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Introduction

As we all know, an imbalance between the production and excretion of uric acid leads to HUA. HUA has become more common in China, rising from 11% to 14%.¹ The study of Sun et al found that the overall prevalence of HUA in diabetes was 21.2%.² HUA places a significant burden on people’s lives and society. At the same time, several studies have suggested a link between HUA and a higher risk of heart disease, hypertension, obesity,^3,4 chronic kidney disease,⁵ metabolic syndrome (MetS),⁶ diabetes mellitus⁷ and diabetic complications.^8–11

Both monocytes and high-density lipoprotein are involved in the MHR, a newly discovered predictive measure for various diseases such as cardiovascular disease (CVD). Activated monocytes could produce a range of oxidizing and inflammatory molecules, which cause endothelial dysfunction, thrombus development, and the body’s inflammatory response through interactions between the endothelium of the vessels and platelets.¹² High-density lipoprotein (HDL) particles play crucial roles in reverse cholesterol transport, inflammation modulation, and antioxidant defense.¹³ HDL-associated proteins, including paraoxonase-1 (PON1) and myeloperoxidase (MPO), further influence oxidative stress and inflammation. Notably, PON1 exerts antioxidant effects, whereas MPO generates reactive species that impair HDL function.¹⁴ HDL cholesterol (HDL-C) levels serve as a marker for cardiovascular disease (CVD) and chronic kidney disease (CKD) risk.^15,16 Impaired HDL function exacerbates lipid accumulation in renal and vascular tissues, suggesting that therapeutic strategies targeting HDL restoration may alleviate oxidative stress and inflammation.¹⁶ Uric acid impairs β-cell function, reducing insulin secretion and β-cell mass. Hyperuricemia also triggers oxidative stress,¹⁷ which is closely linked to insulin resistance and β-cell dysfunction. The resulting oxidative overload may further decrease insulin sensitivity, exacerbating metabolic disturbances in diabetes.¹⁸ Elevated insulin levels due to insulin resistance and β-cell dysfunction can enhance renal uric acid reabsorption. This creates a vicious cycle, promoting mutual amplification between hyperinsulinemia and hyperuricemia through a feedback mechanism.¹⁹

Emerging evidence identifies the cumulative monocyte to high-density lipoprotein ratio (CumMHR) as a potential biomarker for early T2DM screening.²⁰ Prior studies have established MHR as an independent predictor of HUA prevalence.²¹ Li et al found that MHR was significantly and positively correlated with serum uric acid levels in Chinese adults.²² However, in the T2DM population, the relationship between MHR and HUA is still unclear. Therefore, our study specifically investigates the relationship between MHR and HUA in a T2DM population.

Methods

Study Population

This study is cross-sectional and single-center. The subjects are T2DM patients who were treated at our hospital’s Department of Endocrine and Metabolism between 2021 and 2024. The following were the exclusion criteria: (1) age<18 years old or>80 years old, pregnancy; (2) incomplete information; (3) a history of severe hypoglycemia, type 1 diabetes (T1DM), other kinds of diabetes, or acute complications of diabetes tumor; (4) autoimmune diseases, acute and chronic diseases infected persons; (5) tumor diseases and blood system diseases; (6) severe liver function damage, severe renal function damage (including chronic kidney disease Phase 4–5); (7) other endocrine diseases, such as Primary hyperaldosteronism (PA), Cushing’s Syndrome and pituitary disease; (8) Use drugs that affect uric acid levels, including diuretics, SGLT-2i (sodium-dependent glucose transporter 2 inhibitors), aspirin, and benzbromarone, febuxostat, Allopurinol. The current study included 1261 participants in total (Figure 1).

Figure 1 The study population flowchart.

Covariates

With serum uric acid (SUA) values of 7.0mg/dL (420mmol/L), HUA was identified in both males and females^23. T2DM was diagnosed using the 1999 World Health Organization criteria.²⁴ A self-reported history of hypertension, a diastolic blood pressure (DBP) of 90mmHg, and a systolic blood pressure (SBP) of 140mmHg were all considered indicators of hypertension.²⁵ A BMI of 28 kg/m² was considered obesity.²⁶ Total cholesterol (TC) ≧ 6.2, triglyceride (TG) ≧ 2.3, low-density lipoprotein cholesterol (LDL-C) ≧ 4.1, or the use of lipid-lowering medications were considered indicators of hyperlipidemia.²⁷ Every participant in this study underwent an ultrasound of their abdomen.

The following diagnostic standards were used to define kidney stones:^28,29 (1) the presence of a stone or stones with a diameter of at least 4 mm, as well as (2) the direct visualization of the stone or stones during the abdominal ultrasound test. Participants who responded “Yes” to the question, “Did your doctor ever tell you that you had gout?” were considered to have gout. Estimated glomerular filtration rate (eGFR) was calculated using the formula created by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).³⁰

On the morning following admission, all blood samples were taken from patients who had fasted overnight. Our hospital’s biochemical center used standard methods to measure baseline monocyte, lymphocyte, neutrophil, and leukocyte counts, TC, TG, HDL-C, LDL-C, glycated hemoglobin A1c (HbA1c), alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (Cr), and SUA. Monocyte count (×10⁹/L) / HDL-C (mmol/L) was used to calculate MHR.

Statistical Examination

Continuous variables are shown as median (with 25th and 75th percentiles), whereas categorical variables are shown as frequencies and percentages. For continuous variables, the Mann–Whitney U-test was employed, and for categorical variables, the χ² test. The relationship between MHR and HUA was evaluated using logistic regression analysis.

During the multivariate logistic regression analysis, factors such as age, duration, BMI, smoking, drinking, and family history of diabetes mellitus (DM), hypertension, hyperlipidemia, kidney stones, gout, eGFR, FBG, ALT, AST, GGT, and HbA1c were considered. To assess how well various characteristics could predict the existence of HUA, we performed an analysis of the area under the receiver operating characteristic (ROC) curve. To assess for variations among the various parameters on the ROC curves, we employed the non-parametric method of DeLong et al³¹ (MedCalc). SPSS 27.0 was used for the statistical analysis, and P < 0.05 was the threshold for statistical significance. Using RCS analysis, the overall dose-response relationship between MHR and HUA risk was demonstrated. P<0.05 was established as the cutoff point for statistical significance.

