Evidence-based integration of clinicopathological factors with the risk of papillary thyroid carcinoma lateral cervical lymph node metastasis: systematic review and meta-analysis and subgroup study

Introduction

Thyroid cancer is the most common endocrine malignancy, accounting for about 3.4% of annual malignancy diagnoses (1). Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, accounting for about 80% of all thyroid cancers (2). Over the past few decades, thyroid cancer has become a significant public health problem in many countries around the world (3). After standard surgery and adjuvant radioiodine therapy, the long-term prognosis for PTC is good (4). The 2015 American Thyroid Association (ATA) differentiated thyroid cancer (DTC) guidelines state that “Prophylactic central-compartment neck dissection (ipsilateral or bilateral) should be considered in patients with papillary thyroid carcinoma with clinically union evolved central neck lymph nodes (cN0) who have advanced primary tumors (T3 or T4) or clinically involved lateral neck nodes (cN1b), or if the information will be used to plan further steps in therapy”. However, prophylactic lateral neck dissection is still controversial, and how to minimize the residual or recurrence of tumors while reducing unnecessary trauma caused by surgery is the key to the following research (5). Preoperative ultrasonography (USG) has limited diagnostic sensitivity for lateral cervical lymph node metastasis (LLNM), reportedly as low as 27.3% (6). Therefore, it is essential to understand the risk factors of LLNM in patients with thyroid papillary carcinoma and predict LLNM.

Although many studies on LLNM and central lymph node metastasis (CLNM), including some meta-analyses, have been conducted, the number of studies focusing on LLNM is limited and remains partially controversial. In this meta-analysis, we aimed to investigate the risk factors for LLNM in PTC. According to preoperative or intraoperative detection, the contralateral neck lymph node dissection has guiding significance for patients with high-risk factors of lateral neck lymph node metastasis. We present this article in accordance with the PRISMA reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-60/rc).

Methods

Literature retrieval and screening

We conducted a search on the literature related to the risk factors of LLNM in PTC published between 2019 and 2024 in PubMed, Embase, Web of Science, the Chinese biomedical literature database, CNKI, and WANFANG DATA. The English database search is “(Thyroid Cancer Papillary OR papillary thyroid cancer OR PTC OR papillary thyroid carcinoma) AND ((lateral cervical OR lateral neck) AND (lymph nodes)) AND (Risk Factors) Filters: in the last 5 years”. The Chinese database search type was “(subject: (thyroid papillary carcinoma) and subject: (lateral cervical lymph node OR lateral cervical region lymph node) and subject: (risk factors)) and publication time: 2019-*”. Two authors completed the search independently, and differences of opinion were resolved through negotiation.

Inclusion and exclusion criteria

Inclusion criteria

Inclusion criteria: (I) pathologically confirmed PTC; (II) the surgical procedures were total thyroidectomy or unilateral thyroidectomy plus regional cervical lymph node dissection; (III) the risk factors of cervical lymph node metastasis could be obtained; and (IV) assess clinicopathological and/or ultrasound risk factors for LLNM.

Exclusion criteria

Exclusion criteria: (I) duplicate literature; (II) reviews, case reports, conference minutes, and other documents; (III) the subjects were patients with non-PTC, such as follicular thyroid cancer, medullary thyroid cancer, or anaplastic cancer; (IV) the risk factors of cervical lymph node metastasis could not be obtained; and (V) study center or time limit replicated with other studies.

Literature screening and data extraction

Two researchers independently extracted data from studies that met the inclusion criteria and resolved their differences through discussion. The two researchers independently extracted data from the included studies, and differences were resolved through joint discussion. The following data were extracted from each study: first author name, year of publication, country, study duration, study design, diagnosis, number of cases, mode of surgery, investigated risk factors [i.e., gender, age, extrathyroidal extension (ETE), tumor size, multifocality, bilaterality, thyroiditis, Hashimoto thyroiditis, CLNM, capsular invasion, tumor location, BRAF V600E mutation].

Literature quality evaluation

The quality of the included literature was evaluated by two reviewers using the Newcastle-Ottawa scale (NOS). In the evaluation process, if there was any disagreement, it was discussed in focus or ruled by a third party. The maximum score of this scale is 9 points; 7–9 points are considered high-quality literature, and 4–6 points are regarded as medium-quality literature. A score of 4 is considered as low-quality literature.

