Abstract
Objectives
This study aimed to examine the effects of chronic periodontitis and essential hypertension on serum and salivary cartonectin (CTRP3) and procalcitonin (ProCT) levels.
Methods
Sixty non-smokers were seperated into four groups as; 15 people with essential hypertension (EH) and chronic periodontitis (CP) (HT+ CP+), 15 with EH (HT+ CP−), 15 with CP (HT− CP+), 15 control (HT− CP−). PPD, CAL, PI and GI were measured. All groups had their serum and saliva samples collected. Serum and saliva procalcitonin (ProCT) were measured using an electroluminescence method, and cartonectin (CTRP3) levels were determined by enzyme-linked immunosorbent assay.
Results
When compared to the control group, serum and saliva cartonectin (CTRP3) levels were considerably lower in all groups (respectively p<0.0001, p<0.0001). The serum cartonectin (CTRP3) levels were substantially higher in the HT− CP+ group than in the HT+ CP− group (p=0.002). Serum procalcitonin (ProCT) concentrations were found to be lowest in the HT− CP− group and highest in the HT+ CP+ group. Serum ProCT concentrations did not vary significantly across groups (p=0.110). Salivary procalcitonin (ProCT) levels were below the detection limit in all groups.
Conclusions
When periodontitis coexist with hypertension in individuals, they may have adversely affect each other due to the same sathways in the pathogenesis of these two disorders. So we can suggest that, serum and saliva cartonectin (CTRP3) may play a role during hypertension and periodontal inflammation and represent a novel future therapeutic target.
Introduction
Periodontitis is an inflammatory disease characterized by bleeding, pain, and increased gingival sulcus fluid with loss of periodontal attachment and alveolar bone [1, 2]. The chronic inflammation in periodontitis and the host response ensure the basis for the association between cardiovascular disease (CVD) and periodontitis. The main underlying pathology in CVD is atherosclerosis caused by endothelial dysfunction [3]. Periodontitis initiates chronic endothelial inflammation using inflammatory markers. A link among periodontitis, endothelial dysfunction, atherosclerosis and hypertension may occur through the systemic inflammatory response [4]. Because of these links, periodontal disease and hypertension may be comorbid diseases that negatively affect each other.
Both chronic periodontitis and hypertension are characterized by infectious susceptibilty and, in either case, a series of inflammatory mediators are released in serum, saliva and gingival crevicular fluids. These mediators are biomarkers, and they have been utilized in diagnosis and prognosis of various disease in dentistry and medicine [1, 5, 6]. One of these proinflammatory biomarker is procalcitonin (ProCT) that is a prohormone of calcitonin and found to be very low concentration in serum of healthy person (<0.1 ng mL−1). Additionally, the increase in ProCT seen during inflamation states is believed to stem from neuroendocrine cells in the lungs and intestine under physiological condition [7, 8]. In the course of inflammation, ProCT is synthesized primarly by two pathways; direct pathway induced by bacteria’s toxic metabolite such as lipopolysaccharide (LPS), and indirect pathway induced by various inflammatory mediators including IL-6, TNF-α, etc. [5, 9].
The early rise during the infection, high diagnostic accuracy and short half-life make ProCT a great candidate biomarker of infection. Bacterial endotoxin is the strongest stimulus for ProCT secretion, besides that, ProCT concentration does not increase significantly during viral infection or other inflammatory conditions. ProCT can rise in some non-infectious conditions [10], [11], [12]. ProCT is helpful for detecting the stage of inflammation, evaluation of prognosis and observing response to the treatment [13]. ProCT is a natural, strong cytokine that is determined to be rising in some diseases such as acute coronary syndrome, metabolic syndrome and obesity which are related to associated to each other. An association between atherosclerosis and serum ProCT level has been suggested due to the induction of genetic expression of an inducible nitric oxide synthase [14].
