Role of Macrophage Polarization in Chronic Rhinosinusitis Based on the Yin-Yang Theory: A Review

Fei Wang; Ye Xiong; Yaxian Zhu; Xiaoqian Yang; Kai Liu; Zhenhua Zhu

doi:10.2147/JIR.S514060

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Review

Role of Macrophage Polarization in Chronic Rhinosinusitis Based on the Yin-Yang Theory: A Review

Authors Wang F, Xiong Y, Zhu Y, Yang X, Liu K, Zhu Z

Received 24 December 2024

Accepted for publication 16 May 2025

Published 13 June 2025 Volume 2025:18 Pages 7813—7825

DOI https://doi.org/10.2147/JIR.S514060

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Ning Quan

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Macrophage polarization in chronic rhinosinusitis – Video abstract [514060]

Fei Wang, Ye Xiong, Yaxian Zhu, Xiaoqian Yang, Kai Liu, Zhenhua Zhu

Department of Otolaryngology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China

Correspondence: Zhenhua Zhu, Department of Otolaryngology, The First Affiliated Hospital of Hunan University of Chinese Medicine, No. 95, Shaoshan Middle Road, Yuhua District, Changsha, Hunan, 410125, People’s Republic of China, Email [email protected]

Background: Chronic rhinosinusitis (CRS) is a prevalent otolaryngologic condition that markedly impacts patients’ quality of life; however its pathogenesis is intricate and the clinical efficacy of known treatments remains limited.
Methods: In recent years, there has been a growing focus on the role of immune function in the pathogenesis of CRS. Recent studies have revealed a correlation between macrophage polarization and CRS development. Macrophage polarization denotes distinct phenotypes of macrophages in diverse microenvironments, with the M1 and M2 phenotypes sharing similarities with the Yin-Yang concept of traditional Chinese medicine, encompassing mutual support and utilization, a balance between growth and elimination, and self-healing and equilibrium.
Results: This study briefly reviews the latest research on traditional Chinese medicine compound prescriptions and the regulation of macrophage polarization by traditional Chinese medicine monomers, aligned with the main treatment principles of CRS, with the aim of offering novel directions and strategies for the clinical management of this condition.
Conclusion: This study investigated the role of macrophage polarization in CRS from the perspective of the Yin-Yang Theory of traditional Chinese medicine.

Keywords: chronic rhinosinusitis, the Yin–yang theory, macrophage polarization

Introduction

Chronic rhinosinusitis (CRS) is a prevalent condition in otorhinolaryngology characterized by symptoms such as nasal congestion, runny nose, headache, and diminished sense of smell that persists for over 12 weeks. The primary pathological feature of this condition is chronic mucosal inflammation of the nasal cavity and sinuses. In Europe and the United States, the prevalence of CRS among adults exceeds 10%,¹ whereas in China, it surpasses 8%.² CRS has emerged as a significant health concern affecting people’s daily life and work, with ongoing challenges in both understanding its pathogenesis and conducting clinical research.

To understand the variability of clinically observed manifestations and outcomes, many chronic diseases have been classified into genotypes, phenotypes, and/or endosyms. CRS is no exception. The phenotypic classification of CRS has been determined based on endoscopically observed features, the presence of systemic diseases, and the time of onset. The endoscopic presence (CRSwNP) or absence (CRSsNP) of nasal polyps has been the most widely used phenotype of CRS.² However, a precise treatment that relies solely on phenotypic classification remains elusive, driving research on CRS endotype.³ Endotypic classifications subdivide CRS based on pathobiologic mechanisms. For CRS, this was based on histologic features such as the presence of fibrosis, glandular hypertrophy, and epithelial dysmorphosis. Recent efforts attempt to define CRS endotypes based upon specific molecular mechanisms with biomarkers, which appear to be strongly correlated with phenotype, histological features, and treatment response. The endotypic classification of CRS ultimately shifts the focus to molecules produced by T lymphocytes of types 1, 2, and 3 (also known as type 17), which lead to different inflammatory patterns observed in tissues. EPOS 2020 recommends evaluating and treating CRS based on its endogenous correlation with type 2 or non-2 inflammatory diseases, focusing therapeutic choices on specific disease mechanisms and facilitating individualized treatment.⁴

