1. Introduction
Ectopic pregnancy (EP) refers to the implantation and development of fertilized
eggs in organs or tissues outside the uterine cavity, with an incidence of 2.0%,
which can lead to an acute abdomen and internal bleeding [1]. With the
development of new medications, the continuous improvement of ultrasonic
diagnostic technology, and the clinical application of serum human
chorionic gonadotrophin (-hCG) ultrasonic threshold [2], the early
diagnosis of ectopic pregnancy has been significantly improved. A large
proportion of patients with ectopic pregnancy can be conservatively managed [1, 3]. The conservative treatment of ectopic pregnancy includes expectant treatment,
mifepristone, methotrexate, methotrexate combined with mifepristone and other
drugs [4]. There are various conservative treatments for ectopic pregnancy, all
with different curative effects. The success rate of methotrexate (MTX) treatment
of ectopic pregnancy is 70%–95%, and there are some patients who require to
surgical treatment due to the failure of conservative management [5, 6, 7].
Therefore, the efficacy of conservative treatment for ectopic pregnancy and the
risk factors that affect its success need to be further explored. This study
analyzed the clinical data of conservative treatment of ectopic pregnancy in our
hospital during the past 10 years, explored the high-risk factors for failure in
conservative treatment of ectopic pregnancy, and compared the clinical success
rates of the expected treatment group, mifepristone group, methotrexate group,
and methotrexate combined with mifepristone group.
2. Materials and Methods
2.1 Case Data
This study used convenience sampling to include a total of 225 patients
diagnosed with ectopic pregnancy in the obstetrics and gynecology department of
our hospital from January 2012 to November 2022. According to the treatment plan,
the patients were into 4 groups: 41 cases in the expected treatment group, 30
cases in the mifepristone group, 104 cases in the MTX group, and 50 cases in the
MTX combined with mifepristone group. Inclusion criteria: (1) elevated serum
-hCG; (2) gynecologic ultrasound: ultrasound did not reveal a
gestational sac or cystic echo in the uterine cavity, but demonstrated an
abnormal echogenic mass in the adnexal area, which was considered to be an
ectopic pregnancy; (3) the patient had no psoriasis or rheumatoid arthritis, no
history of drug allergies to methotrexate or mifepristone, no family planning
during this pregnancy, no abnormalities in routine blood screening, liver and
kidney function, and normal coagulation tests prior to treatment; (4) therapeutic
methods: expected treatment group: regular follow-up of serum -hCG
levels and ultrasound every 3 to 7 days. If the serum -hCG returned to
normal and the patient had not received any other treatment, this was considered
a therapeutic success. Mifepristone treatment group: Patients received 50 mg of
mifepristone twice a day for 5–7 consecutive days with serial measurements of
serum -hCG and ultrasound every 3–7 days. If the serum -hCG
returned to normal and the patient had not received any other treatment, the
treatment was considered to be successful. Methotrexate treatment group:
methotrexate 0.4 mg/kg/d was administered intramuscularly for 5 days; serial
serum measurements of -hCG and ultrasound every 3 to 7 days. If the
serum -hCG returned to normal and the patient did not receive any other
treatment, the regimen was considered successful. The combination of methotrexate
and mifepristone treatment group: methotrexate 0.4 mg/kg/d was administered by
intramuscular injection for 5 days, and oral mifepristone 50 mg twice a day for
5–7 days; serial levels of serum -hCG and ultrasound every 3 to 7 days.
If the serum -hCG returned to normal and the patient did not receive any
other treatment, the treatment was considered successful. Exclusion criteria: (1)
persistent ectopic pregnancy; (2) MTX was used for more than 1 course in the
methotrexate or MTX combined with mifepristone groups; (3) the utilization of
other drug treatment, such as Chinese patent medicine, traditional Chinese
medicine, etc.; (4) abnormalities in blood work, liver and kidney
function before treatment; (5) or patients with incomplete follow-up data in the
medical records.
2.2 Research Methods
2.2.1 Research Tools
2.2.1.1 Case Data Questionnaire
By using Microsoft Office EXCEL 2013 (Microsoft Corporation, Redmond, WA, USA),
we designed a self-designed questionnaire for case data, including the patient’s
age, gender, weight, height, body mass index (BMI), amenorrhea length,
pre-treatment abdominal pain score (using the Pain Visual Analog Scale (VAS)
score 0–10) vaginal bleeding, initial serum -hCG level, initial serum
progesterone level, maximum diameter of mass in the adnexal area, maximum depth
of pelvic effusion, and treatment outcome of each regimen.
