Monitoring Severity of Multiple Organ Dysfunction

Syndrome: New and Progressive Multiple Organ

Dysfunction Syndrome, Scoring Systems
Katri V. Typpo, MD1; Jacques R. Lacroix, MD2

Objective: To describe the diagnostic criteria of new and progres-
sive multiple organ dysfunction syndrome and scoring systems
that might be used to assess and monitor the severity and pro-
gression of multiple organ dysfunction syndrome in children pre-
sented as part of the Eunice Kennedy Shriver National Institute of
Child Health and Human Development MODS Workshop (March
26–27, 2015).
Data Sources: Literature review, research data, and expert opinion.
Study Selection: Not applicable.
Data Extraction: Moderated by an experienced expert from the
field, issues relevant to the monitoring of the severity of multiple
organ dysfunction syndrome including new and progressive
multiple organ dysfunction syndrome and scoring systems were
presented, discussed, and debated with a focus on identifying
knowledge gaps and research priorities.
Data Synthesis: Summary of presentations and discussion sup-
ported and supplemented by relevant literature.
Conclusions: Many sets of diagnostic criteria of multiple organ
dysfunction syndrome are presently available. All are useful, but
their diagnostic and predictive value can be improved. Several
types of diagnostic criteria are candidates to describe the severity
and to monitor the progression of cases of multiple organ dys-
function syndrome, which include existing scores of organ dys-
function: Pediatric Logistic Organ Dysfunction, version 2, daily
Pediatric Logistic Organ Dysfunction, version 2, organ failure-free
days, etc. If a new set of diagnostic criteria of multiple organ dys-
function syndrome is created, its value must be validated. Further-
1
Department of Pediatrics and the Steele Children’s Research Center,
University of Arizona College of Medicine, Tucson, AZ.
2
Department of Pediatrics and Sainte-Justine Hospital, Université de
Montréal, Montréal, QC, Canada.
This information or content and conclusions are those of the authors and
should not be construed as the official position or policy of, nor should
any endorsements be inferred by, the National Institutes of Health, the
U.S. Department of Health and Human Services, or the U.S. government.
The authors have disclosed that they do not have any potential conflicts
of interest.
For information regarding this article, E-mail: jacques_lacroix@ssss.gouv.qc.ca
Copyright © 2016 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000001049
more, the epidemiology of multiple organ dysfunction syndrome
based on these new diagnostic criteria must be compared with
the epidemiology found with the preexisting sets of diagnostic
criteria. The reliability as well as the added values of additional or
new candidate markers of organ dysfunction and multiple organ
dysfunction syndrome severity must be studied and compared.
(Pediatr Crit Care Med 2017; 18:S17–S23)
Key Words: diagnosis; monitoring; multiple organ dysfunction
syndrome; multiple organ failure; pediatric
DIAGNOSTIC CRITERIA OF NEW MULTIPLE
ORGAN DYSFUNCTION SYNDROME (MODS)
AND PROGRESSIVE MODS
Past and Present
The first set of diagnostic criteria of Pediatric MODS
(P-MODS) was suggested by Wilkinson et al (1) in 1987. The
list was revised in 1996 by Proulx et al (2). The term “MODS”
was used to indicate the simultaneous dysfunction of at least
two organ systems. The organs and systems considered were
respiratory, cardiovascular, neurologic, hematologic, renal,
hepatic, and gastrointestinal. In 2005, a new set of diagnostic
criteria appeared as a result of an international pediatric sep-
sis consensus conference (3). The sets of diagnostic criteria of
Proulx et al (2) in 1996 and of Goldstein et al (3) in 2005 are
detailed in another article published in this supplement (4).
Both sets of diagnostic criteria have strengths and weak-
nesses. For example, the number of dysfunctional organ sys-
tems that are considered is arbitrary: seven-organ systems in
the list of diagnostic criteria published in 1996, only six in 2005.
Furthermore, the same diagnostic value—the same “weight”—
is given to each organ system. Although that is acceptable as
diagnostic criteria, data suggest that individual organ system
failures may be associated with different risks. For example,
Leteurtre et al (5) demonstrated that the risk of death is at least
two-fold higher with neurologic dysfunction than it is with
respiratory dysfunction.
There are also concerns with respect to the individual crite-
ria within each organ system. For example, Goldstein et al (3)

