748224

review-article2017
SJS0010.1177/1457496917748224C. Friis, J. P. Rothman, J. Burcharth, J. RosenbergOptimal timing for cholecystectomy after ERCP

Review Article
SJS
SCANDINAVIAN
JOURNAL OF SURGERY

Optimal Timing For Laparoscopic Cholecystectomy After

Endoscopic Retrograde Cholangiopancreatography:
A Systematic Review

C. Friis1, J. P. Rothman1 , J. Burcharth2, J. Rosenberg1

1 Center for Perioperative Optimization, Department of Surgery, Herlev Hospital, University of Copenhagen,
Herlev, Denmark
2  Department of Surgery, Sjællands Universitetshospital, Køge, Køge, Denmark

Abstract

Background and Aims: Endoscopic retrograde cholangiopancreatography followed

by laparoscopic cholecystectomy is often used as definitive treatment for common bile
duct stones. The aim of this study was to investigate the optimal time interval between
endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy.
Materials and Methods: PubMed and Embase were searched for studies comparing
different time delays between endoscopic retrograde cholangiopancreatography and
laparoscopic cholecystectomy. Observational studies and randomized controlled
trials were included. Primary outcome was conversion rate from laparoscopic to open
cholecystectomy and secondary outcomes were complications, mortality, operating time,
and length of stay.
Results: A total of 14 studies with a total of 1930 patients were included. The pooled estimate
revealed an increase from a 4.2% conversion rate when laparoscopic cholecystectomy was
performed within 24 h of endoscopic retrograde cholangiopancreatography to 7.6% for 24–
72 h delay to 12.3% when performed within 2 weeks, to 12.3% for 2–6 weeks, and to a 14%
conversion rate when operation was delayed more than 6 weeks.
Conclusion: According to this systematic review, it is preferable to perform
cholecystectomy within 24  h of endoscopic retrograde cholangiopancreatography to
reduce conversion rate. Early laparoscopic cholecystectomy does not increase mortality,
perioperative complications, or length of stay and on the contrary it reduces the risk of
reoccurrence and progression of disease in the delay between endoscopic retrograde
cholangiopancreatography and laparoscopic cholecystectomy.