2.2.1.2 Treatment Outcome Criteria
The outcomes of this study were divided into success and failure. Success: using
one of the four regimens alone, the patient was followed up for a decrease in
serum -hCG value to normal and did not undergo surgery or other
treatments. Failure: patients who were transferred to surgery or received other
treatment options due to an increase in abdominal pain or intraperitoneal
bleeding during or after treatment, or an increase or decrease of 15% in
serum -hCG levels on days 4–7 after treatment.
2.2.2 Data Collection Methods
One investigator collected the data according to the self-designed case data
questionnaire, and the accuracy of the collected data was checked by another
investigator. Abdominal pain score, serum -hCG level, progesterone
level, maximum diameter of adnexal mass, and maximum depth of pelvic effusion
were measured within the first 1–2 days for the four conservative treatment
groups.
2.2.3 Statistical Methods
SPSS 20.0 (IBM Corp., Armonk, NY, USA) and Microsoft Office EXCEL 2013 were used
to analyze the data. The statistical data were expressed by frequency or
percentage, and test was used for comparison between groups.
Continuous data were described by mean standard deviation or M
(quartile). One-way analysis of variance was used for comparison between groups,
and Student-Newman-Keuls (SNK) or Tamhane method was used for pairwise
comparison. Binary logistic regression model was used to analyze the influencing
factors of conservative treatment for all ectopic pregnancies, and the area under
the receiver operating characteristic (ROC) curve was used to test the predictive
effect of the model. p 0.05 was considered statistically
significant.
3. Results
3.1 Comparison of General and Clinical Data among the Four Groups
Using one-way analysis of variance, there were no statistically significant
differences in age, weight, height, BMI, length of amenorrhea, abdominal pain
score, initial progesterone level, maximum diameter of ultrasonic detected mass,
and maximum depth of pelvic effusion between the four groups (p
0.05). There were statistically significant differences in the initial serum
-hCG levels among the four groups (p 0.05). Vaginal
bleeding occurrence was statistically significant (p 0.05) as was
the treatment success rate (p 0.05).
The three indicators (initial serum -hCG level, vaginal bleeding rate,
and treatment success rate) that were statistically significant between the
groups were compared pairwise respectively. For initial serum -hCG
levels: the serum -hCG 200.45 mIU/mL (105.13, 517.58) in the expectant
treatment group was compared with that in the MTX group 497.15 mIU/mL (278.55,
1971.95) and the serum -hCG 560 mIU/mL (250.00, 1480.00) in the MTX
combined mifepristone group, and the differences were statistically significant
(p = 0.004, p = 0.021). There was no significant difference
between the other groups (p 0.05). The comparison of the vaginal
bleeding rate between MTX group (87/104, 83.65%) and MTX combined mifepristone
group (49/50, 98%) demonstrated statistical significance (p = 0.009),
while no significant difference was noted among other groups (p
0.05). For the success rate of treatment, there was a significant difference
between the expectant treatment (37/41, 90.24%) and MTX group (70/104, 67.31%)
(p = 0.005), and there was no significant difference between the other
groups (p 0.05) (Table 1).
Table 1.Comparison of general and clinical data among the four groups.