Proteins secreted from adipose tissue are collectively called adipokines and these hormones are involved in many pathological pathways. C1q/tumor necrosis factor-associated proteins (CTRPs) have been reported as a novel and highly secreted family of proteins. C1q/TNF-related protein-3 (also known as CTRP3, cardboardectin, cartducin, CORS26) is a member of the CTRP superfamily and is secreted by human adipocytes and is also one of the new recently identified adipokines [15], [16], [17]. CTRP3, which is functionally, structurally and closely related to adiponectin, has also been identified as an antiinflammatory adipokine that inhibits vehicle-like receptor (TLR) and nuclear factor-κB (NF-κB) signaling pathways and also reduces IL-6 and TNF-α secretion [18]. In addition, it has glucose-lowering effects, antiapoptotic, proangiogenic, cardio-protective properties and stimulates adiponectin secretion [19], [20], [21].
ProCT and CTRP3 would serve as a hopeful tool for understanding the prediction, diagnosis, cause, progression, regression and outcome of the treatment regimes, and when the literature was searched, a study comparing serum or saliva concentrations of CTRP3 in individuals with periodontal disease was not found. Our hypothesize is that local or systemic ProCT and CTRP3 secretion may be stimulated by periodontal disease or hypertension. The aim of this study was to examine the association of serum and saliva concentrations of ProCT and CTRP3 with indicators of periodontal disease and increased blood pressure.
Materials and methods
Study population
A total of 60 subjects, who applied to Atatürk University, Faculty of Dentistry, Department of Periodontology, were divided into four groups designed according to the systemic and periodontal status of participants, each group consisted of fifteen individuals.
HT+ CP+: Essential hypertension patients with chronic periodontitis (had moderate to severe alveolar bone loss and clinical attachment loss (CAL) of ≥5 mm and probing depth (PPD) of ≥6 mm in multiple sites of all four quadrants of the mouth).
HT+ CP−: Periodontally healthy patients (had no sites with PPD>3 mm, a bleeding on probing (BOP), score of <15 % at the examination and no alveolar bone loss) with essential hypertension.
HT− CP+: Systemically heathy participants with chronic periodontitis.
HT− CP−: Heathy participants had no systemic disease and no sites with PD>3 mm and CAL, a BOP score of <15 % at the examination and no alveolar bone loss was sighted.
Following criteria were selected for inclusion in the study: no history of having systemic disease such as thyroid, liver and or kidney disease, diabetes mellitus, immunologic disorders, malignancy, any bone disease, non-pregnant and non-lactating women, no use of antibiotic medicine for the past 3 months, no periodontal treatment during last 6 months, non smoking, do not losing more than 70 % of the teeth. Thirty patients that diagnosed with essential hypertension were consulted with Cardiology Department of Medical Faculty of Atatürk University and participants in this study according to the results of the necessary tests and blood and saliva samples were collected before the patients were started anti-hypertensive drug treatment. Essential hypertension, which is the most common hypertension, has no identifiable cause. Diagnosis is made when blood pressure remains above 140×90 mmHg.
Clinical periodontal parameters
The periodontal examinations comprising of PPD, CAL, BOP, pIaque index (PI) and gingival index (GI) were determined [22, 23]. PPD, BOP and CAL were determined at six sites of per tooth (mesio-buccal, buccal, disto-buccal, mesio-lingula, lingual and disto-lingual) using a manual William’s periodontal probe (Hu-Friedy, Chicago, IL). PI and GI were observed at four sites per tooth (mesial, buccal, distal and lingual). The examination was performed by the same calibrated (ÖŞA) (kappa=0.91).
Collection of serum and saliva samples
In the morning of the periodontal appointment, almost 5 mL of blood was taken from anticubital fossa. Later on, the blood was transferred to non-ethylene diamino tetra-acetic acid containing test tube and was let to clot at room temparature. In one hour, serum and plasma were extracted from the blood by centrifuging the test tube at 4,000 rpm for fifteen minutes. After this process, extracted serum was stocked at −80 °C until the time of assay.
