Asynchronous changes of normal lung lobes during respiration based on quantitative computed tomography (CT)

Introduction

The current understanding of pulmonary anatomy is based on gross morphology dissection, while in vivo studies for lung volume (LV), lung strain, and lung ventilation have mainly been restricted to animal models (1,2). In clinical practice, pulmonary function tests (PFTs), such as spirometry and LV tests, are currently used to show the status and function of the whole lung by inhaling and exhaling repeatedly (3-5). However, PFTs cannot provide information at an individual lobar level.

With the fast development of computed tomography (CT) and image post-processing technology, a chest CT scan can now show the overall and partial pulmonary anatomical and morphological information in a non-invasive, rapid, and objective way. In addition to presenting lesions, CT can also be used as an effective way to identify interlobular fissures and establish normal pulmonary vessel diameters (6,7). Studies have also reported on the use of quantitative CT values in patients with chronic obstructive pulmonary disease (COPD) and relapsing polychondritis (8-10). Many studies have found that CT quantitative indexes are correlated with clinical lung function indicators, which could indicate emphysema, air trapping, bronchial wall thickening, or airflow limitation (11-13). Pulmonary dual-energy CT (DECT) angiography can even assess pulmonary perfusion (14).

Furthermore, paired exhalation breath-hold and inhalation breath-hold CT or 4 dimensional (4D) CT scans collected during coached breathing can provide an estimate of lung function at a per-voxel level (15,16). Cumulatively, these features make it possible for chest CT to shift from a routine visual evaluation to a detailed quantitative assessment.

The purpose of our study was to demonstrate that normal CT features, at both the total lung (TL) level and lobar level, combined with quantitative CT indices, can be used to explore the coordination and differences among lung lobes during inspiration and expiration. In doing so, we aimed to deepen the in vivo understanding of pulmonary anatomy and create a baseline for quantitative CT in respiratory disease research and clinical applications.

Methods

Cases

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Institutional Review Board approved the study (No. 0271-01) and waived the requirement for informed consent due to the retrospective nature of the analysis. We retrospectively collected the records of patients who had attended our hospital for health examination from April 2020 to October 2020 by screening in Picture Archiving and Communication Systems (PACS) and Outpatient system. The inclusion criteria were as follows: (I) PFTs results were normal according to Chinese PFTs report specifications issued by the Chinese Medical Doctor Association (17); and (II) there were paired inspiratory-expiratory chest CT scans with normal imaging findings (no abnormal pulmonary parenchymal or airway process was present) as assessed by 2 radiologists (FW and FY with 5 and 27 years of thoracic radiology experience, respectively). The exclusion criteria were as follows: (I) acute and chronic diseases of other organ systems; (II) incomplete inspiration or expiration during the CT scan; and/or (III) the quality of the CT image did not meet the post-processing requirements (e.g., significant motion artifacts, congenital lobar variation).

CT scan

Prior to screening, all cases were trained in breathing and instructed to perform multiple deep inhale-breath-hold and deep exhale-breath-hold cycles by experienced technicians. Then, the cases underwent CT scanning and paired inspiratory-expiratory chest CT scans in the supine position (IQon Spectral CT, Philips Healthcare, Best, The Netherlands). The scanning range was from the apex to the base of the chest, and the scanning direction was head-to-foot. The scanning conditions were as follows: fixed tube voltage of 120 kV; 3D tube current automatic modulation technology; pitch of 0.984; and detector at 64×0.625 mm.

Quantitative image analysis

The CT images in digital imaging communications in medicine (DICOM) format were sent to the Philips IntelliSpace Portal post-processing workstation. Then, 2 radiologists (FY and FW) with 27 and 5 years of experience, respectively, performed the measurements described below using the COPD analysis software. Any disagreements were resolved through discussion to reach a consensus. First, the trachea-bronchial tree was defined and automatically extracted out in the recognition of the respiratory system based on CT images, and then the left lung (LL) and right lung (RL) contours were identified. Second, the 5 lobes [left upper lobe (LUL), left lower lobe (LLL), right upper lobe (RUL), right middle lobe (RML), and right lower lobe (RLL)] were automatically segmented by identifying the interlobular fissures, and manual corrections were performed when inaccurate segmentation was recognized by the software. The flow chart of the post-processing is shown in Figure 1. The following data were then automatically generated for the inspiratory and expiratory phases: the LV (mL) and mean lung density (MLD; HU) of the TL, LL, RL, and the 5 lobes. To better explore the coordination and difference among the lobes in the respiratory process, we calculated some extra parameters according to the following formulae:

ΔLVa=LVin−a−LVex−a[1]

Figure 1 Flow chart of obtaining quantitative CT results by imaging post-processing software. CT, computed tomography; DICOM, digital imaging and communications in medicine; LV, lung volume; MLD, mean lung density.

∆LV represents lung (or lobe) volume change during respiration; a indicates the TL, LL, RL, or one of the 5 lobes; LV_in represents inspiratory lung (or lobe) volume; and LV_ex represents expiratory lung (or lobe) volume.

VVR=ΔLVaΔLVTL[2]

VVR represents the ventilation volume ratio (the ratio of lobar to total LV change); a indicates the LL, RL, or one of the 5 lobes; ΔLV indicates the volume change during respiration; and ΔLV_TL indicates the total LV change during respiration.

ΔMLDa=MLDex−a−MLDin−a[3]

∆MLD represents mean lung (or lobe) density change during respiration; a indicates the TL, LL, RL, or one of the 5 lobes; MLD_ex represents expiratory mean lung (or lobe) density; and MLD_in represents inspiratory mean lung (or lobe) density.

λin−a=LVin−aLVin−TL[4]

λ_in indicates the lobe volume ratio in inspiratory phase; a indicates the LL, RL, or one of the 5 lobes; and LV_in-TL means the inspiratory total LV.

λex−a=LVex−aLVex−TL[5]

λ_ex indicates the lobe volume ratio in expiratory phase; a indicates the LL, RL, or one of the 5 lobes; and LV_ex-TL means the expiratory total LV.

We evaluated interlobar differences in the volume ratio of each lobe compared to the inspiratory or expiratory TL by using the pairwise mean absolute difference (PMAD) on λ_in and λ_ex to calculate the difference between a pair of lobes, averaged among the whole cohort. This was similar to the mean absolute distance (MAD), which measures the average of the absolute signed distance between 2 contours (18-20). The PMAD of the inspiratory or expiratory phase between two lobes was calculated as follows:

PMAD(a1,a2)=1n∑i=1n|λ1,i−λ2,i|[6]

a₁ and a₂ were indicators for the 2 lobes needed to be compared; λ_1,i and λ_2,i were calculated by Eq. [4] or Eq. [5] in the corresponding phase; i referred to the case under study; and n was the sample size. A high value of PMAD indicated a statistically large difference in the volume ratio between the pair, whereas a low PMAD value indicated a similar volume ratio between the pair.

Statistical analysis

Data analysis was performed using SPSS statistics (version 26.0; IBM Corp., Armonk, NY, USA) and GraphPad Prism 9 (GraphPad Software Inc., La Jolla, CA, USA). Analysis of the PMAD in the volume ratio was performed using MATLAB (R2020a; MathWorks, Natick, MA, USA). Continuous variables from the quantitative CT results were expressed as the median and interquartile range (IQR) and were compared between inspiratory and expiratory phases or between bilateral lungs using the Wilcoxon signed-rank test. Pairwise comparisons of LV and MLD between the 5 lobes in inspiration and expiration were performed with the Friedman test in a post hoc analysis. Stepwise multivariable linear regression analysis was used to explore the relationship between baseline demographic data (gender, age, height, and weight, for which gender was assigned as 1, male; 2, female) and the quantitative CT results (LV_ex, MLD_ex, LV_in, and MLD_in), with an entry criterion of P<0.05 and a removal criterion of P>0.10. The P values <0.05 were considered statistically significant. When necessary, Bonferroni correction was used for multiple comparisons.