|
Group |
Statistical value |
p value |
|
Expectant treatment |
Mifepristone |
MTX |
MTX + Mifepristone |
|
Cases (n) |
41 |
30 |
104 |
50 |
|
|
Age (y) |
30.46 5.85 |
31.97 6.26 |
31.31 5.83 |
30.12 5.79 |
0.851 |
0.467 |
BMI (kg/m) |
21.94 3.61 |
22.47 3.32 |
21.10 2.80 |
21.50 3.20 |
1.823 |
0.144 |
Amenorrhea length (d) |
44.17 7.87 |
47.17 9.52 |
46.48 10.16 |
45.95 9.75 |
0.737 |
0.531 |
Abdominal pain score (F) |
0 (0, 2) |
0 (0, 2) |
1 (0, 2) |
0 (0, 2) |
1.167 |
0.323 |
Initial progesterone level (ng/mL) |
2.33 (1.21, 4.57) |
3.28 (1.57, 6.14) |
4.54 (2.72, 7.92) |
4.1 (1.71, 8.10) |
1.98 |
0.119 |
Maximum diameter of the mass (cm) |
2.1 (1.33, 2.9) |
2.0 (1.48, 2.9) |
2.0 (1.18, 2.73) |
1.7 (1.40, 2.40) |
0.091 |
0.965 |
Maximum depth of pelvic effusion (cm) |
0 (0, 1.85) |
0 (0, 1.68) |
0.8 (0, 1.73) |
1.1 (0, 1.60) |
1.126 |
0.339 |
Initial serum -hCG level (mIU/mL) |
200.45 (105.13, 517.58) |
206.50 (81.85, 488.08) |
497.15 (278.55, 1971.95) |
560 (250.00, 1480.00) |
2.773 |
0.042 |
Vaginal bleeding rate (%) |
92.68 |
90 |
83.65 |
98 |
7.959 |
0.047 |
Treatment success rate (%) |
90.24 |
83.33 |
67.3 |
80 |
10.299 |
0.016 |
MTX, methotrexate; BMI, body mass index; -hCG, human
chorionic gonadotrophin.
3.2 Comparison of General and Clinical Data for the Four Groups of
Patients with Serum -hCG Levels Less than 1000 mIU/mL
Among the four groups of patients with serum -hCG level less than 1000
(37 patients in the expectant treatment group, 28 patients in the mifepristone
group, 76 patients in the MTX group, and 35 patients in the MTX combined with
mifepristone group), there were no significant differences in age, BMI, length of
amenorrhea, abdominal pain score, initial progesterone level, vaginal bleeding
rate, maximum diameter of adnexal mass, and maximum depth of pelvic effusion
among the four groups (p 0.05). Serum -hCG levels of four
groups of patients before treatment showed statistical significance between the
expected treatment group and the mifepristone group (p = 0.002), while
the other groups (expected treatment group, MTX group, MTX combined with
mifepristone group) showed no significant difference (p 0.05). The
success rates of treatment in the four groups were 94.59%, 82.14%, 81.58% and
88.57%, respectively. Pearson Chi-square test showed no significant difference
between groups (p = 0.263) (Table 2).
Table 2.Comparison of general and clinical data of serum -hCG
level less than 1000 mIU/mL in four groups.
|
Group |
Statistical value |
p value |
|
Expectant treatment |
Mifepristone |
MTX |
MTX + Mifepristone |
|
Cases (n) |
37 |
28 |
76 |
35 |
|
|
Age (y) |
30.51 6.10 |
32.11 6.47 |
31.58 6.06 |
30.43 4.95 |
0.684 |
0.563 |
BMI (kg/m) |
21.88 3.57 |
22.64 3.36 |
21.22 2.97 |
21.70 3.31 |
1.443 |
0.232 |
Amenorrhea length (d) |
44.22 7.77 |
47.36 9.83 |
45.95 9.74 |
44.51 9.75 |
0.782 |
0.505 |
Abdominal pain score (F) |
0 (0, 2) |
0 (0, 2) |
0 (0, 2) |
0 (0, 2) |
1.029 |
0.381 |
Initial progesterone level (ng/mL) |
2.33 (1.24, 4.23) |
3.27 (1.72, 6.73) |
4.38 (2.56, 7.19) |
5.17 (1.69, 8.13) |
1.801 |
0.151 |
Maximum diameter of the pelvic mass (cm) |
2.00 (1.40, 3.20) |
2.00 (1.63, 3.03) |
2.10 (1.20, 2.70) |
1.65 (1.35, 2.30) |
0.318 |
0.812 |
Maximum depth of pelvic effusion (cm) |
0 (0, 2) |
0 (0, 1.65) |
1.10 (0, 1.80) |
1.15 (0, 1.65) |
1.253 |
0.292 |
Initial serum -hCG level (mIU/mL) |
188.80 (102.20, 337.00) |
186.05 (80.00, 316.40) |
387.60 (214.30, 562.80) |
307.50 (123.78, 561.65) |
5.343 |
0.002 |
Vaginal bleeding rate (%) |
94.59 |
92.86 |
85.53 |
94.29 |
3.613 |
0.306 |
Treatment success rate (%) |
94.59 |
82.14 |
81.58 |
88.57 |
3.987 |
0.263 |
3.3 Comparison of General and Clinical Data for the Four Groups of
Patients with Serum -hCG Levels 1000 mIU/mL
Among the four groups of patients with serum -hCG level 1000
mIU/mL, there were 4 patients in the expectant treatment group, 2 in the
mifepristone group, 28 in the MTX group, and 15 in the MTX combined mifepristone
group. Due to the small number of patients in the expectant management group,
mifepristone group and MTX group, the three groups were combined into one group
and renamed as the other treatment group, with a total of 34 patients. The MTX
combined with mifepristone group was compared with the other treatment groups,
and there were no significant differences in age, BMI, length of amenorrhea,
abdominal pain score, serum -hCG level, progesterone level, maximum
diameter of adnexal mass, and maximum depth of pelvic effusion between the two
groups (p 0.05). For the comparison of treatment success rate, MTX
combined with mifepristone group (9/15, 60%) was significantly higher than other
treatment groups (10/34, 29.4%), and the difference was statistically
significant (p = 0.045) (Table 3).