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 Typpo and Lacroix
stated that a respiratory dysfunction could be diagnosed if any
of the following criteria are met:
●● Pao2/Fio2 less than 300 in the absence of cyanotic heart dis-
ease or preexisting lung disease or
●● Paco2 greater than 65 or 20 mm Hg over baseline Paco2 or
●● Proven need for greater than 0.50 Fio2 to maintain satura-
tion greater than or equal to 92% or
●● Need for nonelective invasive or noninvasive mechanical
ventilation.
This list of diagnostic criteria has not been scientifically vali-
dated, and the contention that these four criteria have the same
diagnostic value remains to be determined. Furthermore, some
criteria are not adjusted to age (i.e., hemoglobin concentration,
WBC count, blood urea nitrogen [BUN], creatinine, etc).
Another problem is that only the presence of two simul-
taneous organ dysfunctions is needed to diagnose MODS,
independent of the pathophysiology of the organ dysfunc-
tion. This is not always appropriate. A severe systemic inflam-
matory process is typically observed in patients with MODS.
However, some patients present with two organ dysfunctions
in the absence of systemic inflammation. This may occur in
a patient with acute arrhythmias who acquires respiratory
insufficiency. Less than 5% of MODS occurs without evi-
dence of a systemic inflammatory response syndrome (SIRS)
(2). Alternatively, contemporary patient populations include
critically ill children with chronic organ failures, such as
chronic ventilator dependence, who may present with addi-
tional acute organ failure(s) and/or dysfunction(s). Existing
MODS definitions fail to discriminate these patient popula-
tions and treat chronic organ dysfunction similar to acute
organ dysfunction.
Revisiting Diagnostic Criteria of MODS:
Epidemiologic Impact
Thus, there are many justifications to improve the diagnostic
criteria of MODS. However, it is important to recognize that
revisiting the diagnostic criteria of MODS will have significant
impact on its reported epidemiology.
In a prospective study conducted in 2010, Villeneuve et al
(6) compared the ability of the diagnostic criteria of MODS
suggested by Proulx and Goldstein to predict mortality. The
90-day all-cause mortality of patients with MODS at entry into
the PICU was higher when the diagnosis of MODS was based
on Proulx criteria (17.8% vs 11.5%; p = 0.038). On the other
hand, the 90-day survival rate of patients without MODS at
PICU admission was similar (98.6% vs 98.9%; p = 0.73). The
prevalence of MODS at PICU entry was 15.5% versus 30.7%,
whereas the incidence of new MODS was 22.3% versus 38.6%,
respectively. Similarly, Weiss et al (7) reported a seven-fold dif-
ference in the incidence of severe sepsis when using two differ-
ent sets of diagnostic criteria. As a result, comparing incidence
rates across different studies using disparate diagnostic criteria
may be analogous to comparing apples and oranges. Clearly,
diagnostic criteria are not interchangeable; one cannot modify
the diagnostic criteria of MODS without changing its capacity