Saliva sample collection, which was taken from expectorating of the participants, had been kept in polypropylene tubes until 5 mL was accumulated. The morning the saliva samples were collected, the participants were instructed to brush their teeth and not eat or drink. Unstimulated saliva samples were collected from the patients with the accumulation of saliva in the floor of the mouth by keeping their mouths open for 5 min and by providing conditions where patients can sit in a comfortable and resting position. Then saliva samples were centrifuged at 3,500 rpm for 5 min at +4 °C for removing cell debris. After that; the supernatant was stored at −80 °C until the time of assay.
Serum and saliva ProCT were assayed by using electroluminescence method in Roche Modular E170 device. Serum and saliva CTRP3 levels were determined by enzyme-linked immunosorbent assay (human CTRP3 ELISA kit, Cloud-Clone Corporation, Lot: L150914389, USA). All the assays were duplicate, and there was not any significant cross-reactivity or interference was not observed. The inter-assay co-efficients of variation (%CV) was 9 % while intra-assay %CV was 11 %. The measuring range of the CTRP3 kit was between 0.156–10 ng/mL while the ProCT assay had a sensitivity of 0.020 ng/mL.
Statistical analysis
Statistical analysis was performed with using IBM Statistical Package for the Social Science (SPSS) software, version 20.0 (SPSS for Windows Ver. Chicago, IL). Kolmogorov-Smirnov normality test was used to determine whether the data had normal distrubition or not. Kruskal-Wallis test was performed for comparisons among the study groups, the following post-hoc evaluation was made by Bonferroni-corrected Mann-Whitney U test. The Pearson’s correlation was used for the calculation of association between variables. p<0.05 values were considered to be statistically significant for all analyses.
Results
There are no significant differences between the test and control groups in terms of age, gender distribution values and body mass index (BMI) (p>0.05) (Table 1). In HT+CP+ group and HT−CP+ were recorded as having significantly higher PPD, CAL, BOP, PI and GI scores than those of HT+CP− and HT−CP− groups (p<0.05) (Table 2).
Demographic characteristic of the groups. There are no significant differences between the test and control groups in terms of age, gender distribution values and body mass index (BMI) (p>0.05).
| (HT+ CP+) | (HT+ CP−) | (HT− CP+) | (HT− CP−) | |
|---|---|---|---|---|
| Age years, mean±SDa | 47 ± 8 | 49 ± 8 | 47 ± 8 | 45 ± 6 |
| BMI, kg/m2a | 22.6 ± 1.8 | 23.2 ± 3.2 | 23.3 ± 2.7 | 24 ± 3.4 |
| Sex female, n | 8 | 6 | 6 | 7 |
| Male, n | 7 | 9 | 9 | 8 |
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aData are expressed as mean ± SD.
Full-mouth clinical parameters of the study groups. For comparison between groups, Kruskal Wallis test and Mann Whitney U test were used.
| (HT+ CP+) | (HT+ CP−) | (HT− CP+) | (HT− CP−) | |
|---|---|---|---|---|
| PI | 2.2 ± 0.4a | 0.7 ± 0.5 | 2.3 ± 0.3a | 0.8 ± 0.4 |
| GI | 2.2 ± 0.5a | 1.0 ± 0.5 | 2.6 ± 0.4a | 0.9 ± 0.4 |
| PPD | 3.9 ± 0,8a | 2.1 ± 0,5 | 3.9 ± 0.5a | 2.0 ± 0.3 |
| CAL | 6.1 ± 1.1a | 3.0 ± 0.5 | 6.2 ± 0.9a | 2.5 ± 0.4 |
| BOP | 83 ± 10a | 13 ± 6 | 82 ± 12a | 11 ± 7 |
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aSignificant difference between HT+CP+ group and HT−CP+ group and the other group (p<0.05).
Salivary ProCT levels were below the detection limit in all subjects for all groups. Serum ProCT concentration was analized the lowest in HT− CP− group, followed by the HT+ CP− group, HT− CP+ group and the highest in HT+ CP+ group. Serum ProCT concentrations did not differ significantly among all groups (p=0.110).
