- Academic Editor
Background: Umbilical cord torsion is one of the known causes of
perinatal fetal death, adding to the increase in perinatal morbidity and
mortality. However, there is no study on the relationship between umbilical cord
torsion and the changes in umbilical artery Doppler parameters. Methods:
The subjects included 962 pregnant women who were discharged from our hospital
from January 2015 to November 2021 and were eligible for inclusion (415 in the
study group and 547 in the control group). The measurement data of umbilical
artery Doppler parameters (peak systolic velocity (PSV), systolic/diastolic ratio
(S/D), resistance index (RI), pulse index (PI)) were collected from 21 to 40
weeks of gestation, and the differences among the collected parameters were
statistically analyzed. Results: The peak systolic velocity (PSV) of
umbilical artery were positively correlated with gestational age, while the
Doppler resistance parameters (S/D, RI, PI) of the umbilical artery were
negatively correlated with gestational age. The mean values of umbilical artery
Doppler parameters (PSV, S/D, RI, PI) in the study group were significantly lower
than those in the control group at the same gestational age (p
The umbilical cord is critical for the normal development, survival and health of the fetus. The proper helix of the umbilical cord and its tissue structure provide some pressure protection for umbilical vessels [1, 2]. The physiological torsion of umbilical cord can reach 6–11 weeks, and the torsion of umbilical cord can be more than 12 weeks [3]. Torsion of umbilical cord may lead to fetal growth restriction, premature delivery, meconium contamination of the amniotic fluid, and stillbirth [4, 5, 6, 7, 8, 9]. Umbilical cord torsion is a known cause of perinatal fetal death [10]. Prenatal ultrasound has been exploring the ultrasonic manifestation of umbilical cord torsion, but no consensus has been reached [11, 12]. At present, there is no study on the relationship between umbilical cord torsion and the changes of umbilical artery Doppler parameters. The purpose of this study is to explore the correlation between umbilical cord torsion and the changes in umbilical artery Doppler parameters, provide valuable information for prenatal ultrasound screening of umbilical cord torsion, and explore the possible mechanism of umbilical artery Doppler parameters changes during umbilical cord torsion.
This study was a retrospective control study. Pregnant women who underwent routine prenatal ultrasound examination and hospital delivery in our hospital from January 2015 to November 2021 were randomly collected.
Inclusion criteria:
(1) Pregnant women who gave birth in our hospital had a definite discharge diagnosis or pathological diagnosis of placental appendages;
(2) Low-risk pregnancy, including no pregnancy complications or major underlying diseases, such as gestational hypertension, gestational diabetes, placental previa, placental abruption;
(3) There was a record of prenatal ultrasound examination in our hospital, and the Doppler parameters of umbilical artery were measured in the free segment of umbilical cord during the examination;
(4) Singleton pregnancy.
Exclusion criteria:
(1) Severe fetal malformations or chromosome abnormalities;
(2) Pregnant women with single umbilical cord artery or other abnormal umbilical cord blood vessels;
(3) Stillbirth or induced labor due to other reasons.
Gestational age was calculated based on the last menstrual period. If the last
menstrual period was unclear, it was calculated and recorded according to the NT
(nuchal translucency) cycle after correcting the gestational age. Obstetricians
evaluated the umbilical cord after delivery, and defined those who were
discharged as having umbilical cord torsion as the study group. Those who were
diagnosed as having no umbilical cord torsion were randomly selected as the
control group. Torsion of the umbilical cord was defined as
The ultrasound instruments used were GE Voluson E10, GE Voluson E8 (GE Healthcare Austria GmbH & Co OG, Tiefenbach, Zipf, Austria), and Mindray Resona 70B (Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, Guangdong, China), with the probe frequency being 4–8 MHz. The free umbilical cord floating in the amniotic fluid was measured by Doppler, and the measurement angle was as parallel as possible to the direction of umbilical cord blood flow. Umbilical artery Doppler blood flow parameters, including peak systolic velocity (PSV), umbilical artery blood systolic/diastolic ratio (S/D), resistance index (RI) and pulse index (PI), were extracted from the scan at each gestational week from 21 to 40 weeks.
IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, NY, USA) was
used for data processing: (1) all umbilical artery Doppler blood flow parameters
in the study group and the control group at 21–40 weeks gestation were evaluated
according to gestational age. The mean of each gestational age measurement in the
two groups was calculated. (2) The change trend of umbilical artery blood flow
parameters for each gestational week was analyzed. (3) Logistic regression
analysis was performed on the umbilical artery blood flow parameters of the study
group and the control group at the same gestational age, with p
PSV, S/D, RI, PI trend chart with gestational age plotted using GraphPad Prism version 9.5.0 for Windows (GraphPad Software, Boston, MA, USA, https://www.graphpad.com/).
This study included 1608 pregnant women who delivered in our hospital (666 in
the study group and 942 in the control group). According to the inclusion
exclusion criteria, 646 pregnant women (251 in the study group and 395 in the
control group) were excluded, and 415 pregnant women in the study group and 547
pregnant women in the control group were included. The two groups of pregnant
women ranged in age from 21 to 44 years, with a mean age of 31 years (no
difference between the two groups, p
GA | Number | S/D | RI | PI | PSV | |||||||||||||
SG | CG | SG | CG | t | p-value | SG | CG | t | p-value | SG | CG | t | p-value | SG | CG | t | p-value | |
21 | 33 | 94 | 3.09 | 3.43 | 2.950 | 0.004 | 0.66 | 0.70 | 2.940 | 0.005 | 1.07 | 1.18 | 2.426 | 0.021 | 33.22 | 35.10 | 1.627 | 0.106 |
22 | 102 | 183 | 3.17 | 3.21 | 0.710 | 0.479 | 0.67 | 0.68 | –0.718 | 0.474 | 1.10 | 1.11 | 0.017 | 0.986 | 35.38 | 35.06 | –0.418 | 0.676 |
23 | 82 | 95 | 3.05 | 3.14 | 0.938 | 0.349 | 0.66 | 0.67 | 0.604 | 0.547 | 1.07 | 1.09 | 0.886 | 0.377 | 35.66 | 36.45 | 0.720 | 0.472 |
24 | 25 | 37 | 2.92 | 3.06 | 0.734 | 0.386 | 0.65 | 0.66 | 0.802 | 0.428 | 1.04 | 1.09 | 0.965 | 0.344 | 36.04 | 36.62 | 0.335 | 0.739 |
25 | 9 | 51 | 2.60 | 2.99 | 2.051 | 0.045 | 0.62 | 0.65 | 1.773 | 0.081 | 0.91 | 1.03 | 1.784 | 0.084 | 37.18 | 40.81 | 1.477 | 0.145 |
26 | 10 | 54 | 2.61 | 2.95 | 2.061 | 0.043 | 0.60 | 0.65 | 1.958 | 0.055 | 0.93 | 1.03 | 1.655 | 0.104 | 44.48 | 42.49 | –0.882 | 0.381 |
27 | 17 | 28 | 2.44 | 2.77 | 2.368 | 0.022 | 0.58 | 0.62 | 1.899 | 0.064 | 0.86 | 0.96 | 1.616 | 0.115 | 37.99 | 42.61 | 2.102 | 0.041 |
28 | 35 | 49 | 2.46 | 2.73 | 2.677 | 0.009 | 0.59 | 0.62 | 2.156 | 0.034 | 0.85 | 0.96 | 2.823 | 0.006 | 41.20 | 45.01 | 2.279 | 0.025 |
29 | 47 | 80 | 2.45 | 2.67 | 2.789 | 0.006 | 0.58 | 0.61 | 2.101 | 0.038 | 0.86 | 0.92 | 1.836 | 0.070 | 42.33 | 46.14 | 2.329 | 0.021 |