Statistical analysis

Meta-analysis was performed by RevMan 5.2 software. Odds ratio (OR) and 95% confidence interval (CI) were used to represent the categorical variables, and P<0.05 was considered statistically significant. Heterogeneity was quantified using I² statistics. The fixed effect model was used for meta-analysis when I²≤50%. If I²>50%, the cause of heterogeneity was further analyzed, and after excluding obvious clinical influencing factors, the random effects model was used for meta-analysis. The results of each analysis will be presented in the form of a forest map. When the number of eligible original studies was more than 10, Begg’s funnel plot was used to determine publication bias.

In the face of missing data, the original data were first obtained. Then, a reasonable imputation strategy was selected to calculate the missing value based on the existing statistics (such as mean and sample size), and the standard deviation was imputed through the regression model. Multiple imputation method was used to generate various data sets for comprehensive analysis of complex missing patterns, and the robustness of the results was verified by sensitivity analysis.

Results

Research description

A total of 915 studies were retrieved, of which 252 were replicated and immediately excluded. Another 663 studies were excluded after careful reading of the title and abstract. After thoroughly evaluating the remaining 54 articles, another 30 studies were excluded for various reasons (did not meet the inclusion criteria, research center or time limit repetitive with other studies, no data available, irrelevant studies). Finally, 24 retrospective studies (a total of 40,190 patients; among them, 4,991 had LLNM) were included in this meta-analysis. The NOS scores of 24 literatures were all ≥7 points, and the quality was good. Figure 1 shows the research selection process, and Table 1 summarizes the characteristics of the included research. All risk factors for LLNM are shown in Table 2.

Figure 1 Flow chart of literature selection and inclusion. CNKI, China National Knowledge Infrastructure.

Gender and LLNM

A total of 24 studies with 39,522 patients were included to investigate the effect of gender on the risk of LLNM (Figure 2) (7-30). Due to the low heterogeneity, a random-effects model was used (P=0.002; I²=52%). Pooled analysis showed a significantly higher risk of LLNM in male patients (OR =1.51; 95% CI: 1.34–1.70; P<0.001).

Figure 2 Forest map of meta-analysis on the correlation between gender and LLNM in PTC patients. CI, confidence interval; LLNM, lateral cervical lymph node metastasis; PTC, papillary thyroid carcinoma.

Age and LLNM

A total of 15 studies with 27,651 patients were included to investigate the effect of age on the risk of LLNM (Figure 3) (7,9,10,12,14,16,18,20-22,24,26,28-30). Due to the high heterogeneity, a random-effects model was used (P=0.006; I²=63%). Pooled analysis showed that the risk of LLNM was not significantly associated with age (OR =1.17; 95% CI: 0.95–1.44; P=0.15).

Figure 3 Forest map of meta-analysis of correlation between age of PTC patients and LLNM. CI, confidence interval; LLNM, lateral cervical lymph node metastasis; PTC, papillary thyroid carcinoma.

ETE and LLNM

A total of 11 studies with 20,631 patients were included to investigate the effect of ETE on the risk of LLNM (Figure 4) (8,10,12,16-18,21,22,25,29,30). Due to the high heterogeneity, a random-effects model was used (P<0.001; I²=87%). Pooled analysis showed a significantly increased risk of lateral neck lymph node metastasis in ETE patients (OR =4.16; 95% CI: 2.82–6.14; P<0.001).

Figure 4 Forest map of meta-analysis of correlation between ETE and lateral neck lymph node metastasis in PTC patients. CI, confidence interval; ETE, extrathyroidal extension; PTC, papillary thyroid carcinoma.

Tumor size and LLNM

A total of seven studies with 7,850 patients were included to investigate the effect of tumor size on the risk of lateral neck lymph node metastasis (Figure 5) (7,10,16-18,23,28). Due to the high heterogeneity, a random-effects model was used (P<0.001; I²=89%). Pooled analysis showed that the risk of LLNM increased significantly when the tumor was larger than 2 cm (OR =0.35; 95% CI: 0.20–0.59; P<0.001).