The serum CTRP3 levels were significantly lower in all groups (HT+ CP+, HT+ CP−, HT− CP+) compared to control group (HT− CP−) (p<0.001). Compared with the HT− CP+ group, the serum CTRP3 levels were significantly lower in the HT+ CP− group (p=0.002). Salivary CTRP3 levels in the HT+ CP+, HT+ CP−, HT− CP+ groups were significantly lower than the control group (HT− CP−) (p<0.001) (Table 3).
Serum and salivary CTRP3 and serum ProCT levels of study groups. For comparison between groups, Kruskal Wallis test and Mann Whitney U test were used.
| HT+ CP+ (n=15) | HT+ CP− (n=15) | HT− CP+ (n=15) | HT− CP− (n=15) | |
|---|---|---|---|---|
| Serum CTRP3 | ||||
| Mean ± SD | ||||
|
|
||||
| CTRP3, ng/mL | 40.21 ± 5.05a | 55.13 ± 5.65b | 62.38 ± 6.51 | 424.13 ± 69.42a |
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|
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| Saliva CTRP3 | ||||
| Mean ± SD | ||||
|
|
||||
| CTRP3, ng/mL | 15.57 ± 3.39a | 31.19 ± 5.51 | 34.70 ± 3.57 | 98.77 ± 24.39a |
|
|
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| Serum ProCT | ||||
| Median ± SD | ||||
|
|
||||
| ProCT (ng/ml) (min-max) | 0.000±0.401 (0–0.139) | 0.020 ± 0.198 (0–0.064) | 0.000 ± 0.027 (0–0.096) | 0.000 ± 0.008 (0–0.023) |
|
|
||||
| Percentiles (25, 50, 75) | ||||
|
|
||||
| ProCT, ng/ml | 0.000 | 0.000 | 0.000 | 0.000 |
| 0.000 | 0.020 | 0.000 | 0.000 | |
| 0.030 | 0.030 | 0.030 | 0.000 | |
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aSignificant difference from all other groups (p<0.0001). bSignificant difference from HT−CP+ (p=0.002).
Serum and salivary CTRP3 levels were negatively correlated with PPD, CAL, GI and PI (Table 4). Also, the significant positive correlation was seen between serum and salivary CTRP3 levels (Figure 1, Table 5).
Correlations of the CTRP3 levels with periodontal parameters. Comparisons between groups were analyzed using the Pearson correlation test.
| Clinical periodontal parameters | ||||||||
|---|---|---|---|---|---|---|---|---|
| PPD | CAL | PI | GI | |||||
| r | p-Value | r | p-Value | r | p-Value | r | p-Value | |
| Serum CTRP3 | −0.478 | 0.0001a | −0.531 | 0.0001a | −0.337 | 0.009a | −0.307 | 0.02a |
| Saliva CTRP3 | −0.565 | 0.0001a | −0.569 | 0.0001a | −0.433 | 0.001a | −0.406 | 0.001a |
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aSignificant negative correlations.
Correlation between serum and salivary CTRP3 levels.
Correlations between serum and salivary CTRP3 levels. Comparisons between groups were analyzed using the Pearson correlation test.
| r | p-Value | |
|---|---|---|
| Serum CTRP3- salivary CTRP3 | 0.884 | 0.001a |
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aSignificant positive correlation.
Discussion
The opinion that hypertension and periodontal disease are somehow related, concluded from the results of many researches has been carried out until today [3, 4, 24, 25]. Based on these results, the systemic inflammatory response concomitant to periodontal disease has been alleged to has adverse effects on blood pressure. Periodontitis may also manage to induce vascular inflammation that results in endothelial dysfunction, which is an initial step for cardiovascular disease. This dynamic and progressive inflammation is mediated by tumor necrosis factor alpha (TNF-α), osteoprotegerin (OPG), C-reactive protein (CRP), matrix metalloproteinase-8 (MMP-8), elastase, cathepsin G, interleukin-1β, interleukin-6 and interleukin-8 as host response indicators. By observing the proportional changes of these biomarkers, the susceptibility and status of diseases can be determined [13, 25], [26], [27].
