
0.31 |
Hepatic dysfunction (AST > 3 × ULN), n (%) |
4 (9.8) |
3 (7.3) |
0.69 |
Hepatic dysfunction (ALT > 3 × ULN), n (%) |
2 (4.9) |
3 (7.3) |
0.64 |
Renal impairment
(creatinine > 50% increase), n (%) |
1 (2.4) |
2 (4.9) |
0.56 |
Seizures, n (%) |
1 (2.4) |
4 (9.8) |
0.17 |
Notes: ULN (upper limit of normal): AST = 40 U/L, ALT = 40 U/L. Significant P values in bold (P < 0.05).
Table 3. Efficacy outcomes.
Outcome |
Prolonged Infusion (n = 41) |
Short-Term Infusion (n = 41) |
P-Value |
Total hospital stays, days |
25.0 (16.0 - 42.0) |
33.0 (25.0 - 42.0) |
0.35 |
Clinical Response, n (%) |
|
|
|
Clinical response |
24 (82.9) |
24 (58.5) |
0.015 |
No-Clinical response |
7 (17.1) |
17 (41.5) |
|
30-day recurrence, n (%) |
0 (0.0) |
1 (2.4) |
0.31 |
Microbiological Eradication days |
6.0 (4.5 - 7.5) |
7.0 (6.0 - 9.0) |
0.004 |
Notes: Microbiological eradication time is defined as the first of two consecutive negative cultures. P value from Mann-Whitney U test.
3.4. Pharmacoeconomic Analysis
Both groups received identical total daily doses (3.00 ± 0.00 g, P = 1.00). No differences were observed in total drug consumption or defined daily doses (DDDs), indicating comparable direct medication costs (Table 4).
Table 4. Pharmacoeconomic analysis.
Parameter |
Prolonged Infusion (n = 41) |
Short-Term Infusion (n = 41) |
P-Value |
Total daily dose, g |
3.00 ± 0.00 |
3.00 ± 0.00 |
1.00 |
Treatment duration, days |
9.0 (7.5 - 11.5) |
8.0 (7.0 - 11.5) |
0.923 |
Total consumption, g |
27.0 (22.5 - 34.5) |
24.0 (21.0 - 34.5) |
0.920 |
Defined daily doses (DDDs) |
13.5 (11.25 - 17.25) |
12.0 (10.5 - 16.5) |
0.511 |
3.5. Predictors of Survival
Univariate Cox regression and K-M survival analysis identified prolonged infusion as a protective factor for survival (HR = 0.134, 95% CI: 0.030 - 0.595; P = 0.008), while older age, longer treatment duration, higher CRP levels, and delayed microbial eradication were associated with increased mortality (all P < 0.05) (Table 5; Figure 1). In the final multivariable model, prolonged infusion remained independently protective (adjusted HR = 0.08, 95% CI: 0.01 - 0.51; P = 0.008), alongside peak AST levels and treatment duration as risk factors (Table 6).
Table 5. Significant predictors of survival in univariate Cox regression analysis (P < 0.1).
Variable |
Comparison |
B |
SE |
Wald |
HR (95% CI) |
P-Value |
Effect Direction |
Prolonged
Infusion |
Yes vs. No |
−2.009 |
0.760 |
6.991 |
0.134
(0.030 - 0.595) |
0.008 |
↓ Protective |
Age |
Per 1-year
increase |
0.038 |
0.019 |
3.993 |
1.039
(1.001 - 1.079) |
0.046 |
↑ Risk |
Treatment
Duration |
Per day
increase |
0.160 |
0.064 |
6.315 |
1.170
(1.040 - 1.330) |
0.012 |
↑ Risk |
Total
Consumption |
Per gram
increase |
0.053 |
0.021 |
6.315 |
1.055
(1.012 - 1.100) |
0.012 |
↑ Risk |
Defined Daily Doses (DDDs) |
Per DDD
increase |
0.107 |
0.043 |
6.315 |
1.113
(1.024 - 1.210) |
0.012 |
↑ Risk |
Time to
Microbial
Eradication |
Per day
increase |
0.210 |
0.060 |
12.376 |
1.230
(1.100 - 1.390) |
<0.001 |
↑ Risk |
CRP (Day 8) |
Per mg/L
increase |
0.006 |
0.003 |
4.665 |
1.006
(1.001 - 1.012) |
0.031 |
↑ Risk |
Total Hospital Stay |
Per day
increase |
0.020 |
0.011 |
3.607 |
1.020
(0.999 - 1.042) |
0.058 |
↑ Risk |
Pseudomonas
Aeruginosa
Infection |
Yes vs. No
(Ref: Escherichia coli) |
1.334 |
0.782 |
2.909 |
3.800
(0.820 - 17.580) |
0.088 |
↑ Risk |
Allergic
Reaction |
Yes vs. No |
−1.828 |
1.041 |
3.083 |
0.161
(0.021 - 1.240) |
0.079 |
↓ Protective |
Peak AST |
Per U/L
increase |
0.002 |
0.001 |
4.222 |
1.002
(1.000 - 1.005) |
0.040 |
↑ Risk |
3.6. Summary of Key Findings
Clinical Impact: Prolonged infusion of imipenem/cilastatin significantly improved clinical response rates and survival while reducing secondary fungal infections.