In recent years, research into the involvement of macrophages in the CRS has been burgeoning. Macrophages, an important component of the immune system present in various tissues and organs throughout the body, help eliminate pathogens and cell debris in the body by acting as phagocytic cells. Macrophages exhibit high plasticity and heterogeneity. They can polarize into M1 and M2 phenotypes in response to growth factors and cytokines present in the microenvironment of nasal and olfactory mucosal tissue.⁵ M1 phenotype promotes inflammation, producing a large amount of inflammatory cytokines, participates in Th1 response, and regulating early repair and pathogen response processes. On the contrary, M2 phenotype exhibits repair function, characterized by high IL-10 and low IL-12 expression. It stimulates the later repair process, participates in Th2 response, and regulates immune function. Therefore, regulating the balance between the two types of macrophages may become essential for treating CRS.

Owing to the complex pathogenesis of CRS,⁶ its clinical treatment has limited efficacy. EPOS 2020 states that CRS is still commonly treated with glucocorticoid-based pharmacotherapy and functional endoscopic sinus surgery (FESS).⁴ However, Tokunaga et al⁷ showed that nearly 20% of patients with CRSwNP had recurrence of nasal polyps after 12 months of systemic glucocorticoid therapy and/or surgical treatment, and these patients often required secondary or even multiple surgical procedures, which not only affects the quality of life, but also greatly increases the time and economic costs. Other managements for CRS include Traditional Chinese medicines (TCM). TCM has a long history in China, which is an important category of complementary and alternative medicine, its use has increased in place in western countries over the past decade. A review that included some of the herbal medicines used in eastern Asia found symptom improvements in CRS.⁸ References to a disorder that may have been CRS, then called bi yuan (excessive turbid nasal discharge), first appeared in the book Huang Di Nei Jing (Yellow Emperor’s Classic of Medicine) which dates back to the Han dynasty, and subsequently appear in multiple books until modern times.⁹ One review of 30 RCTs illustrated that TCM compared with placebo reported significant reductions in SNOT-20, SNOT-22, VAS-TNS, and MTT.¹⁰

The Yin-Yang theory is the theoretical basis of TCM, which guides the clinical thinking and diagnostic practice of TCM. We propose that the pro-inflammatory and anti-inflammatory responses in the immune response can be seen as compatible with the Yin-Yang theory in traditional Chinese philosophy, in which Yang represents active, positive, and aggressive factors, whereas Yin represents passive, negative, and inhibitory factors. Therefore, the modulation of macrophage polarization by TCM has a promising future in the treatment of CRS. This article explored the role of macrophage polarization in CRS from the perspective of yin and yang theory and summarized the herbal medicines that can regulate macrophage polarization. in order to provide new ideas for TCM treatment of CRS. We hope it will provide new ideas for the clinical management of CRS in Chinese medicine.

Overview of Macrophages

Origin and Function of Macrophages

Macrophages were first identified and described as phagocytes in marine organisms by Elie Metchnikoff in the 19^th century.¹¹ They are the most widely distributed cells in the body¹² and play crucial roles in maintaining immune homeostasis and facilitating post-traumatic repair. Most, macrophages originate from bone marrow hematopoietic stem cells.^13,14 Monocytes in the bone marrow differentiate into macrophages under the influence of macrophage colony-stimulating factor,^15,16 and subsequently enter different tissues through the circulatory system. However, morphological and functional differences have been observed among tissue-resident macrophages, suggesting that they may not originate solely from circulating monocytes,¹⁷ and can be categorized as monocyte-derived or tissue-resident macrophages.¹⁸ Tissue-resident macrophages originate predominantly from the yolk sac and fetal liver during embryonic development.^19–22 Primitive macrophages are formed by the red marrow lineage progenitor cells of the extraembryonic yolk sac to produce primitive macrophages under the influence of transcription factors. When residing in the fetal liver, red marrow lineage progenitor cells stimulated by transcription factors produce fetal foetal monocytes.²³ Tissue-resident macrophages have a long lifespan and perform self-renewal in adulthood.^24–26 They serve as the body’s first line of defense against infections by responding promptly to external stimuli and regulating the dynamic balance of the body’s tissues. Monocyte-derived macrophages complement this function and play a regulatory role in inflammation development.²⁷