Figure 5 Forest map of meta-analysis of correlation between tumor size and lateral neck lymph node metastasis in PTC patients. CI, confidence interval; PTC, papillary thyroid carcinoma.

Multifocality and LLNM

A total of 15 studies with 26,906 patients were included to investigate the effect of multifocality on the risk of LLNM (Figure 6) (7-10,14,16,17,19,21-23,25-28). Due to the high heterogeneity, a random-effects model was used (P<0.001; I²=87%). Pooled analysis showed a significantly increased risk of lateral neck lymph node metastasis in multifocality patients (OR =1.94; 95% CI: 1.50–2.52; P<0.001).

Figure 6 Forest map of meta-analysis of the correlation between multifocality and LLNM in patients. CI, confidence interval; LLNM, lateral cervical lymph node metastasis.

Bilaterality and LLNM

A total of 10 studies with 14,934 patients were included to investigate the effect of bilaterality on the risk of LLNM (Figure 7) (7,9-11,16,18,19,21,22,25). Due to the high heterogeneity, a random-effects model was used (P<0.001; I²=88%). Pooled analysis showed that bilaterality was not significantly associated with LLNM (OR =1.18; 95% CI: 0.77–1.80; P=0.45).

Figure 7 Forest map of meta-analysis of correlation between bilaterality and lateral neck lymph node metastasis. CI, confidence interval.

Hashimoto thyroiditis and LLNM

A total of 10 studies with 14,402 patients were included to investigate the effect of Hashimoto thyroiditis on the risk of LLNM (Figure 8) (10,12,16,18,21,24,26-29). Due to the low heterogeneity, a fixed-effects model was used (P=0.53; I²=0%). Pooled analysis showed that Hashimoto thyroiditis was not significantly associated with LLNM (OR =1.06; 95% CI: 0.91–1.22; P=0.45).

Figure 8 Forest map of meta-analysis of correlation between Hashimoto’s thyroiditis and cervical lymph node metastasis. CI, confidence interval.

CLNM and LLNM

A total of 11 studies with 19,252 patients were included to investigate the effect of CLNM on the risk of LLNM (Figure 9) (7,8,10,12,13,16,17,22,24,26,27). Due to the high heterogeneity, the random-effects model was used (P<0.001; I²=97%). Pooled analysis showed a significantly increased risk of LLNM when patients developed CLNM (OR =5.38; 95% CI: 2.62–11.07; P<0.001).

Figure 9 Forest map of meta-analysis of correlation between CLNM and cervical lymph node metastasis. CI, confidence interval; CLNM, central lymph node metastasis.

Capsular invasion LLNM

A total of five studies with 8,083 patients were included to investigate the effect of capsular invasion on the risk of LLNM (Figure 10) (11,14,15,19,29). Due to the high heterogeneity, the random-effects model was used (P=0.002; I²=77%). Pooled analysis showed a significantly increased LLNM risk when the tumor developed capsular invasion (OR =0.07; 95% CI: 0.05–0.08; P<0.001).

Figure 10 Forest map of meta-analysis of correlation between capsular invasion and cervical lymph node metastasis. CI, confidence interval.

Tumor location and LLNM

A total of nine studies with 13,747 patients were included to investigate the effect of tumor location on the risk of LLNM (Figure 11) (7,9,10,12,15,26-28,30). Due to the high heterogeneity, the random-effects model was used (P<0.001; I²=0%). Pooled analysis showed a significantly increased risk of LLNM when patients had higher tumor locations (OR =1.84; 95% CI: 1.63–2.09; P<0.001).

Figure 11 Forest map of meta-analysis of correlation between tumor location and cervical lymph node metastasis. CI, confidence interval.

BRAF V600E mutation and LLNM

A total of four studies with 7,992 patients were included to investigate the effect of BRAF V600E mutation on the risk of LLNM (Figure 12) (10,13,26,28). Due to the low heterogeneity, a fixed-effects model was used (P=0.28; I²=22%). Pooled analysis showed that BRAF V600E mutation was not significantly associated with LLNM (OR =1.17; 95% CI: 0.98–1.41; P=0.09).

Figure 12 Forest map of meta-analysis of correlation between BRAF V600E mutation and cervical lymph node metastasis. CI, confidence interval.