Results

Study cases

A total of 81 cases with normal PFTs results and paired inspiratory-expiratory chest CT images were retrospectively enrolled. Among them, 7 cases were excluded for poor image quality that could not meet the post-processing requirements, 3 cases were excluded for abnormal chest CT image findings (1 had chronic tuberculosis, 1 had chronic pulmonary inflammation, and 1 had emphysema), and 1 case was excluded because the patient’s costophrenic angle exceeded the scanning range in the inspiratory phase. Finally, 70 cases were included in this study, with a median age of 49.5 (IQR, 38.0 to 60.3) years, including 32 males with a median age of 47 (IQR, 38.3 to 62.0) years, and 38 females with a median age of 51.5 (IQR, 38.0 to 60.3) years. There was no significant difference in the age of males and females included in the study (P=0.911).

Comparison of quantitative indices among lobes in inspiration or expiration

From these 70 cases, for the LV and MLD of the TL as measured in CT, the LV_in-TL was 4,509.19 (IQR, 4,039.79 to 5,593.61) mL, the LV_ex-TL was 2,255.3 (IQR, 1,950.73 to 2,650.96) mL, the MLD_in-TL was −861.8 (IQR, −868.85 to −842.13) HU, and the MLD_ex-TL was −712.6 (IQR, −746.68 to −687.85) HU. The LV and MLD in inspiration or expiration of the bilateral lung and each lobe are shown in Table 1, and the comparisons among lobes are shown in Figure 2. Compared with the inspiratory phase, LV_ex decreased and MLD_ex increased in the bilateral lung and in the 5 lung lobes (all P<0.001).

Figure 2 Volume and MLD of the bilateral lung and 5 lobes during inspiration and expiration. (A) Comparison of the volume of LL and RL in inspiration and expiration. (B) Comparison of the inspiratory volume among the 5 lobes. (C) Comparison of the expiratory volume among 5 lobes. (D) Comparison of the MLD of the LL and RL in inspiration and expiration. (E) Comparison of the inspiratory MLD among the 5 lobes. (F) Comparison of the expiratory MLD among the 5 lobes. LV_in, lung volume in the inspiratory phase; LL, left lung; RL, right lung; LV_ex, lung volume in the expiratory phase; LUL, left upper lobe; LLL, left lower lobe; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; MLD_in, mean lung density in the inspiratory phase; MLD_ex, mean lung density in the expiratory phase; MLD, mean lung density.

Comparing the LL to the RL, LV_in-LL [2,068.99 (IQR, 1,860.2 to 2,620.94) mL] and LV_ex-LL [1,006.86 (IQR, 842.83 to 1,199.42) mL] were both lower than LV_in-RL [2,449.42 (IQR, 2,179.17 to 2,912.08) mL] and LV_ex-RL [1,247.05 (IQR, 1,100.12 to 1,491.47) mL], both P<0.0001, Figure 2A. However, there was no difference in the MLD_in of the bilateral lung [MLD_in-LLvs. MLD_in-RL: −859.8 (IQR, −870.4 to −843.28) HU vs. −861.2 (IQR, −869.85 to −841.65) HU, P=0.1118] while the MLD_ex-LL was higher than MLD_ex-RL [−696.5 (IQR, −739.9 to −668.28) HU vs. −724.85 (IQR, −751.93 to −694.98) HU, P<0.0001, Figure 2D].

Comparing the 5 lobes, the volumes during inspiration or expiration were not all the same among lobes (Figure 2B,2C); however, the MLD of the bilateral upper lobes (LUL and RUL) and the bilateral lower lobes (LLL and RLL) showed no difference in inspiration or expiration (inspiration: P=0.480, P>0.999, respectively; expiration: P>0.999, P=0.975, respectively; Figure 2E,2F). As the smallest lobe in volume, the RML showed no difference in MLD_in compared to the LUL [MLD_in-RMLvs. MLD_in-LUL: −873.15 (IQR, −884.33 to −860.38) HU vs. −867.85 (IQR, −877.88 to −850.48) HU, P=0.081], while the RML demonstrated the lowest MLD_ex [MLD_ex-RML: −789.6 (IQR, −814 to −762.05) HU] among the 5 lobes.

Comparison of quantitative indices among lobes during respiration

For the volume change and MLD change of the TL as measured with CT (Table 1), the ∆LV_TL was 2,305.88 (IQR, 1,979.38 to 2,843.55) mL, and the ∆MLD_TL was 146.25 (IQR, 112.85 to 170.43) HU.

