ABSTRACT
Background
Microcirculatory endothelial dysfunction is a complex phenomenon that contributes to the development of cardiovascular disease. However, the relationship between microcirculatory endothelial dysfunction and macrovascular disease remains incompletely understood. Fluid overload is a risk factor for cardiovascular mortality in patients undergoing peritoneal dialysis. Therefore, we investigated the effects of chronic fluid overload on both the microcirculation and macrocirculation in these patients.
Methods
Thirty patients undergoing peritoneal dialysis were included in this cross-sectional study. We measured their central blood pressure and pulse wave velocity, assessed their microvascular endothelial function using drug-induced iontophoresis with laser Doppler flowmetry, and determined the amount of fluid overload using bioimpedance. We conducted a Spearman correlation analysis, univariate analysis, and stepwise multivariate regression models to determine the associations among the hemodynamic parameters.
Results
Acetylcholine-induced iontophoresis with laser Doppler flowmetry showed a correlation with both brachial and central pulse pressure (PP), but not with pulse wave velocity. Fluid overload was associated with both central and brachial PP and remained an independent predictor of central PP even after adjusting for multiple factors. However, fluid overload was not associated with microcirculatory endothelial function.
Conclusion
In peritoneal dialysis patients, we observed a significant association between central PP and microvascular endothelial function, indicating a connection between macrocirculation and microcirculation. However, conclusive evidence regarding fluid overload as a mediator between these circulatory systems is lacking. Further research is needed to investigate this relationship.
Introduction
Microcirculatory endothelial dysfunction is a complex phenomenon that contributes to cardiovascular disease and is the leading cause of death in patients with chronic kidney disease (CKD) (Citation1). However, the association between microcirculatory endothelial dysfunction and macrovascular diseases such as coronary artery disease, stroke, and peripheral artery disease remains unclear. The macrovasculature contains large elastic arteries that sustain the heightened pulsatility resulting from intermittent left ventricular contractions as well as numerous muscular arteries that ensure a constant blood supply to the microvasculature (Citation2).
Central pressure has emerged as a stronger predictor of future cardiovascular events than brachial pressure (Citation3). One study showed that central pressure remained predictive of cardiovascular outcomes in patients with end-stage renal disease after adjusting for confounders (Citation4). Additionally, high central pulse pressure (PP) has been found to be associated with cardiovascular disease in patients with peritoneal dialysis (Citation5).
Fluid overload is highly prevalent among patients undergoing peritoneal dialysis (Citation6), especially following the loss of residual renal function (Citation7). Fluid overload is attributed to the pathogenesis of hypertension and left ventricular hypertrophy (Citation8), both of which are established risk factors for cardiovascular mortality (Citation9,Citation10).
Therefore, we investigated the effects of chronic fluid overload on both the microcirculation and macrocirculation by measuring the central PP and pulse wave velocity (PWV) and performing cutaneous iontophoresis with laser Doppler flowmetry (LDF).
Patients and methods
Patients and study design
This single-center cross-sectional study was conducted at the Nephrology Department of the Dialysis Center of Ewha Womans University Mok-Dong Hospital in Korea from February 2019 to April 2020. The study involved 30 monitored patients aged 18 to 65 years who had been undergoing continuous ambulatory peritoneal dialysis for at least 3 months. They were medically stable and had no acute illness, significant infections, inflammation, or malignancies. Due to their anuric status (<100 mL/day urine output), urinary contributions were excluded, and the total Kt/V was determined by peritoneal Kt/V (Citation11).
Each patient’s enrollment information and medical history were collected from the medical records. The only exclusion criterion was a history of renal transplantation or maintenance of hemodialysis for >3 months prior to the study (). The study protocol was approved by the hospital’s ethics committee (IRB no. ECT13–44A–01), and written informed consent was obtained from all patients prior to their involvement. All clinical investigations were conducted in accordance with the 2013 Declaration of Helsinki.
Figure 1. Flow diagram of patient enrollment.
Study objectives
The primary objective of this study was to evaluate the association between microvascular endothelial dysfunction and macrovascular hemodynamics in patients undergoing peritoneal dialysis, utilizing microvascular iontophoresis with laser Doppler flowmetry (LDF) and central PP measurements. Secondary objectives included investigating the relationship between fluid overload and both macrovascular hemodynamics and microvascular endothelial dysfunction. Furthermore, we aimed to explore whether fluid overload might act as a mediator in the interplay between the microcirculatory and macrocirculatory systems. This study was conducted to provide insights into the interplay between macrocirculation and microcirculation in patients undergoing peritoneal dialysis, with a focus on the potential impact of fluid overload on these circulatory systems.