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to predict outcomes (sensitivity, specificity, etc) and its epide-
miology (incidence, prevalence, etc).
Diagnostic Criteria of New and Progressive MODS
(NPMODS)
NPMODS as an outcome variable is defined as the proportion
of patients who die within a given period post-time zero (e.g.,
from PICU admission or randomization up to death or PICU
discharge) or who develop new or progressive MODS. “New
MODS” is defined as follows: for patients with no or one organ
dysfunction at time zero (PICU entry or randomization) and
the development of two or more concurrent organ dysfunc-
tions at any time during the study period. Patients with MODS
at time zero (PICU entry, randomization) can develop “pro-
gressive MODS,” which is defined as death or the development
of at least one additional concurrent organ dysfunction at any
time during the study period.
It is difficult to conduct randomized controlled trials (RCT) in
PICU patients using mortality as the primary outcome measure
because the mortality rate is very low (range of averages recently
reported in U.S. PICUs, 2.4–2.8% [8–10]). Mortality fails to inform
providers and patients of changes in other meaningful outcomes
for the majority of PICU patients. Similarly, it is difficult to com-
plete an RCT in PICU patients using MODS as the primary out-
come measure because cases of MODS are often already present
at PICU entry: 78% of MODS are observed during the first day
in the PICU (2). Patients who present with the primary outcome
measure before randomization obviously cannot be enrolled in an
RCT. NPMODS could be a better outcome measure. In 2010, the
incidence rate of NPMODS among 842 consecutive admissions at
Sainte-Justine Hospital was 13.1% and 10.5%, respectively (11).
Leteurtre et al (12) determined the incidence rate of NPMODS
in 3,669 consecutive patients enrolled in two European PICUs in
2006 and 2007. The daily Pediatric Logistic Organ Dysfunction,
version 2 (dPELOD-2) score was available at least at day 2 in
2,057 patients. Among the 796 patients without MODS on day
1, 186 (23.3% = 186/796) acquired a new MODS during their
PICU stay; the mortality was 4.9% in children who developed
a new MODS, whereas it was 0.3% among the 610 who did not
(p < 0.0001). On PICU day 1, MODS was present in 1,261 patients;
it worsened during the PICU admission in 157 (12.4%) of these
patients; the mortality was 22.9% in children who contracted a
progressive MODS versus 6.6% in those who did not (p < 0.0001).
Adding progressive MODS to new MODS increases signifi-
cantly the number of events if NPMODS is used as an out-
come measure in a pediatric RCT. NPMODS was the primary
outcome measure of the Transfusion Requirement In PICU
(TRIPICU) RCT (13) and is the primary outcome measure of
the “Age of Blood in Children in PICU” RCT (NCT01977547).
Diagnostic Criteria of MODS: Conclusions
Although there are noted limitations, the existing definitions
of MODS are useful (2, 3). As with the definition of acute
respiratory distress syndrome (ARDS) and of the SIRS, the sets
of diagnostic criteria of MODS are not perfect, but they help
practitioners and investigators to improve their identification,