Results

Baseline Characteristics of the Study Population

Table 1 displayed each patient’s initial features. In the current study, 300 patients had HUA and 961 patients did not. Patients with HUA were younger and more likely to have gout, kidney stones, hypertension, and hyperlipidemia than those without HUA. Additionally, patients with HUA exhibited decreased eGFR and HDL-C but greater BMI, creatinine, ALT, AST, GGT, TC, and TG. Patients with HUA also had a higher family history of lipid-lowering medications and DM. Hematologically, patients with HUA had greater leukocyte, monocyte, lymphocyte, and neutrophil counts than those without. As a result, MHR was higher in HUA patients than in non-HUA patients.

Table 1 Characteristic of Subjects Stratified by HUA

Relationships Between MHR and the Incidence of HUA in T2DM Patients

To ascertain the relationships between MHR and HUA, we employed a logistic regression analysis. As shown in Table 2, the results showed that MHR was associated with HUA without adjusting. After adjusting age, duration, BMI, smoking, drinking and family history of DM, hypertension, hyperlipidemia, kidney stones, gout, eGFR, FBG, ALT, AST, GGT, HbA1c, OR was 2.040 (95% CI=1.023–4.071, p<0.05), which the presence of HUA was still associated with MHR. These results implied a relationship between MHR and the occurrence of HUA.

Table 2 Association Between MHR and the HUA in Participants with T2DM

Figure 2 summarized the general characteristics of the study participants by age, gender, BMI, and HbA1c. Figure 2 showed that patients’ MHR was lower (p<0.001) when their HbA1c was less than 7%. Compared to the males, the females had a lower MHR. In addition, patients aged ≥ 45 had a lower MHR than those aged ≥ 45, and patients with a BMI < 28 had a lower MHR than those with a BMI ≥ 28 (p<0.001).

Figure 2 Comparisons of MHR levels according to HbA1c (a) gender (b) BMI (c) and age (d). (***p<0.001,****p<0.0001).

BMI’s Mediating Role in the Relationships Between MHR and the Risk of HUA

Figure 3 showed an analysis of the mediating role of BMI in the relationship between MHR and the risk of HUA. Causal mediation analysis indicated that BMI partially mediated the association between MHR and HUA risk in patients with T2DM. The average causal mediation effect (ACME) was 0.29 (95% CI: 0.16–0.45), and the average direct effect (ADE) was 1.27 (95% CI: 0.67–1.87), with a total effect of 1.56. The proportion of the effect mediated by BMI was 18.59%, suggesting that BMI plays a modest but significant mediating role in the MHR-HUA pathway (all p < 0.001).

Figure 3 Mediation effect of BMI on the associations of MHR with HUA risk. Average Causal Mediation Effect (ACME) refers to the indirect effect; Average Direct Effect (ADE) refers to the direct effect, and the mediation percentage represents the proportion of the indirect effect to the total effect (sum of indirect and direct effects). ***P-value <0.001.

Nonlinear Effects of MHR on HUA: RCS Findings

Figure 4 revealed that the risk of HUA in patients with T2DM was strongly correlated with MHR. A nonlinear association between MHR and HUA risk was shown using restricted cubic spline analysis (p for overall = 0.005, p for nonlinear = 0.013). The risk of HUA increased at MHR>0.47, peaking at 0.73.

Figure 4 Associations of MHR with HUA in T2DM patients. Restricted cubic splines were used to assess the dose–response associations of MHR with HUA in T2DM patients after adjusted for age, duration, BMI, smoking, drinking and family history of diabetes mellitus, hyperlipidemia, kidney stones, gout, eGFR, FBG, ALT, AST, GGT, HbA1c. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; AlT, alanine transaminase; AST, aspartate aminotransferase; GGT, γ-Glutamyl Transpeptidase; HbA1c, Hemoglobin A1c.

Predictive Performance of MHR for HUA in T2DM

Figure 5 revealed that MHR had significant discriminatory ability for HUA in patients with type 2 diabetes mellitus (T2DM). The area under the curve (AUC) for MHR was 0.62 (95% CI: 0.58–0.65), with a specificity of 71.9% and sensitivity of 46.3%, as was shown in Table 3. These results suggest that MHR demonstrated predictive performance in identifying HUA risk among T2DM patients.

Table 3 Receiver Operating Characteristic Curve Analysis of MHR and Its Predictive Value for HUA in Patients with T2DM

Figure 5 Receiver operating characteristic curve analysis of MHR in predicting hyperuricemia.

Discussion

The association between MHR, BMI, and HUA risk was thoroughly examined in this cross-sectional study of 1261 adults from Tianjin University Medical General Hospital. To the best of our knowledge, this study may be the first to evaluate the mediating function of BMI in the associations between MHR and the risk of HUA. Given the dramatic increase in the incidence of HUA globally, our result highlights the importance of lowering MHR while losing weight in reducing the prevalence of HUA.

The inflammatory response and immunological state are intimately linked to the pathophysiology of HUA. Vascular smooth muscle cell (VSMC) proliferation is induced by soluble uric acid, according to studies.³² Subsequent research showed that soluble uric acid, through the mitogen-activated protein kinase (MAPKs) pathway, mediates the increased proliferation of VSMC. Furthermore, uric acid causes vascular cells to become more inflammatory. Increased serum urate levels have been linked to inflammatory indicators.³³

SUA and monocytes mutually influence each other. According to recent research, soluble uric acid directly affects human primary peripheral blood mononuclear cells (PBMCs) to produce proinflammatory cytokines, and following ex vivo stimulation, PBMCs from HUA patients produce more of these cytokines than healthy controls.^34,35 Monocytes can elevate SUA levels by promoting the production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, IL-12, and IL-23,³⁶ while reducing anti-inflammatory cytokine (IL-10) levels.³⁷ TNF-α not only directly damages vascular endothelial cells but also induces hyperinsulinemia. Elevated insulin and proinsulin stimulate renal tubular sodium-hydrogen exchange, increasing uric acid reabsorption and hydrogen excretion. The resulting rise in SUA further stimulates monocytes to release inflammatory cytokines, creating a positive feedback loop that perpetuates SUA elevation.³⁸

Beyond its pro-inflammatory effects, SUA also exhibits immunosuppressive properties in monocytes.³⁹ An in vitro study by Qiu et al demonstrated that SUA inhibits Toll-like receptor (TLR) signaling in monocytes, thereby impairing classical monocyte migration.⁴⁰ High-density lipoprotein (HDL), an anti-inflammatory factor, suppresses monocyte activation, adhesion, and migration while inhibiting pro-inflammatory cytokine production.^41,42 Consequently, HDL-C serves as a protective factor against elevated SUA. Collectively, these findings indicate a positive correlation between the MHR and SUA levels.