Measurement of central blood pressure and PWV
Central blood pressure and PWV were measured in a quiet, calm room with the temperature controlled at 22°C. The patients were instructed to refrain from consuming food, drugs, tobacco, alcohol, coffee, or tea for 8 hours prior to the test. They also underwent a 20-minute acclimation period in the supine position before the vascular studies. A trained physician performed both vascular measurements, thus ensuring consistency. To minimize any potential effects on subsequent measurements, the patients were given a 20-minute rest period between the vascular studies.
Central blood pressure and PWV were measured using SphygmoCor XCEL hardware and software (ATCOR Medical, Sydney, Australia). Data below 80% were excluded from the validated dataset based on the operator’s index, which estimates the quality of the SphygmoCor-derived waveforms. Central blood pressure measurement was based on the tonometer-recorded radial pulse waveform and brachial blood pressure. Sequential waveforms were obtained from the radial artery, and a validated algorithm and specialized software were used to visualize the average peripheral and central arterial waveforms in real time. The presented parameters included the estimated central (aortic) systolic pressure and diastolic pressure; the central PP, calculated as the difference between the central systolic blood pressure and diastolic blood pressure; and the augmentation index.
PWV was also determined by obtaining noninvasive simultaneous carotid and femoral pressure waveforms using applanation tonometry with the SphygmoCor XCEL device. The carotid pulse was measured using a tonometer, and the femoral pulse was measured using volumetric displacement within a cuff placed around the thigh. For both devices, the transit time was measured as the time between the diastolic feet of the carotid and femoral pulses. The distance was measured as the linear distance from the suprasternal notch to the top of the thigh cuff at the centerline of the femoral artery minus the linear distance from the palpation site of the carotid pulse to the suprasternal notch. To account for operator-measured distance, a built-in algorithm was used to reduce the overall distance by the distance from the site at which the femoral pulse could be felt to the top of the cuff.
Iontophoresis with LDF
Iontophoresis employs electrically repulsive forces to deliver a locally applied drug across the skin for therapeutic and diagnostic purposes. It is a noninvasive and effective tool for determining endothelial dysfunction (Citation12). LDF measures cutaneous blood perfusion using the principle of the Doppler shift for lasers. It provides a linear relationship between the measured signals and the velocity of red blood cells (Citation13).
During the 20-minute acclimation period, the patients were seated comfortably in a temperature-controlled room at 22°C. The skin on the forearm was cleaned using alcohol-soaked cotton. Two drug-delivery chamber electrodes (PF 383; Perimed, Järfälla, Sweden) were used to contain and deliver acetylcholine (Ach) and sodium nitroprusside (SNP) onto the skin. Electric pads were employed to facilitate drug delivery through the skin. The paired Ach-containing chamber and electric pads were attached to the volar aspect side by side, with a 10-cm distance from the paired SNP chamber and electric pad. Subsequently, 0.05 mL of a 1% solution of Ach and SNP were dropped into their respective drug chambers to measure endothelial-dependent and -independent responses (Citation14). The laser Doppler probe connected to the LDF system (PF 408; Perimed) was fixed within the drug chamber to explore the same small area of the skin. The laser Doppler outputs were simultaneously recorded using a computer equipped with acquisition software and measured in arbitrary units known as perfusion units (PU). After recording the baseline perfusion for 5 minutes, dose – response curves to Ach and SNP were obtained with stepwise current applications (Citation15). Ach was delivered in six doses (0.1 mA for 20 seconds each), followed by two additional doses (0.2 mA for 20 seconds each) with a 180-second interval between the two. The absolute maximal response was defined as the flow rate reached after the last drug delivery. To eliminate baseline variability, the blood flow responses to locally delivered Ach and SNP were expressed as ratios of response PU to baseline PU. While there isn’t an established objective reference specifically for defining endothelial dysfunction assessed by iontophoresis in CKD, referring to previous studies, a ratio of < 100 was considered as indicating endothelial dysfunction (Citation16,Citation17).