Correspondence:
Josephine Philip Rothman, M.D.
Center for Perioperative Optimization Scandinavian Journal of Surgery
Department of Surgery 1­–8
Herlev Hospital and University of Copenhagen © The Finnish Surgical Society 2017
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Email: josephineprothman@gmail.com
2 C. Friis, et al.
Key words: Endoscopic retrograde cholangiopancreatography; hepato-pancreatic biliary surgery; laparoscopic
cholecystectomy; conversion rate; time delay; complication
Introduction
Endoscopic retrograde cholangiopancreatography
(ERCP) is considered standard treatment for patients
presenting with common bile duct stones (1) and is
successful in more than 90% of patients (2). However,
ERCP can induce complications including pancreatitis
and cholecystitis (1, 3, 4). These complications may
affect a subsequent laparoscopic cholecystectomy (LC)
leading to conversion to open cholecystectomy, periop-
erative complications, and longer operating time (5–8).
It is not yet known whether or not the time interval
between ERCP and LC plays a part in increasing con-
version rates, complications, and operating time.
The purpose of this systematic review was to inves-
tigate whether or not the time interval between ERCP
and LC affects the rate of conversion to open surgery
and risk of operative complications.
Materials And Methods
This systematic review was conducted according to
the Preferred Reporting Items for Systematic Reviews
and Meta-analysis (PRISMA) guideline (9). Prior to
data extraction and analysis, a protocol for the review
was registered in the PROSPERO database with the
registration number CRD42015029322 (10).
Eligibility Criteria
Observational (cohort and register-based) studies and
randomized controlled trials (RCTs) written in English
or Danish were included. The population included
adults who had pre- or intraoperative ERCP, which
was followed by LC. A comparison of time frames
between each study was made. Patients within the dif-
ferent time frames were compared according to out-
comes. The primary outcome was the rate of
conversion from laparoscopic to open cholecystec-
tomy, and secondary outcomes were 30-day mortality,
length of stay (LOS), perioperative complications, and
duration of surgery.
Information Sources And Search Strategy
The literature search was conducted in PubMed and
Embase on 24 November 2016. The following search
strategy was developed in PubMed, and thereafter
adjusted to fit Embase: (((laparoscopic cholecystec-
tomy or laparoscopic cholecystectomies or celioscopic
cholecystectomy or celioscopic cholecystectomies)
and (endoscopic retrograde cholangiopancreatogra-
phy or endoscopic retrograde cholangiopancreatogra-
phies or ERCP) and (gallstone or gall stones or biliary
calculi or gall stone or common bile duct calculi or
common bile duct gallstones or common bile duct
gallstones or common bile duct biliary calculi or chole-
lithiasis)) not children not infants).
The review tool Covidence (11) was used to screen
the results from the literature search. After import of
the results, duplicates occurring in both databases
were removed prior to the first screening. Two authors
(C.F., J.P.R.) independently screened titles and
abstracts for relevant publications. Any disagreements
were solved by discussion.
Data Collection Process
The extracted data included demographics, methods
used in the study such as aim of study, inclusion and
exclusion criteria, and study design. Details of inter-
ventions used in each group, time between ERCP and
LC, and outcomes such as conversions, mortality,
LOS, perioperative complications, operating time, and
complications in delay between ERCP and LC were
also collected.
Risk Of Bias
As the systematic review includes both cohort studies
and RCTs, two different risk of bias tools were used.
Risk of bias within cohort studies was assessed using
the Newcastle Ottawa Scale (NOS) (12). The scale
judges each study in three areas: selection process,
comparability of groups, and outcome assessment.
Each area rewards a number of stars depending on
bias in the study and a study can receive a maximum
of nine stars. A high amount of stars represents a study
with low risk of bias.
Risk of bias within RCTs was assessed using The
Cochrane Collaboration’s Risk of Bias Assessment
Tool (13). This tool examines six different domains in
each study: sequence generation, allocation conceal-
ment, blinding of participants, personnel and outcome
assessors, incomplete outcome data, selective out-
come reporting, and other sources of bias. In each
domain, a “yes,” “no,” or “unclear” can be obtained
for each individual study. Receiving a “yes” corre-
sponds to a low risk of bias while a “no” equals the
opposite. If a study receives an “unclear” judgment,
there is an uncertain risk of bias in the belonging
domain.
Statistics
The studies were heterogeneous to an extent that we
chose not to perform a meta-analysis (14). Due to low
sample size, many of the studies did not reach a level
of significance but only showed tendencies. In order to
get clinically relevant results, data concerning the pri-
mary outcome were pooled. A chi-square test was per-
formed on the overall results despite the weak
scientific value of the pooled estimate. Data were
pooled if the time frame between ERCP and LC was
stated clearly in the text or tables.
 Optimal timing for cholecystectomy after ERCP
Fig. 1. Flow diagram of identification, screening, and eligibility process.
Results
The literature search produced 1911 publications.
After duplicates were removed, 1652 publications
were screened on title and abstract. Of these, 41 pub-
lications were potentially relevant, and further
assessment revealed 14 publications eligible for this
review (Fig. 1).
The eligible studies included eight retrospective
cohort studies, two prospective cohort studies, and
four RCTs, evaluating a total of 1913 patients (6,
15–27). Table 1 summarizes the characteristics of
each study, including the time delay between ERCP
and LC.
Risk Of Bias
The median score of the observational studies assessed
with NOS score was 7 (range, 5–7). The NOS score was
typically reduced due to selection of the non-exposed
cohort (selection) and adequacy of follow-up of the
cohort (outcome) (Table 2). However, these assess-
ments were not relevant in the included cohort studies
because the cohorts were not as such divided into
non-exposed and exposed cohorts and a long follow-
up was not of particular interest.
Risk of bias in the RCTs varied between studies
(Fig. 2). It was not possible to evaluate risk of bias in
three domains: blinding of participants, personnel and
outcome assessors, and other sources of bias. In three
(22–24) of the four RCTs, there was high risk of bias in
selective outcome reporting.
3
Baseline Characteristics
The baseline characteristics, including age (6, 15, 17–
27), gender (6, 15, 17, 18, 20–27), American Society of
Anesthesiologists (ASA) score (18–20, 23, 24, 27), body
mass index (BMI) (23, 24), size of common bile duct
stone (20, 21, 23, 24, 27), and level of bilirubin (15, 18,
21, 23, 27), were not significantly different in the stud-
ies that registered the characteristics. Only in two stud-
ies (6, 22) there was a significant different between
groups on two parameters, bilirubin and BMI.
The severity of the gallbladder disease was regis-
tered in some of the studies (Table 3). Four studies
excluded patients with acute cholecystitis, cholangitis,
and gallstone pancreatitis (15, 18, 21, 23). In one study,
significantly more patients in the delayed group had
acute cholecystitis (20), and four other studies found
no difference between groups (17, 19, 22, 25). Another
study (26) had significantly more patients with either
cholangitis or gallstone pancreatitis in the delayed
group, and in five studies there was no difference (17,
19, 20, 22, 25).
Conversion Rate
Conversion rate was an outcome in 13 studies (6, 15,
17–27). In the results from the individual studies, there
was no significant difference in conversion rate when
ERCP and LC during the same session or within 24 h
were compared to a delay between ERCP and LC of
less than 2 weeks (15, 18, 19, 21, 24–27). However,
when results from the studies were combined, the
 4
Table 1
Study characteristics of included cohorts and randomized controlled trials..
Demographics Outcomes