MHR integrates several parameters and is quick and easy to calculate. It can more properly depict the inflammatory changes in HUA because it reflects the complementary interactions between many pathways, which is a benefit over using a single indication. According to our research, patients with T2DM who had MHR had a considerably higher chance of developing HUA. In particular, the risk of HUA increased with MHR > 0.47.

Furthermore, this study discovered that BMI is a significant mediating factor in the associations between MHR and the risk of HUA. Our results are supported by certain existing findings. On the one hand, uric acid levels and the risk of HUA are strongly correlated with BMI, a measure of obesity.^43–48 A study including 39,736 Chinese participants from Jiangsu Province found that uric acid concentrations were significantly greater in obese people than in underweight ones. Additionally, the study showed that uric acid levels rose linearly with BMI. Overweight people were about 2.98 times more likely to have HUA than underweight people, and obese people were about 5.96 times more likely to have HUA.⁴⁷ Our results suggested that managing weight would be a useful strategy to lower the risk of HUA and the negative health consequences brought on by elevated uric acid levels.

Some possible biological pathways should receive special attention, even though the precise mechanism underlying the mediating effect of BMI on the favorable associations of MHR with HUA risk is still unknown. First, a protracted state of inflammation may cause an inflammatory reaction in adipose tissue, resulting in adipocyte malfunction that impacts hormone secretion^49,50 and lipid metabolism,⁵¹ thereby contributing to the development of obesity.⁵² Secondly, by altering cell structure and function, oxidative stress may potentially contribute to tissue damage and metabolic problems.^53,54 Lastly, the level of inflammation may also disrupt the balance of gut microbiota, resulting in dysbiosis, which can affect uric acid metabolism and weight control by affecting energy metabolism and nutrient absorption.^55,56 These intricate biological processes interact with one another and raise the body mass index. Through some pathways, the elevated BMI may impact the metabolism of uric acid.⁵⁷

There might be some advantages to our study. First of all, this is the first study to examine the relationship between MHR and the risk of HUA in T2DM. Secondly, this study was the first to evaluate the mediating role of BMI in the relationship between MHR with HUA risk. Our findings suggested that managing weight could be a useful strategy to lower the risk of HUA.

However, our study still had several limitations. Firstly, the cross-sectional study design makes it impossible to prove a causal link between the risk of HUA and MHR. Secondly, there is still a chance that unmeasured confounding variables could interfere with our results, even though we used a variety of covariates to account for potential confounders in our study. Thirdly, limitations include unmeasured diabetic complications (eg CKD), which may affect SUA levels and the observed relationships. Further research is needed to systematically investigate diabetic complications (eg CKD, neuropathy, retinopathy), which would help refine the relationship between MHR and HUA in patients with varying diabetes outcomes.

Lastly, while current evidence indicates that various antihypertensive agents differentially modulate serum uric acid (SUA) levels – with diuretics, β-blockers, and α-1 adrenergic antagonists potentially elevating SUA through reduced glomerular filtration rate, while calcium channel blockers, ACE inhibitors, and specific angiotensin receptor blockers (particularly losartan) appear neutral.⁵⁸ The retrospective nature of our investigation precluded a comprehensive analysis of antihypertensive medication regimens. This important pharmacologic confounder warrants systematic evaluation in future prospective studies to elucidate the potential mediating effects of antihypertensive therapies on uric acid metabolism. Future studies should evaluate these interactions.

Conclusion

When MHR is in the interval of 0.47 to 0.73, adults who were exposed to higher MHR had a higher chance of developing. The associations between MHR and the risk of HUA were significantly mediated by BMI, indicating that losing weight and lowering MHR may be useful strategies to lower the risk of HUA for T2DM patients. A future longitudinal study with a larger sample size is needed to explore this association further. Additionally, although BMI appears to mediate this relationship, further research is needed to elucidate the underlying biological mechanisms.

Data Sharing Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

The 1964 Helsinki Declaration, its subsequent revisions, or similar ethical guidelines were adhered to in all study operations. The Tianjin Medical University General Hospital’s institutional review board examined and approved studies involving human subjects (Approval number: IRB2024-YX-558-01). All participants gave their informed consent.

Acknowledgments

Bo Huang and Xin Li are the co-first authors of this study. We are grateful to all subjects, nurses, and physicians who participated in the study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by the National Natural Science Foundation of China (82070854).

Disclosure

The authors declare that they have no competing interests in this work.

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But earlier this month, Secretary of Health and Human Services Robert F. Kennedy Jr. announced the cancellation of more than $500 million in HHS contracts through the Biomedical Advanced Research and Development Authority (BARDA) that supported mRNA vaccine development. Trump himself seemed indifferent to the attack on arguably the most widely praised legacy of his first term. “That was now a long time ago, and we’re onto other things,” Trump said when asked this month about Operation Warp Speed—the program that helped speed COVID vaccine development. 

Researchers and former biosecurity officials argue the administration’s turn against mRNA will only leave the United States less able to respond to future disease and public health threats, even as geopolitical adversaries like China ramp up on investments in the technology.  

Kennedy’s criticism of the COVID mRNA vaccines as having “fail[ed] to protect effectively against upper respiratory infections like COVID and flu” is in keeping with his anti-vaccine stance and multifront rollback of vaccine policy since taking over at HHS. His stated justifications for pulling back from mRNA vaccines rely on misrepresented studies and unsupported claims about safety and effectiveness. “The idea that mRNA vaccines ‘failed’ because they didn’t block all respiratory infections reveals a fundamental misunderstanding of immunology,” explained Jake Scott, an infectious disease researcher and professor at Stanford University School of Medicine. “No vaccine for flu, RSV, or COVID has ever done that. The goal is preventing severe disease, and mRNA vaccines delivered.”