Calcification and LLNM

A total of six studies with 4,830 patients were included to investigate the effect of calcification on the risk of LLNM (Figure 13) (15,16,19,25,28,29). Due to the high heterogeneity, a random-effects model was used (P=0.002; I²=74%). Pooled analysis showed a significantly increased risk of LLNM when patients had calcification on ultrasound examination (OR =1.97; 95% CI: 1.34–2.91; P<0.001).

Figure 13 Forest map of meta-analysis of correlation between calcification and cervical lymph node metastasis. CI, confidence interval.

Echogenicity and LLNM

A total of seven studies with a total of 5,348 patients were included to investigate the effect of echogenicity on the risk of LLNM (Figure 14) (10,15,16,19,25,28,29). Due to the low heterogeneity, a fixed-effect model was used (P=0.13; I²=39%). Pooled analysis showed a significantly increased risk of LLNM when patients had hyperechoic on ultrasound examination (OR =1.55; 95% CI: 1.16–2.08; P=0.003).

Figure 14 Forest map of meta-analysis of correlation between echogenicity and cervical lymph node metastasis. CI, confidence interval.

Thyroid-stimulating hormone (TSH) and LLNM

A total of five studies with 3,290 patients were included to investigate the effect of TSH on the risk of LLNM (Figure 15) (8,15,16,23,25). Due to the low heterogeneity, a fixed-effects model was used (P=0.68; I²=0%). Pooled analysis showed that TSH was not significantly associated with LLNM (mean difference =0.01; 95% CI: −0.15 to 0.18; P=0.86).

Figure 15 Forest map of meta-analysis of correlation between TSH and cervical lymph node metastasis. CI, confidence interval; TSH, thyroid-stimulating hormone.

Thyroglobulin antibody (TGAB) and LLNM

A total of three studies with 2,512 patients were included to investigate the effect of anti-TGABs on the risk of LLNM (Figure 16) (8,15,23). Due to the high heterogeneity, a random-effects model was used (P=0.06; I²=65%). Pooled analysis showed that TGAB was not significantly associated with LLNM (mean difference =8.98; 95% CI: −12.21 to 30.17; P=0.41).

Figure 16 Forest map of meta-analysis of correlation between TGAB and cervical lymph node metastasis. CI, confidence interval; TGAB, thyroglobulin antibody.

Publication bias

Begg’s funnel plot showed no significant evidence of asymmetry in meta-analyses of gender, age, and multifocality ETE (Figures 17-20).

Figure 17 Funnel plot of meta-analysis of gender risk factors. OR, odds ratio; SE, standard error.

Figure 18 Funnel plot for meta-analysis of age risk factors. OR, odds ratio; SE, standard error.

Figure 19 Funnel plot for meta-analysis of ETE risk factors. ETE, extrathyroidal extension; OR, odds ratio; SE, standard error.

Figure 20 Funnel plot for meta-analysis of multifocality risk factors. OR, odds ratio; SE, standard error.

Discussion

PTC is a low-grade malignant tumor with a good prognosis and a 10-year survival rate of more than 90% (31), but 30% to 80% of cervical lymph node metastases occur (32,33). The increasing incidence of PTC compared to other major histological types has largely accelerated the global trend of thyroid cancer incidence (34). Due to the limited sensitivity of preoperative USG in the diagnosis of LLNM, the analysis of the predictors of cervical lymph node metastasis provides more powerful evidence for clinical decision-making (6). The results of this study showed that the clinical risk factors for LLNM of PTC are male, ETE, tumor size >2 cm, multifocality, CLNM, capsular invasion, high tumor location, calcification, and hyperechoic. In contrast, age, bilaterality, Hashimoto’s thyroiditis, BRAF V600E mutation, TSH, and TAGB were not considered as risk factors for LLNM in these patients.