Measurement of fluid overload
The volume status was assessed using a bioimpedance spectroscopy device (Body Composition Monitor [BCM]; Fresenius Medical Care, Bad Homburg, Germany). The BCM performs impedance spectroscopy measurements at 50 frequencies ranging from 5 kHz to 1 MHz (Citation18). It has undergone extensive validation against all available previously validated gold standard methods (Citation19).
In accordance with a standardized protocol, electrodes were affixed onto the back of the hand and ipsilateral top of the foot after the patient had rested in the supine position for at least 5 minutes. Prior to the measurement, the peritoneal dialyzate was sufficiently drained out to avoid any miscalculations, although bioimpedance spectroscopy does not measure fluid sequestered in the trunk (Citation20,Citation21). For the analysis, we used the patient’s weight adjusted for an empty abdomen. The reproducibility of BCM-derived parameters is high, with an approximately 1.2% coefficient of variation for the interobserver variability of extracellular water (ECW) and total body water (TBW) in studies involving patients undergoing hemodialysis (Citation22). Consequently, each individual patient underwent only one BCM measurement performed by the same physician. The overhydration (OH) value was calculated from the difference between the patient’s actual ECW and expected ECW under normal physiological conditions (Citation23).
Statistical analyses
All data are presented as mean ± standard deviation. Spearman’s correlation rho was employed to determine correlations between the values obtained from hemodynamic measurements, which were assessed for normality. Univariate regression analyses were conducted to examine the factors associated with the macrocirculation, such as central PP, brachial PP, and PWV.
After confirming the absence of multicollinearity among the variables, stepwise multivariate regression analysis was performed to identify predictors for the macrocirculation using variables that showed significant correlations with changes in the macrocirculation in the univariate analysis. All statistical tests were two-sided, and p < .05 was considered statistically significant. All calculations were performed using SPSS 18.0 (SPSS Inc., Chicago, IL, USA).
Results
The patients’ baseline and hemodynamic characteristics are shown in . The causes of end-stage renal disease were diabetes mellitus in 8 patients, hypertension in 10, glomerulonephritis in 5, and unknown in 7. At the time of the study, all patients were prescribed antihypertensive medication, and two patients were also prescribed medication for diabetes mellitus.
Table 1. Baseline characteristics and vascular assessments.
Relationships between brachial and central blood pressure and ach-induced iontophoresis
The relationships between brachial and central blood pressure and the Ach- and SNP-dependent responses are depicted in . No correlation was observed between brachial and central systolic or diastolic blood pressure with Ach- and SNP-induced iontophoresis. However, both brachial PP and central PP showed significant correlations with Ach-induced iontophoresis (brachial PP: r = −0.396, p = .030; central PP: r = −0.398, p = .029). No significant correlation was observed with SNP-induced iontophoresis.
Figure 2. The relationships between brachial blood pressure and Ach-, SNP-induced iontophoresis with laser Doppler flowmetry.
Figure 3. The relationships between central blood pressure and Ach-, SNP-induced iontophoresis with laser Doppler flowmetry.
Factors associated with Ach-induced iontophoresis, PP, and PWV
A univariate regression analysis was conducted to examine the factors related to the assessment of both microvascular and macrovascular function (). Age, male sex, and diabetes mellitus showed significant associations with PWV. The serum calcium level was associated with both central PP (β = 5.33; 95% confidence interval [CI], 0.37–10.28; p = .036) and brachial PP (β = 6.35; 95% CI, 0.64–12.05; p = .031). The serum phosphorus level was associated with brachial PP (β = −4.73; 95% CI, −8.72 to − 0.75; p = .021). The serum albumin level was associated with both central PP (β = −10.78; 95% CI, −21.47 to − 0.09; p = .048) and PWV (β = −3.02; 95% CI, −5.33 to − 0.72; p = .012). A 1-L increase in fluid overload showed significant associations with central PP (β = 3.64; 95% CI, 1.23–6.05; p = .004), brachial PP (β = 4.90; 95% CI, 2.28–7.51; p = .001), and PWV (β = 1.02; 95% CI, 0.54–1.51; p < .001). The use of beta blockers was associated with central PP (β = 10.31; 95% CI, 1.64–18.99; p = .022) and brachial PP (β = 12.71; 95% CI, 2.81–22.60; p = .014). Ach-induced iontophoresis showed no significant association with any factors, including fluid overload.