Kennedy’s advisers at HHS have made even more outlandish and unsupported claims about mRNA vaccines. Steven Hatfill—a virologist who in May joined the HHS Administration for Strategic Preparedness and Response, the office responsible for preparing against pandemic and biosecurity threats—said earlier this month on Steve Bannon’s podcast, “There was no benefit to risk ratio for taking a messenger RNA vaccine. In fact, it was more dangerous to take a vaccine than it was to contract COVID-19 and be hospitalized with it.”   

Studies have estimated that COVID vaccines prevented more than 3 million additional deaths and 18 million hospitalizations in the U.S. alone. The vaccine platform is particularly valuable for pandemic response because of the speed at which mRNA vaccines can be developed and updated to fight newly emergent viruses and strains. The “whole virus” vaccines that Kennedy says HHS will prioritize in lieu of mRNA utilize much older vaccine technology. These vaccines use inactivated or “whole killed” viruses to trigger an immune response. Cultivating these vaccines requires growing and purifying viruses in a lab, an expensive and time consuming process. 

But mRNA vaccines use RNA to deliver a protein from the virus—not the virus itself—that triggers an immune response. Vaccines can be formulated, as was the case with COVID, almost as soon as the genetic code of the virus is known without the need to have a live sample of the virus itself, let alone grow large quantities of it in a lab. 

Kennedy said that canceled grants are part of a “wind-down” and “broader shift” away from investments in mRNA vaccines. Instead, HHS will prioritize “whole-virus vaccines and novel platforms.” The move followed the May cancellation of more than $700 million in HHS funding to Moderna for developing mRNA influenza vaccines, including one against bird flu that had shown promising results in an early clinical trial. The termination also ended the government’s “right to purchase pre-pandemic influenza vaccines.” The company said in a statement it will “explore alternatives for late-stage development and manufacturing” for the bird flu vaccine. 

In the short term, companies will likely shrink or end their work on the BARDA-funded projects. “The 22 terminated projects worth $500 million represent the expensive late-stage development that BARDA uniquely funds—Phase 3 trials, manufacturing scale-up, and strategic stockpiling that private companies can’t afford,” argued Scott, the Stanford infectious disease researcher.  

Over the longer term, biotech investments in mRNA vaccines could fall off, and some investors are already considering pulling back from mRNA vaccines. For the development and innovations that continue, researchers predict the work will find a home in other countries looking to capitalize on the vacuum left by the Trump administration. “The research is going to continue, but it’s going to continue in Europe and Asia and China,” said Drew Weissman, the University of Pennsylvania researcher whose work on mRNA enabled COVID vaccine development and earned him a Nobel Prize. 

For that reason, scientists and health officials who served in the first Trump administration have decried Kennedy’s decision, saying HHS is surrendering a crucial biosecurity tool. “Ending BARDA’s investment in mRNA technology creates a national security vulnerability,” said Chris Meekins, the deputy assistant secretary in the HHS pandemic and biosecurity preparedness office during Trump’s first term. “These tools serve as a deterrent to prevent other nations from using certain biological agents.” Jerome Adams, the surgeon general during Trump’s first term, issued a more dire warning: “People are going to die because we are cutting short funding for this technology.”

Falling behind on mRNA technology would be like losing an arms race, according to Rick Bright, who served as BARDA director during the first Trump administration. He called mRNA technology the “equivalent of a missile defense system for biology … Adversaries who invest in this technology will be able to respond faster to outbreaks, protecting their populations sooner than we can. Right now, the United States has a decisive advantage in mRNA science, manufacturing capacity and regulatory expertise. But in an era where biological threats can be engineered, losing this competitive edge would leave the United States vulnerable and dependent on others for lifesaving tools.”  

The COVID pandemic provided something of a case study in the costs of lacking the most promising biotechnology. Jeff Coller, the director of the Johns Hopkins University RNA Innovation Center whose graduate student helped design the Moderna COVID vaccine,  explained to The Dispatch that China relied on “whole virus” or attenuated virus for its COVID vaccines during the pandemic. “It didn’t work nearly as effectively as the mRNA vaccines,” he said of China’s response. When a pandemic viruses mutates, mRNA vaccines can also be quickly updated. “If you have an emergent pandemic, an emergency situation, where you desperately need to get this vaccine out to the population, or people are going to lose their lives, mRNA, no question, is the way to go,” Coller added. 

China seems to have taken this to heart. Outside of the U.S., the country currently hosts the most clinical trials for mRNA vaccine candidates. “China is doubling down on this, and soon will be the global leader in mRNA based medicines and therapeutics,” Coller said, warning that in future pandemics the U.S. could be forced to acquire vaccines from China. Sen. Bill Cassidy, the GOP senator whose vote advanced Kennedy’s nomination for HHS secretary, said canceling the mRNA contracts “conceded to China an important technology needed to combat cancer and infectious disease.” 

Coller is also a founder of the Alliance for mRNA Medicines, an advocacy group consisting of biotech and pharmaceutical companies and leading mRNA research centers. He said the group’s members have begun to contemplate moving their work elsewhere in light of the administration’s turn against mRNA. “It was really a shot across the bow, a warning that the United States is really not a friendly nation for this technology,” Coller said. “Many of the membership that are involved in the mRNA business recognize that and say, ‘Look, we’re going to have to develop our technologies in other countries, move our brick and mortar somewhere else’ because while the United States is retreating from the technology, most other countries are not.”

Specialty

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Introduction

Aging-related physiological changes, including the development of thyroid masses and other airway pathologies, can significantly impair neck rotation and range of motion (ROM), thereby complicating tracheal intubation.¹ Structural and functional changes associated with aging contribute to anatomical variations that can further hinder successful intubation, even lead to life-threatening “can’t intubate, can’t ventilate” (CICV) scenarios in extreme cases.^2–5 Awake tracheal intubation (ATI), particularly using flexible bronchoscopy, remains the gold standard for managing anticipated difficult airways, as it preserves spontaneous ventilation and provides real-time visualization of the airway.⁶ In clinical practice, videolaryngoscopy has become a common and effective tool for airway management.⁷ However, in patients with distorted anatomy or high CICV risk such as those with laryngeal or hypopharyngeal tumors, severe trismus, cervical spine immobility, prior radiation therapy, or a history of difficult intubation, ATI is often the preferred approach.^8,9 Despite its advantages, Awake flexible bronchoscopy intubation (AFBI) is selectively performed due to challenges including the need for patient cooperation, longer procedural time, specialized training, and reduced effectiveness in the presence of bleeding or secretions.