30 | 101 | 172 | 2.39 | 2.64 | 4.995 | 0.000 | 0.57 | 0.60 | 4.177 | 0.000 | 0.85 | 0.91 | 3.171 | 0.002 | 44.84 | 47.01 | 2.273 | 0.024 |
31 | 111 | 153 | 2.40 | 2.57 | 3.142 | 0.002 | 0.57 | 0.60 | 2.833 | 0.005 | 0.84 | 0.89 | 2.092 | 0.038 | 43.47 | 47.09 | 3.607 | 0.000 |
32 | 97 | 132 | 2.36 | 2.54 | 3.239 | 0.001 | 0.56 | 0.59 | 2.910 | 0.004 | 0.82 | 0.89 | 3.024 | 0.003 | 42.81 | 47.79 | 4.362 | 0.000 |
33 | 50 | 71 | 2.27 | 2.44 | 2.153 | 0.033 | 0.54 | 0.58 | 2.221 | 0.028 | 0.81 | 0.87 | 1.939 | 0.056 | 41.36 | 48.74 | 4.817 | 0.000 |
34 | 47 | 60 | 2.12 | 2.43 | 4.695 | 0.000 | 0.52 | 0.57 | 3.748 | 0.000 | 0.73 | 0.85 | 3.106 | 0.003 | 44.08 | 49.16 | 2.755 | 0.007 |
35 | 54 | 69 | 2.18 | 2.39 | 2.870 | 0.005 | 0.53 | 0.56 | 2.209 | 0.029 | 0.76 | 0.85 | 2.794 | 0.006 | 45.76 | 49.64 | 2.409 | 0.018 |
36 | 128 | 212 | 2.14 | 2.31 | 3.890 | 0.000 | 0.52 | 0.55 | 3.050 | 0.002 | 0.75 | 0.83 | 3.392 | 0.001 | 46.91 | 50.30 | 3.478 | 0.001 |
37 | 243 | 321 | 2.13 | 2.27 | 3.579 | 0.000 | 0.52 | 0.54 | 2.632 | 0.009 | 0.75 | 0.80 | 3.237 | 0.001 | 46.38 | 50.58 | 4.923 | 0.000 |
38 | 183 | 279 | 2.11 | 2.25 | 3.706 | 0.000 | 0.52 | 0.54 | 2.552 | 0.011 | 0.73 | 0.80 | 3.878 | 0.000 | 46.59 | 50.78 | 4.825 | 0.000 |
39 | 202 | 293 | 2.07 | 2.20 | 3.855 | 0.000 | 0.50 | 0.53 | 3.065 | 0.002 | 0.73 | 0.78 | 3.065 | 0.002 | 45.79 | 51.00 | 6.256 | 0.000 |
40 | 96 | 110 | 2.06 | 2.17 | 2.293 | 0.023 | 0.50 | 0.53 | 2.201 | 0.029 | 0.72 | 0.78 | 2.071 | 0.040 | 47.16 | 51.13 | 2.831 | 0.005 |
GA, gestational age; SG, study group; CG, control group; PSV, peak systolic velocity; S/D, systolic/diastolic ratio; RI, resistance index; PI, pulsatility index.
As shown in Fig. 1, the correlation analysis of umbilical artery flow parameters
(PSV, S/D, RI, PI) and gestational age in the study group and control group
respectively revealed that the peak velocity of umbilical artery contraction
(PSV) was positively correlated with gestational age in both groups, while the
correlation parameters of umbilical artery Doppler resistance (S/D, RI, PI) were
negatively correlated with gestational age in both groups (R
PSV, S/D, RI, PI trend chart with gestational age (GA). (A–D) show the trends of PSV, S/D, RI, and PI with GA, respectively. PSV, peak systolic velocity; S/D, systolic/diastolic ratio; RI, resistance index; PI, pulsatility index.
After filling in the missing values by regression analysis, logistic regression analysis demonstrated that at weeks 22–27, the umbilical artery Doppler parameters of both the study group and the control group were greater than 0.05, while in weeks 28–40, the weekly umbilical artery Doppler parameters were less than 0.05, with statistical significance as shown in Table 2.