In our study, we have investigated the salivary and serum levels of ProCT and CTRP3 not only in patients with chronic periodontitis but also in essential hypertension patients to observe if these levels are changed by periodontitis activity or by high blood pressure. We have hypothesized that periodontal disease activity and high blood pressure may act as a stimulus for ProCT production, because endotoxin and TNF-α are a potent stimulators for secretion of ProCT. However, we observed that salivary ProCT concentrations were below the level of detection in all subjects. In their study, Yousefimanesh et al. [5], investigated the association salivary ProCT level in patients with periodontitis. They found that ProCT rate increased in generalized chronic periodontitis patients, but between case and control groups, no differences were found. In another study by Onder et al. [28], ProCT and C-reactive protein (Hs CRP) levels were compared in patients with aggressive periodontitis, chronic periodontitis and periodontally healthy individuals, and serum ProCT level was found to be higher in individuals with chronic periodontitis than in other groups, and it was found that serum ProCT level decreased after non-surgical periodontal treatment. As in this study, in our study, the lowest serum ProCT level was found in the HT− CP− group. In our research, salivary ProCT concentrations have been found below the level of detection in all subjects. Based on these results, we can deduce that the current test may not be susceptible enough to find mild rise of ProCT level and it is necessitate to apply more sensitive test. In another study conducted by Bassim et al. [29], serum and salivary ProCT concentration were analyzed in patients with periodontitis as well as type 2 diabetes. When we compared it with our research, they revealed more significant increase in salivary ProCT level in patients with severe periodontitis than with moderate periodontitis and healthy controls, and serum ProCT levels for the periodontitis/diabetes group were significantly higher than those found in control serum. The differences in serum ProCT among patients with severe periodontitis and moderate periodontitits or healthy control don’t have any significance. This conflicts may be due to some factors such as possible inflammatory effect of diabetes, differences in inclusion criteria (their participants were smokers), differences in ProCT assays (kryptor-trace, ELISA). In addition to this, we have analyzed saliva and serum ProCT concentration in patients with chronic periodontitis as well as hypertension patients, so the effects of underlying diabetes might change salivary level of ProCT more strongly than the effects of high blood pressure. In a study evaluating the salivary and serum ProCT in patients with osteoarthritis or rheumatoid arthritis, it is clearly seen that the serum ProCT level is significantly higher in the moderate/severe group and in patients with severe periodontitis compared to the no/mild group. There are no significant differences in salivary ProCT related to severity of periodontitis [30]. Similarly, in our study, there were no significant differences in saliva ProCT level among all groups, because salivary ProCT levels were not detected in all subjects. Also, we have observed that there was no significant differences in serum ProCT concentration between the patients with hypertension and healthy control. Our study also supports the results of Redman et al. [30]. Hendek et al. [13] evaluated salivary ProCT in varied periodontal disease and they indicated that in agressive periodontitis patients, ProCT level was significantly higher compared to the healthy control and positive correlation between clinical periodontal parameters and salivary ProCT concentration differs from our results. This research mainly focuses on chronic periodontitis and high blood pressure, and we have also analyzed blood samples unlike the study of Hendek et al. [13] and Ziebolz et al. [25]. They assessed CRP, ProCT, neopterin and TNF-α levels in samples of plasma and the concentration of ProCT and CRP were below or almost above the level of detection in almost all participants. They found no significant increase in response to periodontitis.
In a study [14] evaluating the ProCT and Pentraxin-3 levels and their relationship with carotid intima-media thickness (CIMT) in subjects with white coat hypertension (WCH), hypertension and normal tension group, it has been showed that ProCT level significantly was higher in WCH and hypertension group compared to normotensive group. They made an inference that ProCT may be an important biomarker showing subclinical atherosclerosis in the future [14]. Similarly, we observed an increasing trend in ProCT level in the essential hypertension patients compared to healthy control group but this difference was not significant. Mallamaci et al. [31] investigated ProCT level and the inflammatory response to salt in esssential hypertension and they deduced that in essential hypertensive patients, a very low salt diet generates a pro-inflammatory phenotype characterized by a rise in serum ProCT and TNF-α concentration. Consequently, ProCT may be a potential biomarker of inflammation and represent a diagnostic key stone in inflammatory disease.