knowledge, and perhaps, treatment of the syndrome. However,
it must be asked if better definitions of MODS would advance
the field more effectively. Clearly, the lists of diagnostic criteria
for MODS can be improved, with better alignment between
the diagnosis of MODS, contemporary patient populations, its
pathophysiology and outcomes. Furthermore, the construct
validity, the face validity, the predictive validity, and the repro-
ducibility of the new set of diagnostic criteria of MODS must
be estimated, as this was done for ARDS (14) and for SIRS (15,
16). Identified knowledge gaps and potential opportunities for
future study are described in the Table 1.
SCORING SYSTEMS MEASURING SEVERITY
OF MODS
Descriptive Scores
The severity of illness can be estimated using predictive or
descriptive scores. Predictive and descriptive scores are differ-
ent (Fig. 1) (20). The primary goal of predictive, or prognostic
scores such as the Pediatric Risk of Mortality (PRISM) score
(21) or the Pediatric Index of Mortality (22), is to maximize
death prediction, whereas the primary goal of descriptive, or
outcome scores such as the PELOD score (5, 23), is to maxi-
mize clinical course description. The data required to calculate
predictive scores are collected only at baseline, whereas the data
required to calculate descriptive scores are collected from base-
line (PICU entry, randomization, or exposure) to discharge.
Many descriptive scores have been created to estimate the
severity of MODS. The “MODS score” is the number of organ
dysfunctions (0–6 when using the diagnostic criteria of Goldstein
et al [3]). Mortality risk increases with the number of organ dys-
functions not only in the general PICU population (2) but also
in specific subpopulations such as pediatric oncology patients
with sepsis (24). However, the mortality rate is associated more
strongly with dysfunctions in some organs, such as the cardiovas-
cular system, than with others, such as the hepatic system. These
different dysfunctions should not be weighted the same.
The “PELOD score” is a descriptive, outcome-oriented score
that weighs (more points) dysfunctional organ systems differ-
entially. The PELOD score is well validated. It provides a good
estimate of the severity of MODS. It is quantitative but discon-
tinuous. The PELOD uses data collected from baseline to PICU
discharge. A dPELOD score can also be calculated. PELOD and
dPELOD scores are valid measures of the severity of illness in
the PICU. The ∆PELOD score, which is the worst dPELOD
score minus the dPELOD score at baseline, may also be useful
for charting the course of critical illness. A website (www.sfar.
org/s/article.php) may be used to calculate the PELOD score.
Graciano et al (25) developed the P-MODS score based on
data abstracted from 6,456 admissions. The neurologic sys-
tem is missing from this score, which is an important weak-
ness because there is a strong relationship between neurologic
dysfunction and mortality (23). The other main limitation is
that the score was validated in one center and did not undergo
external validation. Despite these limitations, some variables
seem promising.
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MODS Supplement
Leteurtre et al (23) created the PELOD-2 score by re-evaluat-
ing the variables in PELOD and P-MODS scores. Data were col-
lected using up to seven-time points: PICU day 1, 2, 5, 8, 12, 16,
and 18. For each variable considered for the PELOD-2 score, the
most abnormal value observed at the time points was collected.
The outcome was survival at PICU discharge. Identification of
the best variable cutoffs was performed using bivariate analyses.
The investigators enrolled 3,671 consecutive patients from June
2006 to October 2007 (median age, 15.5 mo; interquartile range,
2.2–70.7). The PICU mortality rate was 6.0% (222 deaths). Ten
variables adjusted for age, corresponding to five organ dysfunc-
tions, were retained. The developers found that hepatic dys-
function was not required to enhance mortality prediction in
the composite score; on the other hand, blood lactate level was
very important and was added to the PELOD-2. Discrimination
(area under the receiver operating characteristics [ROC] curve,
0.934) and calibration (chi-square test for goodness of fit = 9.31;
p = 0.317) were excellent for the primary outcome (mortality).
The descriptive value of the dPELOD-2 score has also been vali-
dated (12). The PELOD-2 and dPELOD-2 scores allow assess-
ment of severity of cases of MODS in the PICU with a continuous
scale. It is in the public domain and can be used in clinical trials.
The PELOD-2 score was validated in multidisciplinary
PICUs. All descriptive scores, including the PELOD-2, can
be used in a particular subpopulation of PICU patients only
if it has been validated in that subpopulation. Leclerc et al
(26) demonstrated that the nonrespiratory PELOD-2 score is
indeed a good predictor of mortality in children with acute
respiratory failure.
Other Scoring Systems Measuring Severity of MODS
Many alternative outcome measures have been created to
describe the severity of MODS. The Pediatric Sequential
Organ Failure Assessment (P-SOFA) score is derived from the
SOFA score for adults (27). Rating of P-SOFA ranges from 0 to
21 (28). The P-SOFA has not been validated in PICU patients.
“Organ failure-free days” is the number of days without
organ failure or dysfunction during a given period of time;
it describes organ failure resolution (29). The period is fre-
quently 28 days for trials conducted in the PICU, but it can
be shorter (14 d) or longer (mo). No organ failure-free day is
given if a patient dies within this period. The area under the
ROC curve of organ failure-free days to predict longer term
adverse outcome is unknown; the validity of organ failure-free
days also remains to be determined.
The PRISM III-Acute Physiology Score is an expanded mea-
sure of physiologic instability that has been validated against
mortality. It has been used to monitor the clinical course at the
bedside; it is well validated but rarely used (30).
All MODS scores are “a measure of morbidity, rather than
a predictor of mortality, although it is intuitively evident that
morbidity is a risk factor for death” (31). The goal of descrip-
tive scores is not to predict mortality but to describe severity
of illness. The PELOD score is useful as a short-term outcome
measure; it has not been validated for predicting long-term
outcomes.
 Typpo and Lacroix