Table 2. Associations of variables with Ach-induced iontophoresis, central pulse pressure, brachial pulse pressure, and pulse wave velocity.
Fluid overload as a predictor of central and brachial PP
Multivariate regression models were employed to assess whether fluid overload could serve as an independent predictor of central PP and brachial PP. The results of the associations between fluid overload and both central PP and brachial PP are presented in . Fluid overload remained a significant predictor of both central and brachial PP even after adjusting for multiple factors, including age; sex; diabetes; and serum concentrations of calcium, phosphorus, and albumin. Additionally, when we included the use of antihypertensive medications (such as angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, calcium-channel blockers, and β-blockers) as confounding variables in addition to the previously analyzed model (model 3), fluid overload remained an independent predictor of central PP (r2 = 0.65, β = 3.77, p = .036). However, the association between brachial PP and fluid overload lost statistical significance after further adjustment for the same confounders (model 3).
Table 3. Multivariate regression models of fluid overload as a predictor of central pulse pressure and brachial pulse pressure.
Microvascular endothelial function and fluid overload
The relationship between microvascular endothelial function and fluid overload was evaluated (). Both the Ach- and SNP-induced ratios of response to baseline from iontophoresis with LDF showed no significant correlation with fluid overload.
Figure 4. The relationships between Ach-, SNP-induced iontophoresis with LDF and fluid overload.
Microvascular endothelial function, fluid overload, and large vessel stiffness
PWV showed no association with either Ach- or SNP-induced iontophoresis (Supplementary Figure S1). After adjusting for age, male sex, and diabetes, we found that fluid overload was a significant predictor of PWV. However, with further adjustments, the association between fluid overload and PWV lost its significance (Supplementary Table S1).
Discussion
The macrocirculation and microcirculation exhibit marked physiological differences. The macrocirculation is characterized by pulsatile pressure and flow, while the microcirculation is characterized by steady pressure and flow. The aortic function serves as a temporal buffer during the ejection period of the cardiac cycle, effectively reducing cardiac afterload. Pulsatility gradually diminishes from the thoracic aorta to the end of the arterioles. In contrast to the macrovasculature, such as the central aorta and brachial artery, the microcirculation contributes to peripheral vascular resistance and represents a segment of the vascular tree in which pulsations are nearly absent. The microcirculation encompasses arterioles, capillaries, and venules with a diameter of <150 µm. Extensive studies have explored the pathophysiology of both the microcirculation and macrocirculation in hypertension. It has been proposed that these distinct vasculatures are tightly interconnected, particularly during primary hypertension (Citation24). However, few studies have elucidated the relationship between endothelial dysfunction and macrovascular assessment, especially in patients undergoing peritoneal dialysis. To the best of our knowledge, the present study is the first to demonstrate the quantitative relationship between the macrocirculation and microcirculation and to investigate whether fluid overload facilitates cross talk between the macrocirculation and microcirculation in patients undergoing peritoneal dialysis.
To explore these distinct circulatory systems, we performed central aortic blood pressure measurement and drug-induced iontophoresis with LDF. Central aortic systolic pressure has been suggested to be a relevant predictor of cardiovascular disease because the left ventricle encounters the aortic systolic pressure during systole; by contrast, the aortic pressure during diastole is a determinant of coronary perfusion. A previous study demonstrated that central PP was more useful than brachial PP in predicting progressive kidney function loss and incident cardiovascular disease in patients with CKD who were not undergoing dialysis (Citation25). Another study showed that high PP, indicative of macrocirculatory disorder, was associated with elevated risks of cardiovascular events, all-cause mortality, and cardiovascular death in patients undergoing peritoneal dialysis (Citation26). These studies imply that assessment of central blood pressure is more appropriate than other hemodynamic assessment tools for prediction of cardiovascular outcomes, particularly in patients undergoing dialysis who have risk factors for cardiovascular disease.