There is no research comparing serum or saliva concentration of CTRP3 in patients with any periodontal disease. So far, findings of this study have been reported for the first time about clinical characteristic of CTRP3 in patients with chronic periodontitis, besides that, serum concentration of CTRP3 was analyzed in various diseases including obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome, coronary artery disease and polycistic ovary syndrome. In particular, an inverse correlation was observed among serum CTRP3 level and insulin, Hs-CRP, LDL-cholesterol, BMI and carotid intima-media thickness (CIMT) values [14]. In our study, we investigated the relationship between hypertension and CTRP3 to understand the connection better and we found significant reduction in serum and saliva concentration of CTRP3 in patients with essential hypertension. Furthermore, we have found that when chronic periodontitis were accompany with hypertension, serum and saliva concentration of CTRP3 were analyzed lower.
In other studies, researchers have showed direct effects of CTRP3 on endothelial cells. CTRP3 is able to promote endothelial cell proliferation and migration over distinct mitogen-activated protein kinase (MAPK) signaling pathways [19]. Because endothelial dysfunction is the first stage in the development of atherosclerosis, it is an important condition associated with both hypertension and chronic periodontitis. Chronic inflammation caused via periodontitis is involved in endothelial dysfunction which finally increases the risk of hypertension [24, 32]. In this context, CTRP3 that we found significantly lower in serum and saliva concentration in HT+ CP+, HT+ CP−, HT− CP+ group compared to HT− CP− group, may have played a role in these results.
Clinical periodontal parameters including CAL and PPD are vital and essential evaluations for the diagnosis of periodontal disease, nevertheless, the current situation of the disease and prognosis could not be clarified with these parameters [13, 32, 33]. Biochemical parameters can provide early information about implantation before clinical symptoms of periodontal disease occur. In this way, various biological fluids can help us to identify early indicator of disease in periodontology and medicine [13, 34, 35]. Because of the simple and non-invasive nature of saliva and high sensitivity assay development, saliva might be used to analyze CTRP3 and ProCT levels for the diagnosis and prognosis of periodontal disease, hypertension and other disorders. If salivary and serum ProCT and CTRP3 concentration can be postulated as a biomarker for periodontal disease and hypertension activity, its decrease with treatment could be used as an objective end point and therapeutic goal for individual with periodontal disease and high blood pressure. However, in our study, the level of salivary ProCT could not be measured because the salivary ProCT levels were below the detection limit in all subjects. In future studies, this marker can also be measured in saliva using a more sensitive measurement method.
Our data has showed that analysis of ProCT in saliva samples is not a reliable method and may not be regarded as a good indicator in terms of providing information about high blood pressure and periodontal disease activity. There has been inconsistencies among the researches about this topic so far. In this study, we also demonstrated a decrease of serum and saliva concentration of CTRP3 in hypertensive and chronic periodontitis patients. According to our data, CTRP3 and ProCT have a prominent pathophysiological role in chronic periodontitis and hypertension possibly.
A reduced serum and saliva levels of CTRP3 in hypertension and periodontal disease support the idea that these biomarkers can be used as potential biomarkers for the diagnosis and follow-up of these diseases for the limits of the study. In addition to this, it might be suggested that CTRP3 may protect individuals against the development of these disorders. Future analysis will require studies that will be conducted with larger study population and with other periodontal disease patients.
Conclusions
When periodontitis and hypertension coexist, they can negatively affect each other due to the common pathways in the pathogenesis of these two diseases. Cartonectin (CTRP3) may be a new therapeutic target in the future due to its joint effects in hypertension and periodontal inflammation.
Funding source: Ataturk University Scientific Research Projects Coordination Unit
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Research funding: This study was supported by Atatürk University Scientific Research Projects Coordination Unit.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: This study was approved by the Ethic Committee of Atatürk University Faculty of Dentistry. Approval number: 07.04.2015/70. The patients who accepted to participate in the study were included in the study after the patient consent forms were read and signed in accordance with the ethics committee approval.
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