Several cohort studies on AFBI have reported clinical outcomes such as incidence rates, success rates, and complications.^8,10–12 It has been observed that difficult airways in head and neck pathologies account for a significant portion of intubation failures, especially among the patients where the risk of airway pathologies.^8,11,13 Furthermore, substantial variations exist in AFBI practices, particularly in drug management and procedural protocols, across different medical centres.^9,14,15 It is important to comprehensively report the detailed procedures and clinical outcomes of AFBI specifically among head and neck surgery patients. Additionally, multiple intubation attempts have been identified as a significant risk factor for ATI related complications,^8,10,12 emphasizing the importance of closely monitoring and analysing AFBI procedures in this patient population.

The quality of AFBI performance relies heavily on both technical and non-technical skills, requiring all participants to maintain a high level of concentration throughout the procedure. This complexity makes it challenging for practitioners to independently analyse procedural details in real time. To address this challenge, we have established a comprehensive data collection system that includes AFBI scenario recordings, endoscopic videos, and electronic medical records. This unified and standardised recording system enables a detailed review of procedural parameters and patient reactions, providing a thorough and objective assessment of all aspects of AFBI operations.

In summary, this study aims to comprehensively analyze the procedural details, patient characteristics and reflexes, and clinical outcomes of AFBI performed on otorhinolaryngology patients at our centre. By utilizing a unified and standardized data collection system that includes video recordings, endoscopic views, and electronic medical records, this study seeks aims to deliver a comprehensive, objective and detailed assessment of AFBI practices. The findings will contribute to improving the quality and safety of AFBI procedures, particularly for patients with challenging airways, and will serve as a valuable resource for refining clinical protocols and guiding future research in airway management.

Methods

This single-centre, observational study utilised EENTPM database from the Eye & ENT Hospital of Fudan University. Ethical approval was granted by the ethics committee of the Eye & ENT Hospital of Fudan University (2020116).The study was also registered with the Chinese Clinical Trial Registry (ChiCTR2000036862). The study’s performance adhered to the guidelines outlined in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)¹⁶ recommendations for the design and reporting of observational research and also complied with principles of Declaration of Helsinki.

Study Setting and Subjects

This study included all patients over 18 years old who underwent AFBI for otorhinolaryngology surgery at the Eye & ENT Hospital of Fudan University between January 1, 2022 and July 31, 2023. The exclusion criteria involved the absence or incomplete AFBI scenario recordings, endoscopic video recordings, and missing data within the electronic medical records (EMR).

AFBI Procedure Protocol

Our centre developed a standardised AFBI protocol for otorhinolaryngology surgery patients, influenced by the Difficult Airway Society guidelines for ATI in adults (2021),⁹ addressing sedation, topicalisation, oxygenation, and performance. All AFBI supervisor physicians had completed standardised ATI training through the All-in-One Airway Training Program in China (http://www.linaatp.com).

The protocol of AFBI was described below:

• Patient and equipment preparation: On the day of surgery, the patient was transferred to the area of the procedure once all the equipment, like patient monitor, FB, anesthesia machine, required medications like opioids and sedatives, and emergency airway trolley had been verified and checked. Before starting the procedure, the patient was monitored using electrocardiography (ECG), non-invasive blood pressure (NIBP), and pulse oximetry (SpO₂).
• Oxygenation: The oxygenation method included a nasal cannula (2–4 L/minute O₂) and high-flow nasal oxygen (HFNO), or mask.
• Topicalisation: Lidocaine or tetracaine (2%, 2 mL per time) was chosen for administering local anesthesia to the nasal cavity (specifically for nasal intubation), oropharynx, laryngopharynx, or endotracheal areas separately. If the anesthesiologist performing the AFBI determined that enhanced local anesthesia was needed for any area, additional doses were administered, and the effectiveness was reassessed.
• Sedation and adjunct systemic medications: Administering a dose of 0.5–1 µg.kg⁻¹ dexmedetomidine was recommended to achieve optimal sedation for procedural cooperation while retaining spontaneous breathing and partial consciousness. The administration of intravenous fentanyl and lidocaine was based on the clinical judgment of the operator performing the AFBI. The prescribed doses were 0.5–1 µg/kg for fentanyl and 0.5–1.0 mg/kg for lidocaine, respectively.
• Performance: Following sedation and airway topicalisation, the flexible bronchoscope was introduced into the trachea via the nasal or oral route. Finally, the tracheal lumen presence was visualized in fiberoptic bronchoscopy view, and the correct catheter position was confirmed by capnography.

ATI Procedural Video and Clinical Digital Data Collection System

The ATI procedural video recording system included a wide-angle camera for recording the intubation process, patient’s cough and gag reflexes, vital signs monitoring screen and the view from the video flexible bronchoscope (see Supplementary Figures 1 and 2).

Additional detailed clinical data were collected using standardised forms documenting baseline characteristics such as age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) classification, severity of laryngeal obstruction, and clinical indications for AFBI. Additionally, the forms recorded details regarding the administration of topicalisation and adjunct systemic medications, oxygenation methods, procedural characteristics, and changes in the patient’s vital signs. A designated anesthetic nurse was responsible for data documentation.

The procedure duration was defined as the time elapsed from the patient entering the procedural location to when the tube entered the trachea along with the presence of capnographic waveform. The difficulty score of AFBI given by the chief operator was defined as 1 being easy and 5 as the extremely difficult attempt. Operator experience is defined as <10 cases refers to operators who had performed fewer than 10 ABFI procedures prior to the study, ≥10 but <50 cases refers to operators who had performed between 10 and 49 AFBI procedures prior to the study, ≥50 but <100 cases refers to operators who had performed between 50 and 99 AFBI procedures prior to the study, ≥100 cases refers to operators who had performed 100 or more AFBI procedures prior to the study.