Age was not associated with the risk of LLNM. The 8^th edition of the American Joint Committee on Cancer (AJCC) guidelines raised the age threshold from 45 to 55 years, which had been used as the threshold in most previous studies. Zhao et al. suggested that PTC patients than 45 years old were at an increased risk of LLNM (35). On the contrary, Qu et al. concluded that LLNM was significantly higher in younger people (age <45 years) (36). It is more common in patients age <45 years, and a study has shown no statistical significance between age and lymph node metastasis (37). The latest study showed no correlation between age and Delphian lymph node metastasis (38). As the relationship between age and lateral neck lymph node metastasis is not clear, most studies use 55 years old as the critical value. Therefore, this study was also conducted at 55 years old. Fifteen studies were included, with a total of 27,651 patients, and no significant statistical significance was found, which is still controversial, and the critical value should be changed and a larger sample should be investigated.

The incidence of thyroid cancer in women is significantly higher than that in men; the ratio of male to female is about 1:3, but the incidence of cervical lymph node metastasis in men is higher than that in women. The incidence of PTC in women is significantly correlated with estrogen level (39). Fan et al. found that estrogen receptor α can promote the growth of PTC by enhancing autophagy, an essential pro-survival catabolic process in PTC cells (40). Men are more likely to have LLNM; the mechanism is not completely clear, mainly related to hormone levels. Jiang et al. pointed out that testosterone can promote the malignant behavior of PTC, such as growth, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process by up-regulating Tnnt1 expression, and the function of testosterone may be achieved by activating the p38/JNK signaling pathway (41). In addition, female patients often have Hashimoto’s thyroiditis, whose immunomodulatory effect may reduce the risk of metastasis, while the proportion of male patients with HT is low. Male PTC is more aggressive, characterized by larger tumor size (>1 cm), higher proportion of multifocality, and more invasion of the capsule and surrounding tissues, which increase the probability of lymphatic metastasis. Male patients have a higher rate of BRAF V600E mutation, which may accelerate cancer cell invasion and metastasis. Men are more likely to develop LLNM than women in this study, which is consistent with previous studies (39,42).

A study has shown that ETE is an independent risk factor for LLNM in PTC patients, and the prognosis with ETE includes worse lymph node metastasis compared with patients without ETE (21). ETE is a risk factor for LLNM, which may be due to the tendency of tumor cells to metastasize along the abundant lymphoid tissue surrounding the thyroid gland to peripheral lymph nodes once they invade the thyroid capsule and extrathyroidal tissues. Our findings are consistent with previous studies showing that ETE increases the risk of LLNM in PTC patients (37,42).

In our study, biological indicators, such as TSH, TGAB, and BRAF V600E mutation, were innovatively included, which were rarely included in a previous similar study (42). Studies have found that TSH, thyroglobulin (Tg), anti-TGAB, thyroid peroxidase antibody (TPOAb), TSH receptor antibody (TRAb), and other thyroid-related serological indicators can be used as reliable indicators to predict the occurrence, metastasis, and recurrence of PTC. It is a simple, efficient, and cost-effective clinical method to identify PTC disease progression (43). TSH is the main stimulator of thyroid cell function, differentiation, and proliferation. TSH induces thyrocyte growth directly by binding to its autoreceptor and indirectly by stimulating other growth factors such as vascular endothelial growth factor and amyloid precursor. The relationship between serum TSH and lymph node metastasis in PTC patients remains controversial. The mechanism of its occurrence may be that TSH stimulates the massive release of growth factors, which may induce cancer cell growth and neovascularization and may assist malignant cell immune escape to avoid apoptosis, thereby increasing the risk of metastasis (44). Vasileiadis et al. pointed out that patients with DTC with positive TGAB were more likely to have lymph node metastasis, and the results of this study showed that preoperative TGAB had certain predictive value for DTC lymph node metastasis (45). However, there are few studies on preoperative TGAB and DTC, so the value of preoperative TGAB in predicting distant metastasis needs further study. BRAF is the strongest activator of the MAPK signaling pathway, which can regulate cell proliferation, differentiation, and apoptosis. It is composed of 18 exons. BRAF mutation is the missense mutation of exon 15 leading to sequence change at codon 600, which accounts for most mutations, so BRAF V600E mutation is also known as BRAF mutation (46). BRAF mutation can cause the continuous proliferation and differentiation of cells, leading to the occurrence and development of tumors, which is closely related to the invasive biological characteristics of thyroid cancer (thyroid capsule invasion, lymph node metastasis, etc.) (47). However, the predictive value of BRAF V600E mutation remains inconclusive (48). The BRAF V600E mutation will remain important in the preoperative diagnosis of PTC (49). Therefore, whether BRAF V600E mutation can be used as an independent risk factor for lateral neck lymph node metastasis in PTC is still controversial, and further study is needed. To our surprise, BRAF V600E mutation, TSH, and TGAB had no significant difference in our research. Considering the small samples we included and the discrepancies between different studies, a comprehensive evaluation should be performed with other clinicopathological features.