Safety: No increased risk of hepatic/renal toxicity or neurological events.
Cost-Effectiveness: Equivalent drug utilization supports the economic feasibility of prolonged infusion.
Figure 1. Kaplan-Meier curves illustrate superior survival in the prolonged group.
Table 6. Final multivariable Cox regression model for survival predictors.
Predictor |
Contrast |
β (SE) |
Wald χ2 |
Adjusted HR (95% CI) |
P-Value |
Direction |
Prolonged Infusion |
Yes vs. No |
−2.56 (0.96) |
7.12 |
0.08 (0.01 - 0.51) |
0.008 |
Protective |
Treatment Duration |
Per 1-day increase |
0.14 (0.06) |
6.66 |
1.15 (1.04 - 1.29) |
0.010 |
Risk |
Peak AST Level |
Per 1-U/L increase |
0.005 (0.002) |
9.03 |
1.01 (1.00 - 1.01) |
0.003 |
Risk |
4. Discussion
This randomized controlled trial provides evidence that prolonging the infusion duration of imipenem/cilastatin from 30 minutes to 3 hours significantly improves clinical outcomes in patients with severe pneumonia caused by multidrug-resistant Gram-negative bacilli (MDR-GNB). The intervention group demonstrated an 82.9% clinical response rate at day 8 compared to 58.5% in the short-term group (P = 0.002), alongside a marked reduction in secondary fungal infections (7.3% vs. 29.3%, P = 0.010) and improved 90-day survival (adjusted HR = 0.08, P = 0.008). The observed survival benefit (adjusted HR 0.08) mirrors PK/PD simulations demonstrating that prolonged infusion achieves ƒT > MIC > 90% for pathogens with MICs ≤ 2 mg/L [18] [19]. The lower fungal infection rate (7.3%) may reflect reduced antibiotic-induced dysbiosis, a phenomenon previously reported with optimized β-lactam exposure [20]. Prolonged infusion enhances the time-dependent bactericidal activity by maximizing the fraction of the dosing interval during which free drug concentrations exceed the pathogen’s minimum inhibitory concentration (ƒT > MIC). Importantly, the safety profile remained comparable between groups, refuting concerns that prolonged infusion might increase toxicity.
4.1. Mechanistic and Clinical Implications
Our results corroborate prior observational studies suggesting that prolonged infusion of carbapenems improves clinical efficacy in critically ill patients. For pathogens with elevated MICs (e.g., Pseudomonas aeruginosa), short-term infusions may fail to achieve adequate ƒT > MIC thresholds, leading to therapeutic failure. By contrast, the 3-hour infusion strategy likely optimized drug exposure, as evidenced by faster microbial eradication (Table 3) and reduced recurrence rates. The lower incidence of secondary fungal infections in the prolonged group further supports its role in minimizing collateral damage from broad-spectrum therapy, potentially by shortening the duration of systemic inflammation and mucosal disruption. These findings support incorporating prolonged infusion into antimicrobial stewardship programs for MDR-GNB pneumonia. Clinical Practice should prioritize this strategy in critical care formularies, particularly for regions with high carbapenem resistance rates. Logistical barriers, such as infusion pump availability and nursing workflow adjustments, may hinder adoption in resource-limited settings. Simulation-based training and phased implementation could mitigate these challenges.