Macrophage Polarization

When the internal environment of the body is compromised, macrophages play a crucial role in restoring immune homeostasis by removing exogenous substances via phagocytosis and endocytosis. This phenomenon is referred to as macrophage activation. Macrophages show considerable plasticity and heterogeneity. Influenced by various cytokines, macrophages change their appearance and manifest different phenotypes, a phenomenon referred to as macrophage polarization.^28,29 Polarized macrophages primarily exist in two states: Classically activated (M1) macrophages and alternatively-activated (M2) macrophages³⁰ (Figure 1).

Figure 1 Pattern of Macrophage polarization.

M1-type macrophages primarily polarize through the binding of Th1 cytokines, such as IFN-γ, or are activated by bacterial lipopolysaccharide (LPS) alone. They release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, IL-12, IL-23, and COX-2, which actively participate in the elimination of pathogens during infections. Additionally, M1 macrophages contribute to pathogen clearance by over-stimulating the nicotinamide adenine dinucleotide phosphate oxidase system, leading to the production of reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) levels.^31–33 Consequently, when an external stimulus or inflammation affects an organism, M0 macrophages initially polarize into the M1 phenotype, secrete inflammatory cytokines, stimulate the immune response of Th1 and Th17 cells, and safeguard the host during the early stages of inflammation.^34–36

M2 macrophages predominantly polarize under the influence of Th2 cell cytokines such as IL-4 and IL-13, leading to the production of anti-inflammatory factors (such as IL-10, CCL17, CCL18, CCL22, CCL24) and pro-fibrotic factors (such as transforming growth factor(TGF)-β, insulin-like growth factor).^37,38 M2-type cells exhibit various phenotypes demonstrating distinct characteristics in response to microenvironmental and signalling stimuli, categorized as M2a, M2b, M2c, and M2d.^28,39–41 M2 macrophages activate TGF-β by modulating the Th2 cell response, and produce matrix metalloproteinases (MMPs) to eliminate necrotic cells and components of destruction generated by the M1 macrophage response, thus mitigating potential tissue injury.⁴²

Polarization of Macrophages Intervenes in the Mechanism of CRS

Limited research has been conducted on the role and function of macrophages in the pathogenesis of CRS. Some studies have suggested a notable increase in both M1 and M2 macrophage populations in CRS, particularly among patients with CRSwNP, where M2-type macrophages are markedly increased.^43–45 Notably, an increase in M1-type macrophages was observed in patients with non-eosinophilic CRSwNP, whereas M2-type macrophages were more prevalent in patients with eosinophilic CRSwNP, indicating the potential involvement of M2-type macrophages in the inflammatory response and tissue remodeling processes.^46,47 Despite the increased number of M2-type macrophages in eosinophilic CRSwNP, the quantity and percentage of IL-10⁺CD₆₈⁺ M2 macrophages decreased. This specific subtype of M2 macrophages exhibits a negative correlation with disease signs and symptoms, polyp size, computed tomography scores, and inflammatory cell counts, suggesting a potential relationship between the inflammatory state of eosinophilic CRSwNP and the IL-10 secretion by M2 macrophages.^48–51