The ratios relative to volume (∆LV, VVR, λ_in, λ_ex, and PMAD) based on LV_in and LV_ex are shown in Table 2, Figures 3,4. From the perspective of the proportion of each part to the TL (λ_in and λ_ex), the end-expiratory proportion of the LL (λ_ex-LL) was 0.44 (IQR, 0.43 to 0.46), while the end-inspiratory ratio (λ_in-LL) had risen to 0.46 (IQR, 0.45 to 0.47; P<0.001). This indicated that the LL played a larger role in ventilation than its own volume ratio would be assumed take to TL during respiration.

Figure 3 Ratios of volume derived by LV_in and LV_ex. (A,B) The ratio of each lobe volume to the total LV in the inspiration (λ_in) and expiration (λ_ex). (C) The VVR, which indicates the ratio of the volume change of each lobe compared with the total LV change. RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe; LL, left lung; RL, right lung; LV_in, inspiratory lung (or lobe) volume; LV_ex, expiratory lung (or lobe) volume; VVR, ventilation volume ratio.

Figure 4 The PMAD of each lobe in the inspiration and expiration. (A) The PMAD value matrix of the inspiratory phase between two lobes (left figure) and the corresponding visualization (right figure). (B) The PMAD value matrix of the expiratory phase between two lobes (left figure) and the corresponding visualization (right figure). The smaller the value, the bluer the color, which represents the smaller the difference between the two lobes. Conversely, the larger the value, the yellower the color, which represents the greater the difference between the two lobes. PMAD, pairwise mean absolute difference; LUL, left upper lobe; LLL, left lower lobe; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe.

As for the 5 lobes, the λ_in-LLL [0.23 (IQR, 0.21 to 0.24)] and λ_in-RLL [0.25 (IQR, 0.24 to 0.27)] were higher than λ_ex-LLL [0.19 (IQR, 0.18 to 0.21)] and λ_ex-RLL [0.22 (IQR, 0.21 to 0.24)], respectively (both P<0.001), while the ratios of the other lobes reduced. This suggested that the bilateral lower lobes were responsible for more ventilation than it should proportionately take. On the other hand, both the PMAD_(LLL-RLL) were low during inspiration (0.0288) and expiration (0.0346), indicating that the volume of the bilateral lower lobe was similar during both phases of respiration.

In addition, results showed larger PMAD values of RML compared to other lobes, indicating that the differences between the RML and other lobes were much larger than the differences in other pairs in both inspiration and expiration (Figure 4, in which the color bar indicates the PMAD for each pair). The multivariable linear regression analysis of the baseline demographic factors (gender, age, height, and weight) that related to the LV_in and MLD_in of each lobe showed that weight was only related to LV_in-RML and gender was only related to MLD_in-RML (Table 3).

Discussion

This study involved anatomical research to quantitatively describe the respiratory status of healthy lungs in vivo. Previous studies about quantitative CT on healthy participants have focused on the relationship between quantitative indices of different CT threshold ranges and clinical pulmonary function indicators, or explored the differences between different groups (e.g., gender, smoking history) (21-25). Our study used the quantitative values derived by chest CT to demonstrate the baseline CT characteristics from the TL to lobar level in inspiration and expiration of healthy people, and to further explore the coordination and difference in inspiration-expiration cycles both for the TL and for each of the 5 lobes.

From the perspective of the TL, the LV_in-TL was measured at 4,509.19 (IQR, 4,039.79 to 5,593.61) mL, which was close to the 4,423 (IQR, 3,614 to 5,294) mL obtained using quantitative CT in the Chinese normal LV reported by Cheng et al. (26). The ΔLV was 2,305.88 (IQR, 1,979.38 to 2,843.55) mL, which was lower than the normal forced vital capacity (FVC; the maximal volume of air exhaled with maximally forced effort from a maximal inspiration) of the Chinese clinical PFTs value reported by the China Pulmonary Health Study Group (mean male FVC: 4,300 mL; mean female FVC: 3,000 mL) (4,27). We speculated that this observation might be due to the following reasons: (I) FVC and the CT measurements in our study scope involved different breathing patterns. The FVC requires repetitive maximal inspiration to the total lung capacity (TLC) level, followed by fast and complete exhalation to the end of test (4). In comparison, the paired inspiratory-expiratory chest CT scan only acquires the normal deep-breathing pattern. (II) The examination position is different. FVC is measured in the seated position, while the CT scan is conducted in the supine position. Mendes et al. (28) reported that the LV in the seated position was greater than that in the supine position.