Table 3.Comparison of general and clinical data of blood -hCG
level greater than or equal to 1000 mIU/mL in four groups.
|
Group |
Statistical value |
p value |
|
Other treatment groups |
MTX + Mifepristone |
|
Cases (n) |
34 |
15 |
|
|
Age (y) |
30.47 4.78 |
29.40 7.55 |
0.362 |
0.55 |
BMI (kg/m) |
20.93 2.55 |
21.06 3.68 |
0.021 |
0.886 |
Amenorrhea length (d) |
47.24 10.76 |
48.00 11.92 |
0.049 |
0.825 |
Abdominal pain score (F) |
2 (0, 1.75) |
0 (0, 1.50) |
1.479 |
0.23 |
Initial progesterone level (ng/mL) |
5.44 (2.76, 14.78) |
2.60 (1.57, 8.79) |
1.534 |
0.224 |
Maximum diameter of pelvic mass (cm) |
1.9 (1.03, 2.80) |
2 (1.20, 1.95) |
1.527 |
0.223 |
Maximum depth of pelvic effusion (cm) |
0 (0, 1.6) |
0 (0, 1.4) |
0.333 |
0.567 |
Initial serum -hCG level (mIU/mL) |
2476.90 (1454.5, 3313.70) |
3106.75 (2130.97, 4555.17) |
1.484 |
0.229 |
Vaginal bleeding rate (%) |
76.47 |
100 |
4.218 |
0.04 |
Treatment success rate (%) |
29.4 |
60 |
4.036 |
0.045 |
3.4 Binary Logistic Regression Model Analysis of the Effect of
Conservative Treatment on Ectopic Pregnancy
The clinical data of 225 patients in 4 groups were included in the logistic
regression equation to explore the main risk factors affecting the efficacy of
conservative treatment of ectopic pregnancy. The risk factors that may be
considered to be influential, including age, weight, height, BMI, length of
amenorrhea, maximum diameter of adnexal mass, maximum depth of pelvic effusion,
serum -hCG value, serum progesterone level, abdominal pain score and
vaginal bleeding, were used as independent variables. Treatment efficacy was used
as the dependent variable. The independent variable of vaginal bleeding was
assigned as “0” = none, “1” = yes; the efficacy was assigned a value of “0” =
failure and “1” = success. Using binary logistic regression for statistical
analysis, the results demonstrated that the pre-treatment serum -hCG
level (odds ratio (OR) = 0.999, 95% confidence interval (95% CI) 0.999–1) and
abdominal pain score (OR = 0.4, 95% CI 0.267–0.6) were independent risk
factors. Serum -hCG was more valuable in predicting the outcome of
conservative treatment for ectopic pregnancy, while other indicators had no
significant impact on the treatment outcome (Table 4). The ROC curve was used to
test the prediction effect of the model, and the area under the ROC curve was
0.881, 95% CI (0.814, 0.949), indicating a positive prediction effect (Fig. 1).
Table 4.Results of Logistic regression analysis of the efficacy of
conservative treatment of ectopic pregnancy.