Author Study No. of Group: time intervals Primary Secondary

design patients between ERCP and LC
Conversion Mortality Complications LOS
(%) p (%) p (%) p (days) p OT (min) p

Golub et al. (19) RC 99 Group 1: 0 days (ERCP during LC) 13.6 0.99 0 – 0 – 2.9 0.005 122.4 0.12
Group 2: 2 days (in average) 15.6 1.3 5.2 5.2 142.9
Wright et al. (26) RC 67 Group 3: 0 days (ERCP during LC) 0.0 – 0 – – – 3.4 ± 0.5 NS 210 ± 9 NS
Group 1: 1.7 ± 0.2 days (ERCP prior 0.0 0 – 6.8 ± 1.6 115 ± 4
to LC)
Rábago et al. (22) RCT 123 Group 1: 0 days (ERCP during LC) 5.1 NS 0 NS 0 – 5 ± 3 <0.001 142 ± 58 <0.0001
Group 2: <8 weeks 8.6 0 1.6 8 ± 5 102 ± 52
Morino et al. (21) RCT 91 Group 1: 0 days (ERCP during LC) 4.4 – 0 – 4.3 ± 3.1 <0.0001 127 (90–180)  
Group 2: 4.3 days (1–18) 0 0 – 8 ± 5.5 ERCP 45 (25–60)  
LC 125 (55–180)
Tzovaras et al. (24) RCT 99 Group 1: 0 days (ERCP during LC) 4.0 NS 2 NS – – 4 (2–19) 0.0004 95 –
Group 2: <2 days (<48 h) 2.0 0 2 5.5 (3–22) 79 min (ERCP
29 min, LC 50 min)
Zang et al. (27) RC 156 Group 1: 0 days (ERCP during LC) 1.1 NS 0 – – – 3.13 ± 0.96 0.27 53.6 ± 12.1 0.7
Group 2: >3 days 1.5 0 – 2.95 ± 1.08 52.8 ± 13.4
Ding et al. (18) RC 150 Group 1: 0 days (ERCP during LC) 1.4 0.74 0 – – – 3 (2–6) <0.001 112.1 ± 30.8 >0.05
Group 2: 1–3 days (24–72 h) 0.0 0 – 4.5 (3–12) 104.9 ± 18.2
C. Friis, et al.