GA | S/D | RI | PI | PSV | ||||
OR (95% CI) | p-value | OR (95% CI) | p-value | OR (95% CI) | p-value | OR (95% CI) | p-value | |
21 | 0.324 (0.139–0.753) | 0.009 | 0.000 (0.000–0.030) | 0.005 | 0.016 (0.001–0.246) | 0.003 | 0.944 (0.877–1.015) | 0.120 |
22 | 0.815 (0.520–1.277) | 0.372 | 2.725 (0.054–137.377) | 0.616 | 0.886 (0.183–4.292) | 0.881 | 1.010 (0.970–1.051) | 0.631 |
23 | 0.768 (0.461–1.277) | 0.308 | 0.191 (0.002–20.673) | 0.489 | 0.287 (0.043–1.920) | 0.198 | 0.981 (0.941–1.023) | 0.378 |
24 | 0.721 (0.338–1.539) | 0.397 | 0.045 (0.000–39.299) | 0.370 | 0.212 (0.011–4.122) | 0.306 | 0.985 (0.912–1.065) | 0.705 |
25 | 0.234 (0.044–1.256) | 0.900 | 0.000 (0.000–27.335) | 0.158 | 0.008 (0.000–1.839) | 0.820 | 0.913 (0.803–1.037) | 0.161 |
26 | 0.210 (0.043–1.024) | 0.054 | 0.000 (0.000–1.847) | 0.065 | 0.012 (0.000–1.224) | 0.061 | 1.048 (0.938–1.170) | 0.405 |
27 | 0.194 (0.037–1.004) | 0.051 | 0.000 (0.000–1.335) | 0.057 | 0.012 (0.000–1.344) | 0.066 | 0.909 (0.819–1.009) | 0.074 |
28 | 0.248 (0.082–0.746) | 0.013 | 0.001 (0.000–0.587) | 0.034 | 0.036 (0.002–0.589) | 0.020 | 0.927 (0.868–0.989) | 0.021 |
29 | 0.276 (0.109–0.701) | 0.007 | 0.002 (0.000–0.580) | 0.031 | 0.065 (0.005–0.920) | 0.043 | 0.952 (0.910–0.996) | 0.032 |
30 | 0.210 (0.101–0.436) | 0.000 | 0.000 (0.000–0.016) | 0.000 | 0.046 (0.008–0.277) | 0.001 | 0.964 (0.932–0.997) | 0.034 |
31 | 0.355 (0.185–0.680) | 0.002 | 0.005 (0.000–0.206) | 0.005 | 0.141 (0.024–0.842) | 0.032 | 0.942 (0.911–0.975) | 0.001 |
32 | 0.354 (0.178–0.705) | 0.003 | 0.005 (0.000–0.264) | 0.009 | 0.112 (0.019–0.673) | 0.017 | 0.928 (0.895–0.962) | 0.000 |
33 | 0.345 (0.129–0.927) | 0.035 | 0.002 (0.000–0.430) | 0.024 | 0.057 (0.005–0.690) | 0.024 | 0.887 (0.838–0.938) | 0.000 |
34 | 0.085 (0.023–0.311) | 0.000 | 0.000 (0.000–0.025) | 0.001 | 0.009 (0.001–0.145) | 0.001 | 0.945 (0.903–0.989) | 0.014 |
35 | 0.262 (0.098–0.699) | 0.007 | 0.006 (0.000–0.687) | 0.034 | 0.056 (0.005–0.598) | 0.017 | 0.955 (0.915–0.997) | 0.036 |
36 | 0.289 (0.152–0.550) | 0.000 | 0.011 (0.001–0.194) | 0.002 | 0.087 (0.020–0.372) | 0.001 | 0.954 (0.928–0.980) | 0.001 |
37 | 0.424 (0.262–0.687) | 0.000 | 0.053 (0.006–0.495) | 0.010 | 0.230 (0.080–0.661) | 0.006 | 0.958 (0.940–0.976) | 0.000 |
38 | 0.378 (0.223–0.642) | 0.000 | 0.043 (0.004–0.449) | 0.009 | 0.180 (0.058–0.557) | 0.003 | 0.949 (0.928–0.971) | 0.000 |
39 | 0.408 (0.244–0.682) | 0.001 | 0.038 (0.004–0.354) | 0.004 | 0.231 (0.079–0.678) | 0.008 | 0.936 (0.915–0.958) | 0.000 |
40 | 0.407 (0.177–0.935) | 0.034 | 0.028 (0.001–0.876) | 0.042 | 0.097 (0.014–0.673) | 0.018 | 0.934 (0.991–0.999) | 0.011 |
OR, odds ratio; 95% CI, 95% confidence interval; GA, gestational age; PSV, peak systolic velocity; S/D, systolic/diastolic ratio; RI, resistance index; PI, pulsatility index.
Table 3 summarizes the relationships between umbilical cord torsion and perinatal outcomes. The incidences of, fetal heart rate abnormalities during labor (1.7% vs. 0.4%, p = 0.044), and meconium staining of amniotic fluid (18.1% vs. 7.3%, p = 0.000) were significantly higher in the study group and control group.