Risk factors |
Partial regression coefficient |
Standard error |
Wald value |
p value |
OR value |
95% CI |
Age |
0.027 |
0.048 |
0.322 |
0.571 |
1.027 |
0.936–1.128 |
Weight |
0.042 |
0.543 |
0.006 |
0.938 |
1.043 |
0.360–3.021 |
Height |
0 |
0.38 |
0 |
1 |
1 |
0.475–2.106 |
BMI |
−0.061 |
1.341 |
0.002 |
0.964 |
0.941 |
0.068–13.026 |
Amenorrhea length |
−0.021 |
0.026 |
0.706 |
0.401 |
0.979 |
0.931–1.029 |
Abdominal pain score |
−0.916 |
0.207 |
19.646 |
0 |
0.4 |
0.267–0.6 |
Vaginal bleeding |
−0.062 |
0.753 |
0.007 |
0.935 |
0.94 |
0.215–4.11 |
Progesterone |
−0.048 |
0.046 |
1.079 |
0.299 |
0.953 |
0.871–1.044 |
Serum -hCG |
−0.001 |
0 |
9.835 |
0.002 |
0.999 |
0.999–1 |
Mass diameter |
−0.334 |
0.28 |
1.425 |
0.233 |
0.716 |
0.413–1.24 |
Pelvic effusion |
−0.087 |
0.254 |
0.118 |
0.731 |
0.916 |
0.557–1.507 |
OR, odds ratio; 95% CI, 95% confidence interval.
Fig. 1.
ROC curve of binary logistic regression model influencing the
efficacy of conservative treatment of ectopic pregnancy. ROC, receiver
operating characteristic; TPR, true positive rate; FPR, false positive rate.
4. Discussion
Ectopic pregnancy is the implantation and development of the fertilized egg
outside the uterine cavity, which is a common gynecologic condition causing an
acute abdomen and has the risk of massive intra-abdominal hemorrhage. With the
improvement of medical diagnosis and treatment and the enhancement of patients’
awareness of treatment, most patients diagnosed with ectopic pregnancy do not
have the typical manifestations of acute abdomen. Conservative treatment mainly
includes expectant therapy, mifepristone, methotrexate, and methotrexate combined
with mifepristone. However, in the process of conservative treatment, some
patients will require surgical treatment because of an unsatisfactory decrease in
serum -hCG, increasing abdominal pain, and occurrence of intra-abdominal
hemorrhage [8].
Multiple comparisons of the results of this study found that within the serum
-hCG levels of four groups of patients, there are differences in the
-hCG levels. When the expected treatment group serum -hCG
levels were compared with the MTX group and the MTX combined with mifepristone
group, the difference was statistically significant (p 0.05). There
was no significant difference in comparison between the other groups (p 0.05). Comparison of treatment success rates: the expected treatment group
success was significantly higher than the MTX group, and there was no significant
difference in comparison between the other groups. This indicates that the serum
-hCG level prior to treatment is the main factor affecting the success
of conservative treatment for ectopic pregnancy. Therefore, the level of serum
-hCG at the time of the initial treatment is the most important factor
affecting the success of conservative treatment. Based on previous literature
reports, Kingsbury’s [9] study found that baseline serum -hCG level was
an important factor for predicting the success of conservative treatment of EP
(p 0.05). Women with initial serum -hCG level 1500
mIU/mL could receive expectant treatment, and women with serum -hCG
level 1000 mIU/mL had a higher success rate. In addition, Alsammani et
al. [10] investigated predictors of successful single-dose MTX treatment of EP,
and the results demonstrated that initial serum -hCG concentration was
the best predictor of successful MTX treatment. Their conclusions are consistent
with the results of this study.
There are many factors affecting the success of conservative treatment of
ectopic pregnancy, most being related to the diameter of ectopic pregnancy mass,
the trend of serum -hCG values, abdominal pain symptoms, and the depth
of pelvic free effusion. Other important factors include the patient’s age,
weight, height, length of amenorrhea, and vaginal bleeding [11, 12]. In order to
explore the main risk factors affecting the efficacy of conservative treatment of
ectopic pregnancy, logistic regression analysis was used to show that the initial
serum -hCG level and abdominal pain score were the most important risk
factors affecting the success of conservative treatment of ectopic pregnancy. The
area under the ROC curve was 0.881, 95% CI (0.814, 0.949). This indicates that
the predictive effect is good. It further proves that the serum -hCG
level before treatment was closely related to the success of conservative
treatment of ectopic pregnancy.