Comparing between the bilateral lungs, both the inspiratory and expiratory volume of the LL were smaller than that of the RL, which may be due to the location of the heart in the left thorax. The change in lobar volume to the total LV ratio in pre- and post-breath (λ_in and λ_ex) can be used to observe the ventilation workload of different pulmonary parts. The median ratio of the LL volume to the total LV in the expiratory phase (λ_ex-LL) was 0.44. If the bilateral lung shared the same ventilation work according to the proportion of the volume, the ratio at end-inspiration (λ_in-LL) should also be 0.44, but the actual ratio had increased to 0.46 (P<0.001). This indicated that the LL had completed more ventilation work than its proportionate share during respiration. Furthermore, we also corroborated this finding from the MLD results (Figure 2D), in which the density of any volume of the lung may be considered a combination of “air” and “pulmonary tissue” (29). Therefore, the volume change caused by lung expansion and contraction during the breathing process will cause changes in the composition ratio of these 2 compartments, which is also shown in the MLD value. Compared with the RL, the MLD_ex-LL was higher than MLD_ex-RL, but there was no difference between MLD_in-LL and MLD_in-RL at the end of inspiration when air was inhaled (the air presented as very low density on the CT image). All of the above indicated that the LL had a higher workload during breathing despite its smaller volume. The clinical implication of this is that it may be beneficial to reduce the radiation doses given to the LL during function avoidance radiation therapy, as it has been shown that high-functioning tissues are more susceptible to radiation damage than low-functioning tissues (30,31).

The inspiratory and expiratory LV and MLD of the 5 lobes were not all the same, but we found that bilateral lower lobes were consistent in some respects. First, there were no significant differences between MLD_in-LLL and MLD_in-RLL (P>0.999), and between MLD_ex-LLL and MLD_ex-RLL (P=0.975). This could be explained by the naturally similar structures in blood distribution or lung tissue composition between the bilateral lower lobes since the MLD is related to gas content, gravity factors, blood distribution, and lung parenchymal proportion (32,33). Second, the PMAD of these 2 lobes was low during inspiration and expiration, indicating the volumetric similarity of the bilateral lower lobes. In addition, from findings regarding ventilation workload during respiration, we verified that the bilateral lower lobes undertake more ventilation work than their respective volume ratio during respiration. This was shown in the λ_in of both lower lobes, which had risen when compared with λ_ex (Figure 3). The consistency of bilateral lower lobes can also be explained by the anatomical structure of the lung, which is conical in shape with a narrow apex and a broad base, and the diaphragm and abdominal muscles mainly contribute to the breathing process (34). Furthermore, combined with the structure of the tracheobronchial tree, the air can be taken into and out of bilateral lower lobes more favorably under the abovementioned comprehensive conditions. This suggests that, when patients need to undergo a lobectomy or volume reduction therapy, more caution should be taken when the lesion is located in the lower lobes. Accordingly, segmentectomy or volume reduction may be used as alternative methods following consideration of whether the reduced pulmonary ventilation function will impact on the patient’s quality of life.