Characteristics | Study group | Control group | p-value | ||
Number of nuchal cords | |||||
One loop | 84 (20.2) | 133 (24.3) | 2.678 | 0.431 | |
Two loops | 18 (4.3) | 20 (3.7) | |||
Three loops | 2 (0.5) | 4 (0.7) | |||
Mode of delivery | |||||
Vaginal delivery | 208 (50.4) | 331 (60.5) | 4.619 | 0.033 | |
Cesarean delivery | 207 (49.9) | 216 (39.5) | |||
Fetal heart rate abnormality during labor | 7 (1.7) | 2 (0.4) | 4.444 | 0.044 | |
Emergency cesarean delivery | 78 (18.8) | 63 (11.5) | 9.992 | 0.002 | |
Meconium staining of amniotic fluid | |||||
I° | 11 (2.7) | 5 (0.9) | 28.010 | 0.000 | |
II° | 49 (11.8) | 31 (5.7) | |||
III° | 15 (3.6) | 3 (0.7) | |||
Low Apgar score ( |
20 (4.8) | 9 (1.6) | 8.131 | 0.007 | |
Neonatal intensive care unit admission | 50 (12.0) | 31 (5.7) | 12.336 | 0.001 | |
Small for gestational age | 10 (2.4) | 7 (1.3) | 1.736 | 0.221 | |
Birth weight, g | 3126.99 |
3290.48 |
5.495* | 0.000 | |
Gestational age at delivery of 37 weeks | 382 (92.0) | 538 (98.4) | 22.477 | 0.000 | |
Abnormal amniotic fluid volume | |||||
Polyhydramnios | 11 (2.7) | 3 (0.5) | 14.490 | 0.001 | |
Oligohydramnios | 32 (7.7) | 21 (3.8) |
Data are shown as mean
Admission to the neonatal intensive care unit was significantly associated with
torsion of the umbilical cord (12% vs. 5.7% , p = 0.001). Low
Apgar score (
The mean neonatal weight was significantly lower in the study group and control
group (3126.99
This was a single-center retrospective case-control study. The results demonstrated that the peak velocity of umbilical artery contraction (PSV) was positively correlated with gestational age in both the study group and the control group, and the values of the umbilical artery Doppler resistance related parameters (S/D, RI, PI) were negatively correlated with gestational age.
The results of this study revealed that there was no significant difference in
the mean value of umbilical artery Doppler parameters between the study group and
the control group at 21–27 weeks of gestation (p
When the arteries in other parts of the human body are narrowed, the Doppler changes of the artery blood flow at the distal end of the stenosis are low-speed and low-pulsation changes, forming a “small slow wave” [13, 14]. We believe that the Doppler changes of the umbilical artery blood flow during umbilical cord torsion are consistent with the changes of blood flow Doppler changes after arterial stenosis in other areas. Because umbilical cord torsion occurs mostly at the umbilical wheel [3], the umbilical artery at the umbilical wheel is narrowed by the torsion of the umbilical cord, resulting in “small slow wave” changes in the blood flow Doppler of the umbilical artery at the distal end of the umbilical wheel (Fig. 2).
The umbilical cord (located downstream of the umbilical wheel). (A) When the normal umbilical cord passes through the umbilical wheel, there is no stenosis of the umbilical artery. (B) When the umbilical cord is twisted, the umbilical artery at the umbilical wheel is narrowed due to torsion, and the peak systolic velocity and resistance of the umbilical artery downstream of the umbilical wheel is reduced. (C) Normal umbilical artery Doppler waveform. (D) When the umbilical cord is twisted, the umbilical artery changes with low velocity and low resistance. a, umbilical vein; b, umbilical artery; c, the umbilical wheel.