The 2015 ATA showed that cervical lymph node dissection in area VI is not recommended for patients with PTC (clinical stage cN0), while cervical lymph node dissection in area VI is required for patients with clinical stage cN1a, but preventive cervical lymph node dissection is not necessary, and cervical lymph node dissection is required for patients with cN1b. Lymph nodes and adipose tissue in regions II to V were the scope of dissection (6). At present, there is still controversy about whether preventive lymph node dissection should be performed in the central region. Preventive lymph node dissection may reduce the risk of tumor recurrence and the risk of second operation. Chinese experts unanimously recommend preventive dissection of central lymph nodes on the premise of protecting nerve and parathyroid function (50). However, the current domestic and foreign guidelines do not recommend preventive dissection of lateral cervical lymph nodes (6,50). In this study, it was found that when patients developed CLNM, the risk of LLNM was significantly increased. Therefore, patients with CLNM can be regarded as a risk factor for lateral neck lymph node metastasis, and preventive lateral neck lymph node dissection can be performed with sufficient evidence, which requires more studies to provide sufficient data. The process of glucose oxidation can provide energy for cell growth, development, invasion, and metastasis (51). Fasting serum glucose (FSG) can predict lymph node metastasis in patients with PTC, and higher FSG is a risk factor for CLNM and CLNM combined with LLNM (52). Diabetes may be associated with the development of thyroid cancer, and patients with diabetes mellitus (DM) have a higher risk of thyroid cancer, with a 20% increased risk of thyroid papillary cancer relative to non-diabetic patients, and patients with diabetes and elevated fasting blood sugar levels are more likely to develop thyroid papillary cancer (53). Hyperglycemia can promote the production of advanced glycation end products (AGEs), which then proliferate tumor cells and directly or indirectly promote IGF-1R phosphorylation (54,55). Therefore, glucose concentration can also be used as a predictor of lateral neck lymph node metastasis. Due to the lack of research data, glucose concentration was not included in this study, which is the defect of this meta-analysis. The deepening of research data can be further analyzed in the following studies to better predict lateral neck lymph node metastasis and provide better strategies for sweeping surgery.

However, this study has some limitations, such as no new biomarkers were included, high heterogeneity, and geographic bias. For some risk factors, only a small number of studies have been analyzed, such as the meta-analysis between capsular invasion, tumor location, and BRAF V600E mutation. Different studies used different size intervals and data representation methods, and many studies were excluded from the meta-analysis. The included studies were mainly from Asian countries, and there may be differences along ethnic lines.

Conclusions

In conclusion, this study identified several risk factors for lateral neck lymph node metastasis in patients with PTC, which play an important role in its prediction. We found that the following clinicopathological features were significantly correlated with lateral neck lymph node metastasis, such as male, ETE, tumor size >2 cm, multifocality, CLNM, capsular invasion, high tumor location, calcification, and hyperechoic. It is suggested that for suspected metastatic lymph nodes, patients with the above risk factors can consider lateral cervical lymph node puncture or further treatment to reduce the recurrence and distant metastasis of PTC.

In future studies, more samples can be included to reduce the risk of bias. The inclusion of new biomarkers, such as lipid profile studies, protein molecular signatures, molecular biomarkers, and glucose-related factors, can better predict the risk of lymph node metastasis and disease progression.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-60/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-60/prf

Funding: This work was supported by the Regional Project of National Natural Science Foundation of China in 2022 (No. 82260485), the Yunnan Province “Ten Thousand People Plan” Famous Medical Talents Special Project (No. YNWR-MY-2019-030), and the Yunnan Province “Ten Thousand People Plan” Young Top Talent Special Project (No. YNWR-QNBJ-2019-056).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-60/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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