Tissue remodeling is an important histopathological alteration in CRS.^52–54 Macrophage polarization leads to a state in which the organism or organ is more fibrotic than antifibrotic, resulting in the accumulation of an extracellular matrix (ECM), and ultimately leading to tissue remodelling.^55,56 Once M2 macrophages are polarized, they secrete various cytokines, leading to fibroblast proliferation and disruption in the balance of the extracellular matrix, resulting in the progressive and irreversible destruction of normal tissue structure in organ tissues.⁵⁷ Tissue remodeling due to M2 macrophages may be related to the following mechanisms: Upregulating TGF-βexpression may promote tissue remodeling. M2 cells stimulate and upregulate TGF-β expression.^58,59 On the one hand, TGF-β activates both the ERK/MAPK pathway and the TGF-β/Smads signal transduction pathway, promoting collagen sedimentation over degradation, inducing fibroblast proliferation and differentiation and ECM accumulation;^60,61 on the other hand, TGF-β induces the synthesis of arginase-1, which induces a decrease in NOS (nitric oxide synthase) bioavailability, thereby increasing susceptibility to pathogens and exacerbating tissue remodeling.⁶² Furthermore, TGF-β stimulates increased expression of VEGF, which leads to the accumulation of cuprocytes, vascular endothelial cells, and an ECM, thereby triggering vascular remodeling and airway inflammation.⁶³ A regulatory feedback mechanism may exist between M2 macrophages and TGF-β. By activating the ERK/MAPK signalling pathway, TGF-β promotes the polarization of M2 macrophages, which continuously exacerbates the tissue remodeling process.⁶⁴ M2 macrophages inhibit MMP-9 hydrolysis and increase tissue vascular permeability by stimulating high expression of TIMP3.^65,66 This increased vascular permeability leads to the accumulation of inflammatory mediators within the tissue, exacerbating tissue remodeling by regulating coagulation mechanisms.⁶⁷ M2 macrophages produce FXIII in the tissues, which enhances coagulation and forms stable fibrin polymers that are not degraded by fibrinolysis.⁶⁸ M2 macrophages were found to be the major source of FXIII in CRSwNP, exacerbating remodeling by triggering plasma protein retention in nasal polyp tissue and pseudocyst formation.⁶⁹

Mechanisms of the Yin-Yang Theory and Macrophage Polarization in CRS

Yin–Yang Theory and Macrophage Polarization

Researchers have focused on the role of macrophages in diseases and the mechanism of action of traditional Chinese medicine(TCM).^70,71 The foundation of TCM is based on the Yin–Yang principle, which represents interconnected yet opposing pairs of elements in the natural world.⁷² This principle is instrumental in explaining physiological and pathological changes in the human body, which can be used to diagnose and treat diseases.⁷³ Macrophage polarization comprises two mutually antagonistic and unifying states, which we believe are connotatively related to the theory of Yin-Yang in TCM.

Macrophage polarization is a dynamic process,⁷⁴ in which the M1 and M2 phenotypes represent two extremes, where transitions between these stages can be observed within the same tissue, with macrophages interconversion in specific environments.⁷⁵ Notably, M1 and M2 macrophages exhibit a fundamental and interdependent relationship analogous to the principles of interdependence between yin and yang. In the early stages of inflammation, M1 macrophages primarily play a pro-inflammatory and pathogen-killing role through the release of inflammatory mediators, aligning with the TCM concept of “yang being in charge of activity”. In contrast, M2 macrophages focus on anti-inflammation, tissue repair, and remodeling, corresponding to the TCM principle of “yin controlling quiescence”.⁷⁶ Despite their functional antagonism, M1 and M2 macrophages are functionally unified, with dynamic changes of the yin and yang sides constantly maintaining balance, achieving an ideal state of health. Yang bias creates excessive competition between vital energy and pathogenic factors, damaging positive energy. M1 macrophages excessively promote inflammation and exert antibacterial effects, which are not conducive to tissue repair and may even lead to extensive tissue damage.⁷⁷ When yin is in excess and the pathogenic factors are not eliminated, the pathogenic factors transform and cause illness. M2 macrophages overexpress anti-inflammatory factors and suppress immunity, thereby promoting tissue remodeling.⁷⁷ However, an imbalance in M1/M2 cell polarization, despite their opposing yet coexisting nature, can results in a negative local inflammatory microenvironment, leading to chronic inflammatory pathological reactions in the body.^78,79

Treatment of CRS by Adjusting Yin and Yang

Tao Te Ching wrote that “all things carry yin and embrace yang; they achieve harmony by combining these forces”.⁸⁰ The Yellow Emperor’s Canon of Medicine further advises to “carefully observe the location of yin and yang, and adjust them, aiming for balance”.⁸¹ The Yin-Yang Theory holds paramount significance in the TCM approach to treating diseases. The human body maintains optimal health only when it achieves a harmonious state of balanced yin and yang. CRS has a complex mechanism, and modern medicine had limited therapeutic effects with high recurrence and multiple side effects.^82,83 TCM stands out for its clear therapeutic effects and advantages for the prevention and treatment of CRS.^84–88