Reaction of cough and gag grades during the procedure were defined as: Grade 0: no reaction; Grade 1: minimal coughing and gagging <3 times that does not hinder intubation; Grade 2: mild cough and gag lasting for <1 min hindering intubation; Grade 3: persistent coughing and gagging with defensive movement of head or hands. Secretion Grades were assessed using a 4-point scale, as follows: Grade 0: no visible secretion; Grade 1: small amount of secretion that does not require any oropharyngeal suction; Grade 2: moderate amount of secretion that can be completely removed by oropharyngeal suction; Grade 3: large amount of secretion that requires oropharyngeal suction more than two times during the procedure. An allergic reaction was defined as swelling, mucosal irritation, or rashes associated with topical anesthetics, sedative agents, or lubricants. Desaturation was defined as a peripheral oxygen saturation (SpO₂) of ≤90%. Arrhythmia was defined as a sinus tachycardia or premature contractions, while bradycardia was defined as a heart rate of less than 60 beats per minute.

Ramsay Sedation Scale (RSS) was used to observe the sedation level of the patients.¹⁷ Sedation levels and hemodynamic changes, including heart rate, mean blood pressure, and SpO₂, were documented at several key time points during the procedure. These points were defined as follows: T1, the beginning of the procedure; T2, after the application of local anesthetics to the oral cavity; T3, after local anesthetics were applied to the supraglottic region; T4, after local anesthetics were applied to the subglottic region; T5, after the successful insertion of the endotracheal tube (ETT); and T6, at the end of the procedure. This structured monitoring provided a comprehensive evaluation of the patient’s sedation and hemodynamic status at each critical stage of the intubation process.

Statistical Analysis

Statistical analysis was performed with R Software, Version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria). Data are presented as n (proportion), medians (interquartile ranges [IQR]), or mean (SD). Comparisons between the first-attempt success group and the multiple-attempt (≥2 times) success group were made using the χ² test and unpaired two sample T-test for categorical variables and Mann–Whitney rank test for continuous variables, respectively. Differences were considered significant if P-values were less than 0.05 (two-tailed).

Results

From January 1, 2022, to July 31, 2023, a total of 147 cases undergoing AFBI were included in the analysis. Table 1 provides a detailed overview of the baseline characteristics. The median age of the patients was 66.00 years (IQR: 59.00–70.00), and the median BMI was 22.20 kg.m⁻² (IQR: 19.80–24.60). The majority of AFBIs were performed in male patients (85.03%). The most common indication for AFBI was pathological obstruction of the supra-glottic region, accounting for 117 cases (79.59%). Other indications included limited neck movement in 8 cases (5.44%), limited mouth opening in 6 cases (4.08%), and pathological obstruction of the sub-glottic region in 16 cases (10.88%). Among the 147 cases, 128 patients (87.07%) were successfully intubated on the first attempt, while 19 patients (12.93%) required multiple attempts. Compared to the first-attempt success group, multiple attempts were more frequently observed in patients with laryngeal obstruction (12.50% vs 42.10%), (P = 0.003, Table 1).

Table 1 Baseline Characteristics of the Study Population

In summary, the majority of AFBIs were performed in male patients with supra-glottic obstruction, and most cases were successfully intubated on the first attempt.

Details of Topicalisation and Adjunct Systemic Medications During AFBI

The use of topical and systemic medications during awake flexible bronchoscopy intubation was outlined in Table 2. Lidocaine was the most commonly used topical anesthetic, applied in 78.23% of cases, with a median dose of 3.27 mg.kg⁻¹ (IQR: 2.79–3.94). A combination of lidocaine and tetracaine was used in 20.41% of cases, with median doses of 1.45 mg.kg⁻¹ (IQR: 0.70–1.73) for lidocaine and 0.57 mg.kg⁻¹ (IQR: 0.34–0.77) for tetracaine. Tetracaine alone was rarely used (1.36%), with a median dose of 2.08 mg.kg⁻¹ (IQR: 1.86–2.29). Dexmedetomidine was administered in all cases (100%), with a median dose of 0.71 µg.kg⁻¹ (IQR: 0.51–0.88). Fentanyl was used in 97.28% of cases, with a median dose of 0.87 µg.kg⁻¹ (IQR: 0.72–1.00). Systemic lidocaine was administered in 41.49% of cases, with a median dose of 0.97 mg.kg⁻¹ (IQR: 0.83–1.05).

Table 2 Details of Topicalisation and Adjunct Systemic Medications During Awake Flexible Bronchoscopy Intubation

When comparing the two groups, the use of intravenous lidocaine, dexmedetomidine, and fentanyl was similar between the first-attempt and multiple-attempt success groups, with no significant differences in dosing. However, systemic lidocaine was used more frequently in the multiple-attempt success group (57.89% vs 39.06%), though this difference was not statistically significant (P = 0.192, Table 2).

In summary, lidocaine was the most frequently used topical anesthetic, while dexmedetomidine and fentanyl were the systemic medications, with consistent dosing among the administered population.

Details of Oxygenation Supplementation and AFBI Performance

The oxygen supplementation methods and procedural performance during awake flexible bronchoscopy intubation were summarized Table 3. The majority of patients (94.56%) received oxygen via nasal cannula, followed by HFNO and mask, each used in 2.72% of cases. The minimum SpO₂ during the procedure was 95.00 (IQR: 92.00–97.00). The median duration of the procedure was 20.45 minutes (IQR: 18.55–24.41). Most procedures involved two or three operators (95.92%), and 40.14% of cases were performed by operators with experience of ≥100 AFBI cases. The operation difficulty score was rated as 3.00 (IQR: 2.00–4.00). Procedures were predominantly performed in the preparation room (95.24%) with the operator positioned at the head end (89.12%). The oral intubation route was used in 94.56% of cases, and the median size and depth of the endotracheal tube (ETT) were 5.50 (IQR: 5.50–5.50) and 23.00 cm (IQR: 22.00–23.00), respectively (Table 3).