Busic et al. (16) PC 20 Group 1: <1 day (24 h) – – – – – – 7 (4–11) <0.0001 – –

Group 2: >1 day (24 h) (median – – – 12 (10–60) –
3 days)
de Vries et al. (17) RC 83 Group 1: <2 weeks 4.0 0.052 0 – 4.3 1.0 – – 75 0.35
Group 2: 2–6 weeks 31.0 0 6.7 – 75
Group 3: >6 weeks 16.0 0 11.1 – 65
Salman et al. (23) RCT 79 Group 1: 1–3 days (24–72 h) 2.5 0.02 0 – 0 – 1.96 ± 0.81 NS 38.3 ± 7.8 0.03
Group 2: 3–7 days 17.5 0 0 3.64 ± 2.33 68.4 ± 5.96
Bostanci et al. (6) RC 308 Group 1: <2 days 13.7 – – 1.1 – 2.2 ± 1.8 0.641 52.5 ± 28.9 0.511
Group 2: 3–42 days 11.0 0.472 – 2.0 2.6 ± 3.6 58.4 ± 33.6
Group 3: >6 weeks (>42 days) 16.8 – 1.8 2.7 ± 6.1 53.52 ± 30
Kwon et al. (20) RC 305 Group 1: <2 weeks 14.5 0.71 – – – – –  
Group 2: 2–6 weeks 18.4 – – – – – – –
Group 3: >6 weeks 15.6 – – – –  
Borreca et al. (15) RC 93 Group 1: Same day (but not ERCP 0.0 0.33 0 – – 4.7 0.001 76  
during LC)
Group 2: 1–3 days 3.5 0 – – 8 80 0.7
Group 3: >3 days (mean 15 days) 0.0 0 – 10.7 84  
Wild et al. (25) RC 240 Group 1: Same day (but not ERCP 12.0 0.86 0 NS – – 3 (2–7) <0.0001 88 (70–119) 0.46
during LC)
Group 2: >1 day 14.0 1.1 – 5 (3–7) 89 (68–125)

Bold values are significant results. RC: retrospective cohort; PC: prospective cohort; RCT: randomized controlled trial; LOS: length of stay; OT: operating time; LC: laparoscopic
cholecystectomy; ERCP: endoscopic retrograde cholangiopancreatography; NS: no significant difference; –: no available data.
 Optimal timing for cholecystectomy after ERCP 5

Total

7
7
7
6
7
6
7
7
5
7
of follow up
Adequacy

of cohorts

0
0
0
0
0
0
0
0
0
0
for outcomes to
Was follow-up

occur (1 = yes,
long enough

0 = no)

1
1
1
1
1
1
1
1
1
1
Assessment
of outcome
Outcome

1
1
1
1
1
1
1
1
1
1
complication, or
mortality, LOS,

operating time

Fig. 2. Risk of bias table according to the Cochrane Collaboration’s

controls for

tool (13).
Risk of bias table according to the Newcastle Ottawa Scale (12).

Study

pooled estimate showed an increase in conversion rate

1
1
1
0
1
1
1
1
1
1

as time increased between ERCP and LC, from 4.2%

Comparability

conversions

when operated within 24 h to 14% when operated

controls for

more than 6 weeks after ERCP (p < 0.0005) (Fig. 3). In

Study

two studies a group was excluded, as the time frame

between ERCP and LC was too wide (22) or unclear
1
1
1
1
1
0
1
1
0
1

(27). Conversion rate was lowest when LC was per-

Table 2

formed within 24 h of ERCP and increased signifi-

interest was not
that outcome of
Demonstration

(1 = yes, 0 = no)

cantly to 7.6% with a 24–72 h delay (p = 0.02). Likewise,

present at the
start of study

there was a significant increase in conversion rate

when the delay increased from 24 to 72 h to less than
2 weeks (p = 0.02), hereafter the conversion rate did not
show any significant changes as delay between ERCP
1
1
1
1
1
1
1
1
1
1

and LC increased (Fig. 3).

Considering the individual studies, two small stud-
Ascertainment

ies with 83 and 79 patients, respectively, showed a sig-

of exposure

nificant difference in the conversion rate when there

was a longer delay between ERCP and LC (17, 23). The
first study (17) revealed a time-wise development. The
1
1
1
1
1
1
1
1
1
1

lowest conversion rate (4%) was seen in the group

with a delayed surgery of less than 2 weeks, and then
non-exposed

the conversion rate peaked (31%) in the group delayed

Selection

2–6 weeks, where after it declined to 16% in the group

cohort
of the

delayed more than 6 weeks. This finding was sup-

ported by a tendency in another study (20), this was
0
0
0
0
0
0
0
0
0
0

however not significant. In the same manner, the sec-

Representativeness

ond study (23) showed a higher conversion rate

(17.5%) in the group with a longer delay between
of the exposed

ERCP and LC (3–7 days) compared with the group

receiving surgery within 1–3 days (2.5%).
Selection

cohort

1
1
1
1
1
1
1
1
0
1

Mortality
LOS: length of stay.
de Vries et al. (17)

In all, 11 of 14 studies included mortality in their

Borreca et al. (15)
Bostanci et al. (6)
Wright et al. (26)
Golub et al. (19)

Kwon et al. (20)

Busic et al. (16)

Zang et al. (27)
Ding et al. (18)

results (15, 17–19, 21–27). Of these, three studies

Wild et al. (25)

reported deaths among patients (19, 24, 25). Mortality

was very low; one study (24) reported mortality of 2%
in a group receiving ERCP and LC in the same session,
but no mortality in the group with a delay of 48 h to
 
6 C. Friis, et al.

Table 3
Gallbladder disease severity.