The Doppler parameters of umbilical artery blood flow are the routine indexes of the prenatal ultrasound examination. At present, most of the poor pregnancy outcomes are related to the abnormal increase of umbilical artery blood Doppler resistance parameters [15, 16, 17, 18, 19]. When obstetricians suspect fetal distress or abnormal fetal movement, they usually pay more attention to the abnormal increase in Doppler resistance of umbilical artery blood flow. If there is no abnormal increase in Doppler resistance of umbilical artery blood flow, the conclusion is reached that the fetus is currently stable and the recommendation is that the fetus be reexamined in the future. During the time waiting for reexamination, it is possible that the fetus may die in the uterus due to torsion of the umbilical cord. Therefore, when the fetus has abnormal fetal heart monitoring and abnormal fetal movement, and the Doppler parameters of umbilical artery blood flow do not increase abnormally or actually decrease, the possibility of umbilical cord torsion should be considered. It has been reported that the high helix of umbilical cord is related to umbilical cord torsion [20, 21, 22]. It has been reported that when the umbilical cord is high helical, the umbilical vein blood flow velocity at the umbilical wheel will increase [23, 24] or the a-wave reverse of the venous catheter will occur [25]. Therefore, when umbilical cord torsion is suspected, attention needs to be paid to the contents of unconventional ultrasound examination, such as umbilical cord helix, umbilical vein flow velocity and venous catheter spectrum.
Fig. 3 represent a case of a pregnant woman at 32 weeks of gestation with abnormal fetal heart rate monitoring. Ultrasound examination demonstrated a single umbilical artery.
A case of umbilical cord torsion. (A) Abnormal fetal heart
monitoring at 32 weeks of gestation, frequency spectrum of umbilical cord free
segment. PSV is lower than 5th%, S/D, RI, PI is lower than 10th%. (B) 2D image
of high spiral umbilical (changing like chain). (C) Color Doppler image of high
spiral umbilical (UCI 0.76). (D) The umbilical vein flow velocity at the
umbilical wheel increased (PSV 69 cm/s). (E) Doppler spectrum of intravenous
catheter (a notch significantly deepened, PI 1.22). (F) Umbilical cord torsion
The PSV of umbilical artery was 36.42 cm/s, S/D and 1.84 Magi was 0.46 and Pi was 0.60, in which PSV was lower than normal 5th% [26], and S/D, RI and PI were lower than 10th% [26] (Fig. 3A). The results suggested that there may be umbilical cord torsion. Therefore, we examined the shape of the umbilical cord and the blood flow of the venous catheter. It was found that the fetal umbilical cord spirally increased, UCI (umbilical coiling index) 0.76 [27] (Fig. 3B,C), and the umbilical vein blood flow velocity at the umbilical cord wheel (PSV 69 cm/s) was higher than that of 95th% [24] (Fig. 3D). The a-wave notch of the fetal venous duct was significantly deepened and PI increased, which was larger than that of 95th% [26] (Fig. 3E). We considered the possibility of umbilical cord torsion, and the obstetrician performed a emergent cesarean section. The postoperative diagnosis confirmed umbilical cord torsion for 36 weeks (Fig. 3F). Postoperative pathology of the umbilical cord revealed two umbilical arteries (one of which was atretic) and one umbilical vein.
The decrease of umbilical artery Doppler parameters in late pregnancy is significantly correlated with umbilical cord torsion, which may be used as a reason for prenatal ultrasound screening for umbilical cord torsion. The Doppler characteristics of umbilical artery blood flow during umbilical cord torsion are consistent with the basic principle of the changes of blood flow Doppler parameters after vascular stenosis in other parts of the body. We suggest that a multicenter prospective cohort study is needed to further evaluate these findings.
GA, gestational age; PSV, peak systolic velocity; S/D, systolic/diastolic ratio; RI, resistance index; PI, pulsatility index; NT, nuchal translucency; UCI, umbilical coiling index.
The dataset generated and/or analysed during the study are available from the corresponding author on reasonable request.
YL and DZ designed the research study. YL performed the research. YS provided help and advice on statistics. YL analyzed the data. YL and DZ wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
The study was conducted in accordance with the Declaration of Helsinki. This study passed the exemption of informed consent in Peking University Shenzhen Hospital and the protocol was approved by the Ethics Committee of Peking University Shenzhen Hospital (Ethics number: 2022 NO.010).
We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.
This research was funded by Shenzhen Key Medical Discipline Construction Fund (No. SZXK051), Sanming Project of Medicine in Shenzhen (No. SZSM202111011) and Shenzhen Development and Reform Commission (No. XMHT20190104001).
The authors declare no conflict of interest.
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