Iontophoresis with LDF is a validated noninvasive method to assess microvascular endothelial function (Citation27). This technique involves the transdermal delivery of selective endothelium-dependent vasodilators, such as Acetylcholine (Ach), as employed in our study. Ach-induced vasodilation relies on the presence of an intact vascular endothelium, whereas Sodium Nitroprusside (SNP) directly affects vascular smooth muscle cells; these processes are recognized as endothelium-dependent and -independent vasodilation, respectively. Specifically, Ach-induced vasodilation is mediated by the release of nitric oxide, prostaglandins, and endothelial-derived hyperpolarizing factors. Consequently, endothelial dysfunction can be assessed by comparing the vasodilation induced by Ach and SNP. In our study, both the ratio of response to Ach- and SNP-induced iontophoresis satisfied the criteria for defining endothelial dysfunction, characterized as a ratio of less than 100. Notably, the response to SNP-induced iontophoresis with LDF did not correlate with any macrocirculatory assessments (, 3). In contrast, Ach-induced iontophoresis with LDF exhibited associations with both brachial and central PP. These findings suggest that hemodynamic macrocirculation may be linked to endothelium-dependent vasodilation rather than endothelium-independent vasodilation.
Microvascular endothelial function as assessed by LDF was found to be inversely proportional to both central and brachial PP (). The presence of higher PP with more severe endothelial dysfunction suggests an interconnection between the microcirculation and macrocirculation, indicating that these two components are not separate systems but instead influence each other within the single circulatory system. Several studies have demonstrated that the microcirculation and macrocirculation are interconnected as a unified system rather than discrete organs. One expert proposed a mechanism of connection between these two vasculatures based on the pathophysiology of primary hypertension. This mechanism highlighted the detrimental cross talk between the microcirculation and macrocirculation, exemplified by the vicious circle of small and large artery damage (Citation28). In primary hypertension, small artery damage includes functional and structural abnormalities that lead to increases in total peripheral resistance and mean blood pressure. This causes stiffening of large arteries, resulting in elevated central systolic blood pressure and PP. The cycle perpetuates through wave reflection and transmission of high blood pressure, leading to further increases in total peripheral resistance and mean blood pressure. Another research group investigated the relationship between impaired retinal microcirculation and macrocirculation using noninvasive scanning LDF and assessment of central PP, respectively (Citation29). Their study demonstrated a correlation between the degree of arteriolar remodeling, expressed by the wall-to-lumen ratio of retinal arterioles, and central PP. It also revealed an independent relationship between the wall-to-lumen ratio of retinal arterioles and central PP. Notably, these studies focused on patients with essential hypertension or normal renal function, distinguishing them from our study, which specifically involved patients undergoing peritoneal dialysis. Because CKD is a well-known cause of endothelial dysfunction, and because patients with CKD develop macrovascular diseases such as coronary artery disease, stroke, and peripheral vascular disease rather than microvascular disorders in clinical practice, understanding the interplay between the macrocirculation and microcirculation should be emphasized.
Our study also revealed an independent association between PP and fluid overload. Specifically, fluid overload remained an independent predictor of central PP, even after advanced adjustment for multiple factors (). Although peritoneal dialysis is believed to provide effective fluid control because of continuous ultrafiltration and the fact that residual renal function is better maintained, fluid overload is a quite common problem in patients undergoing peritoneal dialysis (Citation30). Fluid overload leads to adverse clinical outcomes such as hypertension (Citation31), cardiovascular disease, and cardiovascular mortality (Citation32) in patients undergoing peritoneal dialysis. Moreover, one study showed that fluid overload was associated with arterial stiffness in patients undergoing peritoneal dialysis as determined by PWV and the extracellular fluid status using calf bioimpedance spectroscopy (Citation33). These results might be attributed to fluid overload-induced vascular stretch and shear stress in large vessels, leading to increased preload (Citation34). In our study, cardiac afterload (represented by central PP) was independently associated with fluid overload, providing more insight into the relationship between the macrocirculation and fluid overload as well as increased preload.