Acute cholecystitis Cholangitis Pancreatitis

Golub NS NS NS
Wright – Significantly more patients in
delayed group had cholangitis or
pancreatitis
Rabago NS NS NS
Morino Excluded – Excluded
Tzovaras – – –
Zang – – –
Ding – Excluded Excluded
Busic – – –
de Vries NS – NS
Salman Excluded Excluded Excluded
Bostanci – – –
Kwon Significantly more NS NS
patients in delayed
group
Fig. 3. Pooled data demonstrating how delay between ERCP and
Borreca Excluded Excluded Excluded cholecystectomy affects the rate of conversion from laparoscopic to
Wild NS NS NS open cholecystectomy. Overall chi-square test: p < 0.0005.

Excluded: patients excluded from the study; NS: no significant

difference between groups; –: not mentioned in study.
LC, whereas two other studies (19, 25) had no mortal-
ity in the group with LC within 24 h, but respectively
1.3% and 1.1% mortality in the groups with a delay of
more than 2 days. Thus, because of the very low mor-
tality rates, it was not possible to conclude anything
regarding this secondary outcome parameter.
Complications In Waiting Time Between Ercp
And LC
Three studies registered complications in the period
between ERCP and LC (15, 17, 20). One study reported
a risk of recurrence (defined as upper right quadrant
pain combined with common bile duct stones on
imaging and laboratory tests) of 15% at 15 days and
20% at 1 month (15). Two studies reported that 3.6%
and 8.5% developed acute cholecystitis in the delay
between ERCP and LC (17, 20).
Perioperative Complications
Six studies reported perioperative complications (6, 17,
19, 22–24). None of the studies that compared groups
where ERCP and LC occurred within the first 2 weeks
showed any significant results (6, 19, 22, 23, 26).
Perioperative complications such as common bile duct
injury and bile leak were seen in both the same-session
groups and the groups with delay between ERCP and
LC. In two studies, the consequence of a longer delay
between ERCP and LC was explored in relation to peri-
operative complications (6, 17). One of these studies
(17) showed a significant difference in the rate of perio-
perative complications. The group with the longest
delay between LC and ERCP (6 weeks) had the highest
rate of perioperative complications (11.1%). This was
compared with groups delayed 2 weeks and 2–6 weeks
with, respectively, 4.3% and 6.7% perioperative com-
plications. In addition, the complications were more
severe in the group that waited 6 weeks for LC, with
lesions of the common bile duct, ruptured gallbladder,
and bleeding cystic artery. This tendency was not
found in the other study (6).
LOS
A total of 12 studies reported LOS (6, 15, 16, 18, 19,
21–27). Across all studies except one (6), there was a
tendency for a longer LOS as the delay from ERCP to
cholecystectomy increased. One study (23) defining
LOS as the postoperative LOS found LOS to be longest
(median 4 days) in the group delayed 3–7 days for LC
after ERCP compared with LOS of median 2 days
when LC was delayed 1–3 days. The reason for a
longer LOS was due to significantly more converted
procedures in the second group. Two studies (15, 25)
defined LOS as the total LOS including ERCP and
admittance during waiting time for LC if the patient
stayed in hospital. They both found a longer LOS
when patients had a longer delay between ERCP and
LC, but when the time to operation was subtracted
there was no difference in LOS.
Duration Of Surgery
A total of 12 studies reported duration of surgery (6,
15, 17–19, 21–27). Seven studies included a group with
same-session ERCP and LC (18, 19, 21, 22, 24, 26, 27).
Of these, three studies showed a significant difference
with a longer operating time in the same-session
group (22, 24, 26). The difference in mean operating
time was 40, 16, and 95 min, respectively. In the study
with only 16-min difference in operating time, both
ERCP and operating time was included, and this was
not specified in the remaining two studies. In the
remaining five studies, all groups had a delay between
ERCP and LC (6, 15, 17, 23, 25). In these, only one of
the studies showed a significant difference (23).
 Optimal timing for cholecystectomy after ERCP
Operating time was longest (68 min) in the group with
the longest delay between ERCP and LC (3–7 days),
compared with operating time of 38 min when the
delay was 1–3 days.
Discussion
This systematic review concerning the optimal timing
for LC after ERCP showed a tendency for a lower con-
version rate when LC was performed within 24 h of
ERCP. The conversion rate increased when the delay
between ERCP and LC increased but leveled off when