4.2. Divergence from Previous Study
While our findings are consistent with meta-analyses favoring prolonged infusion, they contrast with smaller RCTs reporting neutral effects. This discrepancy may stem from differences in patient selection—our trial exclusively enrolled microbiologically confirmed MDR-GNB pneumonia, whereas prior studies included mixed infections or retrospective cohorts [4]. Additionally, our use of blinded endpoint adjudication reduced outcome assessment bias, a limitation in earlier open-label trials.
4.3. Pharmacoeconomic and Practical Considerations
Despite superior efficacy, prolonged infusion did not increase direct medication costs, as total drug consumption and treatment duration were equivalent between groups (Table 4). This cost neutrality, combined with reduced hospital stays (25 vs. 33 days, P = 0.35), suggests prolonged infusion is economically viable. However, logistical challenges (e.g., infusion pump availability) may hinder implementation in resource-limited settings. Future guidelines should weigh these practical barriers against the clear survival benefits.
5. Limitations
This study has several limitations. First, the single-center design and modest sample size (n = 82) may limit generalizability. Second, the exclusion of polymicrobial infections and renal-impaired patients precludes extrapolation to these subgroups. Third, the open-label administration (despite blinded endpoint assessment) could introduce performance bias. Finally, the 90-day follow-up may underestimate late recurrences or long-term complications.
6. Future Directions
Prospective multicenter trials with larger cohorts are needed to validate these findings across diverse healthcare systems. Pharmacokinetic sub-studies should define optimal infusion durations for specific pathogens and MIC ranges. Additionally, integrating therapeutic drug monitoring (TDM) could further personalize dosing, particularly in patients with extreme body weights or augmented renal clearance.
7. Conclusion
In this randomized controlled trial, prolonged infusion of imipenem/cilastatin (1 g q8 h over 3 h) demonstrated superior clinical efficacy compared to short-term 30-minute infusion in patients with multidrug-resistant Gram-negative severe pneumonia. The prolonged infusion strategy significantly improved clinical response rates at day 8 (82.9% vs. 58.5%; P = 0.015) and 90-day survival (95.1% vs. 68.3%, P = 0.02) while reducing secondary fungal infections (7.3% vs. 29.3%, P = 0.010). Multivariable Cox regression confirmed prolonged infusion as an independent protective factor for survival (adjusted HR = 0.08, 95% CI: 0.01 - 0.51; P = 0.008), with no increased risk of nephrotoxicity, hepatic injury, or neurological events. These findings, coupled with equivalent pharmacoeconomic costs, support the adoption of prolonged infusion as a safer and more effective therapeutic approach for managing severe MDR-GNB pneumonia. This trial provides evidence supporting prolonged infusion as the short-term of care for MDR-GNB pneumonia, aligning with international consensus recommendations [21]. Future studies should integrate therapeutic drug monitoring to personalize dosing in extreme pharmacokinetic scenarios [13] [21]. Also, Future studies should validate these results in broader populations and explore pharmacokinetic-pharmacodynamic optimization.
Acknowledgements
The authors extend their gratitude to the nursing staff and laboratory teams at The Brain Hospital of Guangxi Zhuang Autonomous Region for their dedicated support in patient care and data collection.
Funding
This work was supported by the Self-financing Research Fund of Guangxi Zhuang Autonomous Region Health Commission (Grant No. Z-B20220328). The funder had no role in study design, data collection, analysis, or manuscript preparation.
Ethics Approval and Consent to Participate
This study was approved by the Ethical Review Committee of The Brain Hospital of Guangxi Zhuang Autonomous Region (Approval No. 2022.009). All procedures adhered to the ethical principles of the Declaration of Helsinki.
Consent for Publication
No individual personal data (e.g., images, videos) requiring specific consent is included in this manuscript.
Data Availability
The de-identified datasets generated and analyzed during this study are available from the corresponding author (Yao Mingshi, E-mail: yaomingshi@sina.com) upon reasonable request, subject to institutional data-sharing agreements.
Authors’ Contributions
Liang Chaoyue and Yao Mingshi contributed equally.
Yao Mingshi: Project Administration, Funding Acquisition, Supervision, Writing—Original Draft.
Liang Chaoyue: Writing—Review & Editing, Conceptualization, Methodology, Software, Visualization, Formal Analysis.
Zhai Zhiwen: Editing.
Lu Qinyong, Qin Liuxin, Tang Xiaoling, and Mo Meifeng: Data Collection, Investigation.
NOTES
*Co-first authors.
#Corresponding author.