The CRS is classified under the TCM category of “bi yuan”. Through data mining research on “bi yuan”, it was found that ancient medical experts approached the differentiation and treatment of nasal congestion from three primary aspects: External pathogenic factors, internal organ heat, and organ deficiency.⁸⁹ Bi yuan is considered a condition of deficiency at its origin and excess at its surface. TCM practitioners address bi yuan by lung, spleen, and kidney dysfunction, as well as the obstruction of qi, blood and dampness.⁹⁰ Science of Traditional Chinese Medicine Otorhinolaryngology categorizes CRS into five types: Lung meridian wind heat, excessive heat in the cholecyst, damp heat of the spleen and stomach, deficiency and cold of lung qi and splenic dysfunction due to dampness.⁹¹ When M1 macrophages are overly efficient, resulting in an intense pro-inflammatory response, TCM interprets this as an excessive yang transforming into qi, which manifests as a syndrome of excess heat or even yin deficiency. Conversely, when M2 macrophages dominate, leading to an excessive anti-inflammatory response, TCM interprets this as yin shaping, which results in the formation of cold congelation, phlegm dampness, blood stasis and impairment of the body’s yang qi.⁹² From the perspective of TCM, lung and spleen deficiencies, coupled with dampness accumulation, are considered the primary causes of CRS. The inefficiency of M1 macrophages leads to a state of yang qi deficiency; meanwhile, hyperactive M2 macrophages contribute to the formation of dampness. Qi deficiency and dampness accumulation interacted TCM, which focuses on tonifying the spleen and dispelling dampness, has achieved significant therapeutic effects in CRS treatment^93–96 (Figure 2).

Figure 2 Treatment of CRS by adjusting yin and yang.

Reducing the Hyperactivity of M2 Macrophages Using TCM

Based on the therapeutic principles of balancing yin and yang, TCM may exert its preventive and therapeutic effects on CRS by reducing the hyperactivity of M2 macrophages in the body (Figure 3). TCM treatment has two methods for reducing the hyperactivity of M2 macrophages: (1) Inhibiting macrophage polarization to the M2 type, and (2) promoting the generation of M1 type macrophages (Table 1).

Table 1 TCM That Reduces the Hyperactivity of M2 Macrophages

Figure 3 Reducing the hyperactivity of M2 macrophages using TCM based on the Yin-Yang Theory.

TCM Inhibits Polarization of Macrophages to M2 Type

Quercetin is a natural flavonoid found in various Chinese medicinal herbs, such as Sophora flowers. It inhibits M2 macrophage polarization and ameliorates kidney damage by downregulating the protein levels of p65 in NF-κB and interferon regulatory factor 5 (IRF5).⁹⁷ Peimine, the main component of TCM Fritillaria, can improve pulmonary fibrosis by inhibiting the expression of STAT6, p38MAPK, Akt, and other factors, thus suppressing the M2 polarization of macrophages.⁹⁸ Emodin inhibits the signalling of IRF4, STAT6, and C/EBPβ, while increasing the inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on M2-associated gene promoters, thereby suppressing tumor-associated macrophage infiltration and M2 polarization.⁹⁹ AS-IV inhibits IL-13 and IL-4-induced M2-like macrophage polarization via the AMPK pathway, which reduces lung cancer growth, invasion, migration, and angiogenesis.¹⁰⁰ Resveratrol, extracted from the TCM Polygonum, can prevent tumor growth and metastasis by inhibiting tumor-associated macrophage M2-like polarization, which may be related to STAT3 signalling.^101,115 Isoliquiritigenin(ISG) is a dietary flavonoid derived from licorice.¹¹⁶ Studies have shown that ISG blocks M2 polarization during colitis-associated tumorigenesis by downregulating the expression of PGE2 and IL-6 expression.¹⁰² Protostemonine (PSN) is an active substance extracted from the TCM Baibu, which has anti-inflammatory properties and exerts therapeutic effects in acute lung injury and acute liver failure.¹¹⁷ Song et al¹⁰³ found that PSN improved the inflammatory manifestations of asthma by inhibiting the phosphorylation of STAT6 and suppressing M2 polarization. Wang et al¹⁰⁴ found that osthole suppressed M2 polarization and attenuated the development of pancreatic cancer in mice by inhibiting the phosphorylation of STAT6.