Table 1. Identified Knowledge Gaps and Potential Opportunities for Study

1) Diagnostic criteria of MODS and NPMODS
•  The lists of diagnostic criteria for MODS may be enhanced by review and revision. Such review could be conducted via consensus
conference and any revisions should be evidence-based to the highest degree possible.
•  It will be important to establish the construct validity, the face value, the reliability, and the intra- and interrater reproducibility of
any new set of diagnostic criteria.
•  When diagnostic criteria change, the capacity to predict outcomes and affect epidemiologic calculations also changes. Thus, the
impact of any new set of diagnostic criteria on the epidemiology of MODS, NPMODS, and their relationship with older sets will
need to be evaluated.
2) Scoring systems measuring severity of MODS
•  Identifying the best predictor during PICU stay of post-PICU mortality and morbidity/disability may be an important area of study.
Possible candidates include the PELOD-2 score, progression of dPELOD-2 score, ∆PELOD-2 score, PRISM III-APS, discharge
Functional Status Scale, and organ failure-free days.
•  It is possible that MODS scores may be improved by adding new variables such as the Pediatric Biomarker Risk Model, heart and
respiratory rate variability, or redox measurements (17–19).
3) Monitoring progression of severity of MODS
•  A better understanding of the best way to monitor the progression of severity of MODS at the bedside would be useful. The use
of scores such as the variation in dPELOD-2, PRISM III-APS, or organ failure-free days represents a few potential options. The
value of biomarkers including heart and respiratory rate variability as well as redox measurements for this purpose needs to be
better elucidated.
•  Determining the responsiveness of these scores and tests to treatment provided in the PICU may also be valuable.
•  If the use of MODS scores can be better established as a surrogate outcome to represent and/or predict post-PICU mortality
and morbidity, this may hold promise to inform clinical trials design and patient care.
dPELOD = daily Pediatric Logistic Organ Dysfunction score, MODS = multiple organ dysfunction syndrome, NPMODS = new and progressive MODS, PRISM
III-APS = Pediatric Risk of Mortality III-Acute Physiology Score.

MONITORING PROGRESSION OF SEVERITY In 2010, Leteurtre et al (32) reported that the risk of mortality
OF MODS was approximately 13% if the dPELOD score increased from
day 1 to day 2 after PICU entry, whereas it was less than 7% if
Descriptive Scores such an increase was not observed (Fig. 2). The risk of death
The change in dPELOD score over time can be used to monitor increased even more in the former group (up to 50%) if a fur-
the progression of the clinical status of critically ill children. ther increase of the dPELOD score was observed from day 2 to
day 4. In 2015, Leteurtre et al (12) repeated the same analysis
with the dPELOD-2 score. The serial evaluation of the change
in the dPELOD-2 score from day 1 to day 2, 5, 8, 12, 16, or 18,
adjusted for baseline value, demonstrated an increased risk of
death for each of the seven monitored days post-PICU entry.
For example, the odds ratio was 1.3 (95% CI, 1.21–1.41) if the
dPELOD-2 score increased from day 1 to day 2, and it was 1.45
(95% CI, 1.23–1.71) if it increased between day 1 and day 16.
The reliability of other scores to monitor the progression of
MODS over time remains to be determined.

MODS and MODS Scores: Good Surrogate

Figure 1. Prognostic versus outcome scores. APACHE = Acute Physiol-
ogy and Chronic Health Evaluation, MODS = multiple organ dysfunction
syndrome, PELOD = Pediatric Logistic Organ Dysfunction, PIM = pediat-
ric index of mortality, P-MODS = Pediatric MODS, PRISM = Pediatric Risk
of Mortality, SOFA = Sequential Organ Failure Assessment. Reproduced
with permission from Lacroix J, Cotting J; Pediatric Acute Lung Injury and
Sepsis Investigators (PALISI) Network: Severity of illness and organ dys-
function scoring in children. Pediatr Crit Care Med 2005; 6:S126–S134.
Outcomes?
Presently, ICU mortality is the gold standard outcome mea-
sure of clinical trials conducted in the ICU for adults, mainly
because it is a hard datum. However, as described above,
recent data consistently demonstrate PICU mortality rates
so low (< 3% in U.S. studies) (8–10) that it jeopardizes the
feasibility of conducting clinical trials using mortality as the
primary outcome variable as it significantly increases the
required sample size of PICU patients. A surrogate outcome
measure can reduce needed sample size in clinical trials of