Several studies have investigated the relationship between microendothelial dysfunction and fluid overload. One study of patients undergoing hemodialysis demonstrated a significant association of extracellular OH (represented by OH/ECW, ECW/TBW, or both) with endothelial and microinflammatory biomarkers such as vascular cell adhesion molecule-1, interleukin-6, and thrombomodulin, although the study showed no correlation with the macrocirculation as quantified by PWV and OH (Citation35). Because it is generally believed that OH promotes vascular injury and endothelial dysfunction, the authors considered that ECW expansion across the vascular and interstitial compartments is more clearly elicited at the microvascular level. Based on these findings, we expected that the microcirculation would be associated with the macrocirculation via fluid overload. However, Ach-induced iontophoresis with LDF was not correlated with fluid overload. We measured the absolute amount of OH (calculated as the difference between the expected ECW under normal physiological conditions and the actual ECW) rather than OH/ECW or ECW/TBW. One possible explanation for this discrepancy between our study and the above-mentioned study could be the use of different parameters to reflect the fluid status, as well as imperfections in postulating individual fluid states. Furthermore, we investigated the direct relationship between OH and quantified microcirculatory function rather than the relationship between oxidative stress, inflammation, and quantified microcirculation function. The other research group demonstrated that flow-mediated dilation of the brachial artery, which is a conduit artery, was negatively correlated with ECW as measured by bioimpedance analysis; they therefore concluded that fluid overload was related to worse brachial endothelial function in patients undergoing peritoneal dialysis (Citation36). Although flow-mediated dilation represents endothelial function, the previous study focused on the brachial artery; by contrast, skin microcirculation was investigated in the present study. Finally, fluid overload is present mostly in the extracellular non-circulating compartment (Citation37). A conduit artery is inevitably affected by volume; however, water stays in the extravascular compartment toward the periphery, and the shear stress or vascular stretching in response to the flow volume may be less than in other types of vessels.
PWV, a surrogate marker of aortic stiffness, has shown prognostic value in predicting cardiovascular mortality in patients with end-stage renal disease (Citation38). A Chinese study involving patients undergoing peritoneal dialysis showed a significant association between OH, high blood pressure, and arterial stiffness as assessed by carotid – femoral PWV (Citation39). Another study showed that fluid overload, as assessed by bioimpedance and the responsiveness of blood vessels in the calf muscle (calf normalized sensitivity), was correlated with PWV and served as an independent predictor of carotid – femoral PWV (Citation33). These findings are concordant with our study results, indicating an association between fluid overload and PWV. However, despite a significant association between central PP and Ach-induced iontophoresis with LDF, PWV did not show a correlation with microcirculatory endothelial function. This lack of association may be attributed to the complex mechanisms of arterial stiffness in CKD. Factors such as age, vascular calcification associated with CKD-Mineral and bone disorder, exogenous calcium load, dialyzate calcium, volume status, and dialysis modality could contribute to PWV progression (Citation40). Additionally, the individual administration of multiple medications aimed at managing hyperglycemia, high blood pressure, and/or dyslipidemia might explain the lack of relevance between PWV and microcirculatory endothelial function. These medications could potentially ameliorate the severity of both micro- and macro-endothelial dysfunction (Citation41–43). Further evidence is required to substantiate this claim. Nonetheless, these results imply that the connection between the macrovasculature affected by fluid overload and the microvasculature unaffected by fluid overload in patients undergoing peritoneal dialysis is a complex relationship that extends beyond fluid overload.
This study had several limitations. First, the small number of patients and the cross-sectional and descriptive nature of this study limited our ability to infer a causal relationship between fluid overload and endothelial dysfunction. Second, although several potential confounding factors such as sex; age; diabetes mellitus; serum calcium, phosphorus, and albumin concentrations; and antihypertensive medications were controlled in the multiple regression analysis, unrecognized confounding variables may exist. Third, we obtained the estimated OH values measured in liters using the BCM device. The accuracy of this estimation depends on the physiological hydration properties of body tissues, which are believed to be unaffected by the population being measured. These properties were determined through dilution methods. Importantly, the clinical significance of the same amount of OH can vary depending on the patient’s body size. For instance, 2 L of OH may have greater clinical significance in a small woman than in a large man with more muscle mass. Therefore, future studies should normalize the OH value to OH/ECW, and further validated measurements are needed to assess the fluid status in prospective studies.
Conclusion
Our study demonstrated a significant association between central PP and microvascular endothelial function, suggesting a connection between macrocirculation and microcirculation. However, conclusive evidence supporting overhydration as a mediator between these circulatory systems, particularly in peritoneal dialysis patients, remains elusive. Further study is warranted to explore this interplay between macrocirculation and microcirculation.
Authors’ contributions
S.Y.K, S.J.K and S.L. contributed to the conception or design of the work. S.Y.K., S.J.K and S.L contributed to the acquisition, analysis, or interpretation of data for the work. S.L. drafted the manuscript. S.J.K. critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.
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Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/10641963.2023.2267192.
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