Lin Weibo¹⁰⁵ found that Gujin Xiao Liu Tang promoted the apoptosis of M2-Tumor-associated macrophage(TAMs) through the expression of AKT/FOXO3a/bim and pro-apoptotic proteins, inhibiting the cell migration ability of A549 cells in the co-culture system. Min et al¹⁰⁶ discovered that the a Jianpi Yangzheng Xiaozheng recipe inhibited the number of M2-type TAMs in gastric cancer, thereby suppressing the occurrence of epithelial-mesenchymal transition. The mechanism underlying this effect may be related to the PI3K/AKT signaling pathway. Mai Men Dong Decoction (MMDD), a TCM formula, can mediate fibroblast activation through the PI3K/Akt/FOXO3a signaling pathway by regulating M2 macrophage polarization, and inhibiting pulmonary fibrosis.¹⁰⁷

TCM Inhibits Promotes the Generation of M1 Phenotype Macrophages

Baicalein (baicalin), extracted from Scutellaria baicalensis, can promote macrophage polarization toward M1 and slow tumor growth through the NF-κB signalling pathway.¹⁰⁸ Yin et al¹⁰⁹ found that anemoside A3, the active ingredient of Pulsatilla chinensis, increased the polarization of M1 macrophages and inhibited tumor growth and angiogenesis in a dose-dependent manner. A novel polysaccharide, WCCP-N-b, isolated from Cantharellus cibarius, can inhibit the polarization of M2-like macrophages by suppressing STAT6 activation and convert M2-like macrophages to the M1 type through the activation of MAPK and degradation of IκB-α.¹¹⁰ Poria cocos polysaccharide (PPS), the primary components of Polyporus umbellatus, can inhibit the polarization of M2 macrophages through the NF-κB signaling pathway, while promoting the generation of M1-TAMs and the release of M1-related cytokines.^111,118 Ginsenoside Rh2 effectively converts macrophages from the M2 phenotype to the M1 phenotype, and simultaneously reduces the expression levels of VEGF, MMP2, and MMP9 in a lung cancer cell-macrophage co-culture system, suggesting that it inhibits the migration of lung cancer cells.¹¹² The Ganoderma lucidum polysaccharide (PSG-1) dynamically regulates the macrophage M1/M2 polarization phenotype via the Notch signaling pathway, thereby altering the inflammatory state of the body.¹¹³ Water extracts of ginseng and astragalus promote M1 polarization of macrophages and inhibit M2 polarization, thereby suppressing the proliferation of lung cancer cells and synergistically enhancing the anticancer effect of cisplatin.¹¹⁴

Conclusion

Overall, M2 polarization macrophage drives the development of CRS by altering the inflammatory environment and tissue remodeling. However, the specific mechanisms governing the occurrence and development of CRS, as well as the mechanisms of TCM, remain unclear and require further research. Guided by the Yin-Yang Theory of TCM, there are broad prospects for achieving the prevention and treatment of CRS by balancing macrophage polarization by adjusting the body’s yin, yang, qi, and blood. Exploring the role of macrophages in CRS based on the Yin-Yang doctrine can deepen our understanding of the pathogenesis of CRS and enrich the connotation of the Yin-Yang doctrine in TCM. This study serves not only as an exploration of the mechanism of TCM from a modern perspective, but also serves as a positive means for treating CRS with the help of TCM. Such an approach is of considerable importance for improving patients’ quality of life and reducing the societal burden associated with CRS.

Data Sharing Statement

The datasets used and analyzed during the current study are available from the corresponding author on 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 research was financially supported by grants from Foundation of Hunan University of Traditional Chinese Medicine School (Grant No. Z2023JBGS01) and Key Projects of Hunan Provincial Administration of Traditional Chinese Medicine (Grant No. A2024023).

Disclosure

The authors report no conflict of interest.

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