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 MODS Supplement

health-related quality of life,

quality-adjusted life-years
(QALYs), and physical func-
tion (e.g., measured using the
Functional Status Scale) (36),
are more important than out-
comes at PICU discharge (37).
Morrison et al (38) reported
that the 24-month post-PICU
death rate is 6.3%, which is
higher than the PICU mortality
rate recently reported in North-
America (about 2.8% [8–10]).
Conlon et al (39) reported
severe disability in 20% of PICU
survivors. Interestingly, Typpo
et al (8, 40) reported that MODS
and the severity of MODS can
predict risk of morbidity and
mortality at PICU discharge.
The hypothesis illustrated in
Figure 2. Variation in daily Pediatric Logistic Organ Dysfunction (dPELOD) score to monitor clinical course at
Figure 3 is that PICU-events,
the bedside (32). The d1PELOD indicates daily PELOD score on first day during PICU admission. Three trajec- like severity of MODS or ARDS,
tories are considered: the dPELOD score increases over time (d2 > d1 PELOD or d4 > d2 PELOD); the dPELOD can be a reliable surrogate for
score does not change over time (d2 = d1 PELOD or d4 = d2 PELOD); and the dPELOD score decreases over
time (d2 < d1 PELOD or d4 < d2 PELOD). The mortality rate associated with a given trajectory is reported with outcomes observed at PICU
its 95% CI. discharge, such as PICU mortal-
ity, and of post-PICU outcomes,
pediatric critical illness. Monitoring the severity and the pro- such as mid-term mortality, health-related quality of life,
gression of cases of MODS, using the incidence of NPMODS QALYs, and Functional Status Scale. There is some evidence
or MODS scores, may represent a useful surrogate outcome that severity of MODS can be a good predictor of post-ICU
and an effective alternative to mortality. A good surrogate morbidity. For example, MODS score predicted the neurologic
outcome must fulfill a list of qualities (33, 34). outcome of critically ill adults with severe traumatic brain
injury (41). However, more data are required before NPMODS
●● Meaningful cause-effect relationship—MODS is indeed the
and/or MODS scores can be considered reliable predictors of
cause of death of almost all children dying in the PICU. post-PICU outcomes.
●● Its prevalence, incidence, or frequency should be significantly
In summary, descriptive scores of MODS severity such as
greater than that of the gold standard.—NPMODS are more the dPELOD-2 score can be used in epidemiologic studies to
frequent than mortality in the PICU (approximately 20% vs measure how much a group of patients deviates from normal.
3%). MODS scores can be measured daily in all patients. In RCTs, the dPELOD-2 score can validate that the arms of a
●● The relationship between the surrogate outcome and the refer-
trial are balanced at baseline and can be used to monitor clini-
ence standard must be good.—The association between sever- cal course. Furthermore, the dPELOD-2 score may potentially
ity of MODS and PICU mortality is excellent; Leteurtre et al be used as a surrogate outcome although this must be better
(5, 23) reported that the area under the ROC curve is 0.91 studied and confirmed in further prospective study (Table 1).
for the PELOD score and 0.934 for the PELOD-2 score.
●● The responsiveness of the surrogate outcome to therapeutic

intervention must be good.—At least one RCT reported that

a treatment (plasma exchange) modulated the PELOD score
(35), and two studies demonstrated a close relationship
between the progress of dPELOD and outcomes (12, 32).
Thus, NPMODS and MODS scores like the PELOD-2 score
may represent useful surrogate outcome parameters and a
good alternative to PICU mortality in clinical trials of pediatric
critical illness (Fig. 3).
However, some experts consider that patient-centered
Figure 3. PICU outcomes such as multiple organ dysfunction syndrome
outcomes that integrate intermediate and long-term post- (MODS) and MODS scores as surrogate outcomes for short- and long-
PICU morbidity and mortality, such as mid-term mortality, term post-PICU outcomes.

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 Typpo and Lacroix
CONCLUSIONS
The diagnostic criteria of MODS that are presently available
are useful, but they can be improved. If a new set of diagnos-
tic criteria of MODS is created, its value must be validated.
Furthermore, the epidemiology of MODS based on these new
diagnostic criteria must be compared with the epidemiology
found with the established diagnostic criteria. There is a vast
array of clinical scores (PELOD-2, dPELOD-2, organ failure-
free days, etc) that can be used to describe the severity and to
monitor the progression of cases of MODS.
ACKNOWLEDGMENT
We thank the Eunice Kennedy Shriver National Institute of
Child Health and Human Development and their Office of Sci-
ence Policy, Analysis and Communications for their support of
this Workshop.
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