For the lobar data analysis, we also found differences between the RML and the other lobes. The inspiratory and expiratory MLD of the RML were lower when compared with other lobes [MLD_in-RML: −873.15 (IQR, −884.33 to −860.38) HU, MLD_ex-RML: −789.6 (IQR, −814 to −762.05) HU], but these values did not reach the upper limit of emphysema (−950 HU for emphysema in inspiratory CT) and air trapping (−856 HU for air trapping in expiratory CT) (35). Mets et al. (23) also found this manifestation in healthy young men, indicating that the relatively low MLD (air-trapping-like change) of the RML is normal in the CT scan. The PMAD measurements showed that the RML had a larger difference in the volume ratio to other lobes than the differences between other lobes. Furthermore, we calculated the ΔLV ratio and ΔMLD ratio of each lobe relative to its own inspiratory volume or MLD (γ_LV and γ_MLD; Table 4). The γ_LV and γ_MLD of the RML was also the lowest among the 5 lobes [γ_LV-RML: 0.36 (IQR, 0.28 to 0.44); γ_MLD-RML: 0.09 (IQR, 0.07 to 0.12)], indicating that the RML experienced the least change during a respiration cycle. We speculate that this might be related to the anatomy of the RML, where the right main stem bronchus has a vertical orientation with the lower trachea, and the direction of the lower bronchus is the continuation of the right main bronchus. In addition, the contraction of the airway prevents the dispersion of airflow to maintain its axial direction momentum during respiration analyzed from the perspective of fluid dynamics (36,37), hence smaller volume change ratio of RML, which was reflected by less change of the MLD. Through stepwise multivariable regression analysis, we found that factors such as height, gender, and age affected the inspiratory volume of each pulmonary part to varying degrees. Weight was the only factor related to volume of the RML which was distinguished from other lobes. The MLD_in-RML was only related to gender, while other lobes were mostly related to age. These findings demonstrated that the RML has special characteristics worthy of further investigation.

Previous studies have established the normal and abnormal LV and MLD range of the cohort at the TL level, and differences were identified between different races (21,24,26). Since focal lesions may be overlooked when the lung function is evaluated at the TL level, the relationships between demographic data, LV, and MLD that we established could provide references for the normal values of LV_in and MLD_in in each lobe. Our study showed that age was a more important factor than other demographic information (gender, height, and weight) on MLD both at the TL and lobar level. This conflicts with observations in previous studies on lung density and age, which showed that the alveolar number growth ceases between 2 and 8 years of age, suggesting that an increase in age would not affect the MLD of normal lung parenchyma (32,38-41). However, Kalef-Ezra et al. (33) indicated that MLD decreases with age in men, while no age dependence was found in women. The reason for this difference may be related to the race, sample size, or CT imaging and reconstruction parameters. Further investigation was performed via multivariable regression analysis on expiratory LV and MLD (Table 5). For MLD, age was the main influencing factor whenever MLD_ex was fitted to MLD_in or vice versa, so the relationship between age and MLD is worth revisiting.

The limitations of this study were as follows: (I) an assumption of this study was that all lobes reach their maximum volume at the end of the inspiration phase and reach their minimum volume at the end of the expiration phase; however, some local regions may reach extreme volumes at different respiratory points, for example, the RUL reached its maximum volume at 80% of the inspiratory phase and its minimum volume at 20% expiratory phase (16). This limitation could be overcome if the 4DCT scans that track volumetric change of the entire breathing cycle are used for future analysis. (II) The evaluation of PFTs is affected by gender and age, but these cases were not grouped based on gender and age in our study due to the relatively small sample size. (III) This study only provided CT measurements of Chinese adults, but there are differences reported in lung capacity among people of different races (24,42). Conversely, the differences and synergies among the lobes during respiration may be similar across different races. (IV) We were also not able to collect information about the smoking history of all the cases, while smoking may cause MLD to increase (43).

Conclusions

The LL undertakes a higher ventilation workload than its proportionate share. The 5 lung lobes were non-synchronous in breathing, but the bilateral lower lobes showed similarities and carried a high-ventilation function, while the volume and MLD of the RML had the least changes within a respiration cycle. This information could help to deepen the understanding of lung anatomy and provide baseline data for quantitative chest CT to be used in research and clinical practice related to different respiratory diseases.

Acknowledgments

Funding: This study was supported by Key Research and Development Projects of Hubei Province (2020BAB022); the Huazhong University of Science and Technology COVID-19 Rapid Response Call (2020kfyXGYJ021) and National foundation of Science in China (11701201, 11871061 to CL; 11871262 to YZ).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/qims-21-348). JW was employed by Philips Healthcare. The other 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Institutional Review Board approved the study (No. 0271-01) and waived the informed consent for this retrospective analysis.

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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