the delay was longer than 2 weeks. LOS also sup-
ported a short delay between ERCP and LC, however,
when studied carefully it became clear that the increase
in LOS was due to the intentional delay between ERCP
and LC. The review also showed a high risk of reoc-
currence of bile duct stones or acute cholecystitis as
delay between ERCP and LC increased.
The most noticeable finding in this systematic
review was the conversion rate when all data were
pooled (Fig. 3). It was clear that patients should prefer-
ably be operated within 24 h of ERCP or at least within
the first few days. This is supported by one of the big-
ger RCTs (22) with a significant lower conversion rate
when operated within 72 h than 3–7 days after ERCP.
The results are also supported by other studies, despite
the fact that they do not reach significance (14, 16, 18,
19, 21, 24, 26). The explanation to these findings could
be that the ERCP itself creates an inflammation of the
hepatoduodenal ligament, making recognition of the
anatomy and dissection of Calot’s triangle more diffi-
cult in the following LC, and thereby increasing the
risk of conversion (17). Another explanation could be
that the longer delay between ERCP and LC allows the
disease to progress, for example with acute cholecysti-
tis or additional stones in the common bile duct, and
thereby complicating the following LC (1). Supporting
this theory, one study showed that risk of recurrence of
bile duct stones were 15% at 15 days and 20% at 1 month
(15), while two other studies showed an increase in
acute cholecystitis when the delay from ERCP to LC
was increased (17, 20). Regarding LOS, a shorter LOS
was obtained when ERCP and LC was in the same ses-
sion. The combined endoscopy and surgery allowed
an earlier discharge compared with the groups that
had to wait for surgery. While waiting for the LC,
patients were still hospitalized and therefore it leads to
a longer LOS. These results were supported by the
studies that only included groups with a delayed LC
after ERCP—the longer the delay, the longer the LOS.
The shorter total LOS could positively affect the eco-
nomical expenses, risk of nosocomial infections, and so
on. Operating time was, not surprisingly, longer when
ERCP and LC were performed in the same session,
compared to only performing LC.
The strength of this review is that it, to our knowl-
edge, is the first review regarding this subject. This
review aimed for a high transparency, as it followed
PRISMA guidelines as well as the registration of a
protocol in the PROSPERO database. However, a lim-
itation comes from the available studies with low
comparability caused by the high variety of time
frames between the subdivided groups. Between the
7
studies there was also a variety in inclusion and exclu-
sion criteria based on gallbladder disease severity;
however, the baseline characteristics show that there
was only little variety between groups in the individ-
ual studies. Another limitation was that this review
did not only include RCTs but also cohort studies.
More than 190 different tools exist for risk of bias
evaluation within studies (14), and the recommended
tool NOS was used for observational studies. It is,
however, difficult to deduce each individual study’s
weaknesses from a score on a scale. Therefore, risk of
bias assessment is a considerable limitation when
observational studies are used in systematic reviews.
Studies in this review were all relatively small, the
biggest study including 308 patients. Due to the small
sample sizes and heterogeneity between studies, a
meta-analysis was not relevant. Instead, data were
pooled and a chi-square test was performed. This
may also be regarded as a limitation but was the only
possible solution to reach a clinically relevant out-
come.
In conclusion, LC should optimally be performed
within the first 24 h of ERCP, and at least within
3 days, in order to decrease risk of conversion to lapa-
rotomy as well as perioperative complications. If local
logistics permit same-session ERCP and LC, this
could be a good option with low rates of conversions
and complications. A routine of postponing LC to a
period of 2–6 weeks after ERCP and sometimes even
longer does not seem optimal based on the available
data.
Acknowledgements
C.F. and J.P.R. shared first authorship as both authors con-
tributed equally to the study.
Declaration Of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of
this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
J. P. Rothman http://orcid.org/0000-0002-7301-2702
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Received: April 7, 2017
Accepted: October 4, 2017