Table 3 Details of Oxygen Supplementation, Awake Flexible Bronchoscopy Intubation Performance

When comparing the two groups, the multiple-attempt success group had a slightly lower minimum SpO₂ [93.00 (IQR: 91.00–97.00) vs 95.00 (IQR: 92.00–97.00) P = 0.392] and a significantly longer procedure duration [23.33 minutes (IQR: 20.80–26.86) vs 20.01 minutes (IQR: 18.33–24.09), P = 0.007]. Other variables, including oxygenation methods, operator experience, and intubation route, were similar between groups.

In summary, nasal cannula was the most common oxygenation method, and the procedure was typically performed in the preparation room with consistent operator positioning and intubation techniques across the study population.

Cough and Gag Reflex, Secretion Grades, and Adverse Events Related to AFBI

Table 4 summarizes the events associated with AFBI, including cough and gag reflex grades, secretion grades, and adverse events. Pre-intubation, most patients exhibited no reflex (Grade 0: 134 [91.16%]), while 13 (8.84%) showed mild reflex (Grade 1). During intubation, the majority of patients experienced mild reflex (Grade 1: 134 [91.16%]), with 13 (8.84%) displaying moderate reflex (Grade 2). After intubation, 121 (82.31%) patients had no reflex (Grade 0), 23 (15.65%) exhibited mild reflex (Grade 1), and 3 (2.04%) showed moderate reflex (Grade 2). Severe reflex (Grade 3) was not observed at any time point. Regarding secretion grades, most patients had no visible secretion (Grade 0: 64 [43.54%]) or scanty secretion not requiring suction (Grade 1: 53 [36.05%]), while moderate secretion requiring suction (Grade 2) was observed in 28 (19.05%), and only 2 (1.36%) required repeated suction due to large amounts of secretion (Grade 3). Adverse events were uncommon, with desaturation (SpO2 ≤ 90%) occurring in 8 (5.44%), bradycardia in 9 (6.12%), mild allergic reaction of mucosal irritation and arrhythmia of sinus tachycardia in 1 (0.68%) patient, respectively. A change to a more experienced operator occurred in 11 (7.48%), and a change in ETT size was required in 3 (2.04%).

Table 4 Details of Related Events Associated with Awake Flexible Bronchoscopy Intubation

When comparing the first-attempt and multiple-attempt groups, patients in the first-attempt group were more likely to have no reflex (Grade 0) pre-intubation (96.09% vs 57.89%, P < 0.001) and during intubation (97.66% vs 47.37%, p < 0.001). After intubation, the first-attempt group also had a higher proportion of no reflex (84.38% vs 68.42%, P = 0.048). The multiple-attempt group required more frequent changes to a more experienced operator (26.32% vs 4.69%, P = 0.004) and changes in ETT size (15.79% vs 0, P < 0.001). No significant differences were observed in secretion grades (P = 0.169) or adverse events, including allergic reaction, desaturation, bradycardia, and arrhythmia (P > 0.999 for all, Table 4).

In summary, most patients undergoing AFBI experienced minimal reflexes, low secretion grades, and rare adverse events. First-attempt success was associated with lower reflex grades and fewer procedural adjustments compared to multiple attempts.

Hemodynamic Stability and Sedation Levels During AFBI

The hemodynamic changes and sedation level variations during awake flexible bronchoscopy intubation were noted across six time points (T1–T6) (Figure 1 and Supplementary Tables 1 and 2). Heart rate (HR) remained stable overall, with a slight decrease over time. However, the multiple-attempt success group exhibited significantly higher HR compared to the first-attempt success group at T2 (P = 0.002), T3 (P = 0.045), T4 (P = 0.033), and T5 (P = 0.020). Mean non-invasive blood pressure (MBP) showed a gradual decline across all groups, with no significant differences between the first-attempt and multiple-attempt success groups. Oxygen saturation (SpO₂) remained consistently high (above 97%) throughout the procedure, with no significant differences between groups.

Figure 1 Changes over time in heart rate (HR), mean non-invasive blood pressure (MBP), oxygen saturation (SpO2), and Ramsay sedation scale (RSS). (A) Statistically significant differences in HR between the first and multiple attempt success groups were observed at T2 (P = 0.002), T3 (P = 0.045), T4 (P = 0.033), and T5 (P = 0.020). No statistically significant differences were noted between the first and multiple attempt success groups in MBP (B), SpO2 (C), or RSS (D) between the groups at any time point. Filled circles represent means / proportion of the groups.

Sedation levels, measured using the RSS, showed that most patients achieved a tranquil state (Score 2) after the application of local anesthetics (T2), with 94.56% of patients overall reaching this level. A small proportion of patients (4.08%) reached a deeper sedation level (Score 3) at T2, with no significant differences between the first-attempt and multiple-attempt success groups (P = 0.534). Sedation levels fluctuated slightly during the procedure, with most patients maintaining a tranquil state (Score 2) at later time points (T3–T6). At T5 and T6, a small proportion of patients in the multiple-attempt success group had a sedation score of 1, indicating they were more anxious or restless compared to the first-attempt success group, though the differences were not statistically significant.

In summary, hemodynamic parameters remained stable during the procedure, with HR being slightly higher in the multiple-attempt success group at specific time points. Sedation levels were adequate and consistent across groups, with most patients achieving a tranquil state during the procedure.

Discussion

Our study comprehensively evaluated 147 AFBI cases using video recordings and electronic medical records. The integration of video recordings and a detailed review of procedural data represented a novel approach to studying AFBI. This methodology allowed for an objective assessment of operator performance, patient responses, and procedural outcomes, offering a unique contribution to the field of airway management. Among the 147 AFBI cases, the success rate was 100%, with a first-attempt intubation success rate of 87.7%. Hence, patients with pre-operative laryngeal obstruction, severe coughing, or a strong gag reflex were more likely to require multiple intubation attempts to achieve success and the implementation of an AFBI protocol revised according to the ATI guidelines⁹ significantly contributed to improving the quality and safety of clinical practice.