The degree of abdominal pain is related to the abortion or rupture of the tubal
pregnancy, and the level of -hCG in patients with severe abdominal pain
is often higher than that in patients with mild abdominal pain [13], which has a
great influence on the choice of the clinical treatment [14, 15]. It is necessary
to evaluate the severity of abdominal pain before choosing drug conservative
treatment or expectant management, and to evaluate the intra-abdominal bleeding
by combining ultrasound examination and vaginal posterior fornix puncture. If
there is minimal intra-abdominal bleeding and abdominal pain is absent,
conservative treatment can be selected. In addition, attention should be paid to
the degree of abdominal pain in the treatment process, because the aggravation of
abdominal pain usually indicates the possibility of increased abdominal bleeding
or rupture of the tubal pregnancy.
The conservative treatment options for ectopic pregnancy mainly include
expectant management, mifepristone, methotrexate, and methotrexate combined with
mifepristone. Determining the efficacy of these four options and how to choose
them in clinical practice remains to be explored. Since serum -hCG level
is the main risk factor affecting the conservative treatment of ectopic
pregnancy, the serum -hCG level was divided into two levels: less than
1000 mIU/mL and greater than or equal to 1000 mIU/mL. Comparison of general and
clinical data of serum -hCG level less than 1000 mIU/mL among the four
groups showed statistical significance between the expectant treatment group and
the mifepristone group (p = 0.002), and no significant difference among
the other groups (p 0.05). The success rates of the four groups were
94.59%, 82.14%, 81.5% and 88.57%, respectively. There was no significant
difference among the four groups (p = 0.263). Comparing the general and
clinical data of the four groups of patients with serum -hCG levels
greater than or equal to 1000 mIU/mL, the MTX combined with mifepristone group
(9/15, 60%) was significantly higher than the other treatment groups (10/34,
29.4%), and the difference was statistically significant (p = 0.045).
Therefore, this study suggests that there is no significant difference in the
efficacy of these four conservative treatments for patients with serum
-hCG level less than 1000 mIU/mL. For patients with serum -hCG
level greater than or equal to 1000 mIU/mL, the cure rate of MTX combined with
mifepristone is significantly superior to the other regimens. Since this study
was a retrospective study with a small sample size and was limited to only one
hospital, the conclusions of this study need to be supported by further
multi-center clinical studies.
5. Conclusions
Initial serum -hCG level and abdominal pain score are the main risk
factors affecting the success rate of conservative management of ectopic
pregnancy. When the serum -hCG level was less than 1000 mIU/mL, there
was no significant difference between the four conservative treatment regimens.
When the serum -hCG level 1000 mIU/mL, the success rate of MTX
combined with mifepristone had obvious advantages over the other treatments.
However, there are some limitations in this study, and the conclusions need to be
supported by more multicenter clinical trials.
Availability of Data and Materials
The datasets used and/or analyzed during the current study are available from
the corresponding author on reasonable request.
Author Contributions
HX and HT designed the research study. QJ and YC performed the research. WS and
WL analyzed the data. CS and JC designed the research. All authors contributed to
editorial changes in the manuscript. All authors read and approved the final
manuscript. All authors have participated sufficiently in the work and agreed to
be accountable for all aspects of the work.
Ethics Approval and Consent to Participate
All subjects gave their informed consent for inclusion before they participated
in the study. The study was conducted in accordance with the Declaration of
Helsinki, and the protocol was approved by the Ethics Committee of Notification
Letter of Ethics Committee of Zigong Fourth People’s Hospital (approval number:
2023 No. (005)).
Acknowledgment
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.
Funding
This work was supported by grants from Zigong Science and Technology Bureau Fund
(2021ZC27); Top Talent of Changzhou “The 14th Five-Year Plan” High-Level Health
Talents Training Project (2022CZBJ074), the maternal and child health key talent
project of Jiangsu Province (RC202101), the maternal and child health research
project of Jiangsu Province (F202138).
Conflict of Interest
The authors declare no conflict of interest. Jiming Chen is serving as one of the Guest editors of this journal. We declare that Jiming Chen had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Michael H. Dahan.