Laryngeal pathologies contributing to difficult intubation were often the result of structural changes, which can complicate both ventilation and intubation. Older individuals with laryngeal malignancies were reported to be much vulnerable to difficult intubation due to age-related airway pathologies. Previous studies have reported that those patients have a higher likelihood of complications, including arrhythmias, cardiac arrest during intubation, post-intubation hypotension, and other adverse events.^1,18 Notably, awake tracheal intubation has been associated with a lower incidence of severe adverse events compared to intubation under general anesthesia, highlighting its potential advantage in high-risk populations.¹⁹

Compared with the incidence of ATI (1%–1.7%) reported by general hospitals.^8,10,11 The incidence of ATI in otolaryngology-focused institutions was reported to be higher and is attributed to the complexity of cases with head and neck tumors.^20,21 Our study focused specifically on AFBI in otorhinolaryngology patients, a population that is underrepresented in previous research. By addressing this gap, our findings provided valuable insights into the challenges and solutions associated with managing difficult airways in this high-risk group. Supporting this observation, a related study involving 600 AFBI cases found that 86.2% of cases were associated with specialized head and neck care, with otorhinolaryngology procedures accounting for the highest proportion of awake intubations.⁸

The success rate of AFBI (100%) was higher than the previously reported 98% to 99%.^{8,10–12,22–24} The main reasons were that our study has a small sample size, and more importantly, it was attributed to the comprehensive training provided to operators at our center, which included a structured airway management program. Additionally, the use of a standardized AFBI protocol, developed in accordance with ATI guidelines, ensured consistency and reproducibility in clinical practice. This combination of advanced training²⁵ and protocol-driven care represented a significant innovation in improving outcomes for patients with complex airways.

We observed a 12.93% incidence of multiple attempts during AFBI, which falls within the previously reported range of 4.2% to 14.8%.^8,10,23 The study identified pre-operative laryngeal obstruction and vomiting or coughing before intubation as significant factors contributing to multiple attempts. Under a standardised AFBI protocol, repeated attempts were associated with prolonged procedure times, the need for more experienced operators, changes in endotracheal tube size, and elevated heart rates. Previous studies have shown that patients requiring ATI face a higher risk of severe complications during multiple attempts, potentially leading to patient discomfort, operator anxiety, and iatrogenic airway injury.^26,27 These findings highlight the need for refined strategies in managing complex airways, including enhanced pre-operative assessment, improved operator experience, optimized endotracheal tube selection, and individualized AFBI protocols to minimize complications. This study underscores the importance of identifying factors contributing to multiple attempts and developing targeted interventions to reduce their occurrence. By systematically analyzing procedural details, our findings provide a foundation for improving patient safety and reducing the risk of complications.

Adequate airway anesthesia and appropriate sedation depth are critical to ensure the smooth performance of AFBI.²⁸ Compared to other local anaesthetics, lidocaine offers superior cardiovascular safety and lower risks of systemic toxicity.²⁹ Studies indicated that lower concentrations of lidocaine are as effective as higher ones.^30,31 As a result, our centre primarily used 2% lidocaine for airway surface anesthesia.

Our analysis found that a median dose of 3.27 mg/kg of 2% lidocaine was effective for airway surface anesthesia in ear, nose and throat (ENT) procedures. This study also highlights the innovation of optimizing sedation and anesthesia practices,^32–34 including the use of dexmedetomidine (median dose, 0.71 µg/kg) to achieve effective sedation while maintaining spontaneous respiration.^14,35–39 By balancing patient comfort with safety (RSS score of 1 to 2), the evidence-based practices could be tailored to meet the unique demands of AFBI.

It has been reported that as high as 65% of awake intubation failures were caused by the difficulty of the initial tube passing through the glottis.^10,12 Tracheal tubes with a smaller external diameter, particularly in patients with malignant tumours, could significantly reduce the intubation failure rate and the risk of complications.^10,40,41 In our study cohort, the average tracheal tube size was 5.5 mm, usually considered undersized for adult patients. 15.79% of patients who required multiple intubation attempts succeeded after switching to a smaller one. These findings highlighted that selecting appropriate tube sizes is crucial, especially for patients with airway abnormalities. Switching to a smaller tube during difficult intubation could be an effective strategy to improve overall success, offering valuable guidance for managing high-risk populations.

In our study, the majority of patients (94.56%) were provided with low-flow oxygen therapy via nasal cannula, rather than using HFNO as a routine approach. Although HFNO with heated humidification had been associated with a reported desaturation rate of only 0–1.5%,^8,42 we only prioritised nasal cannula oxygen due to the high cost of HFNO. Even though, the results showed a median lowest oxygen saturation of 95% among our patients, with a hypoxemia incidence of 9.52%, lower than the 12–16% reported in studies on low-flow oxygen therapy in the guidelines.⁹ This is most likely because we used a relatively small dose of dexmedetomidine to alleviate anxiety and sedate patients, maintaining the RSS score at 1–2, and only administered a single intravenous injection of fentanyl before attempting intubation if being suggested by the operator.

Limitations

This study offers clinical data supporting AFBI procedures, though several limitations must be acknowledged. Firstly, the sample size of the study is relatively small, primarily because the incidence of awake intubation is as low as 1–1.7%. Secondly, since this study was conducted at a single center with a protocol tailored to the unique conditions and practices of that center, the applicability and generalizability of the results to other settings or institutions may be limited. Future studies should aim to incorporate data from multiple centers and further investigate more refined procedural techniques and personalized management strategies to enhance the applicability and robustness of the findings.

Conclusion

This study provides a comprehensive review of the detailed procedures of AFBI in otolaryngological surgeries, achieving a 100% overall success rate and 87.7% first-attempt success. As the first study to systematically evaluate sedation, patient responses, and detailed drug dosages during AFBI, it emphasizes the importance of standardized protocols in enhancing safety and success rates. These findings underscore the clinical significance of optimizing intubation strategies to reduce complications and improve outcomes, particularly for high-risk patients with difficult airways.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by grants-in-aid for scientific research from the Continuing Education Programs of Shanghai Medical College Fudan University [Grant No. FDYXYBJ-20222004,2022 to WX-L], Global Development Programs of Fudan University [Grant No. IDH6282016/049,2023 to WX-L], the National Natural Science Foundation of China [Grant No. 82171264 & 82171282 to WX-L], the Natural Science Foundation of Shanghai [Grant No. 23ZR1409300 to WX-L], the National Natural Science Foundation of China [Grant no. 82201375 to SS-L], the National Natural Science Foundation of China [Grant No. 82271295 to YH].

Disclosure

The author(s) report no conflicts of interest in this work.

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