Prognosis of cardiovascular and non-cardiovascular multimorbidity after acute coronary syndrome
Prognosis of cardiovascular and non- cardiovascular multimorbidity after acute coronary syndrome
Silvia Canivell 1 2 3
Olivier Muller 0 1 3
Baris Gencer 1 3
Dik Heg 1 3
Roland Klingenberg 1 3 5
Lorenz RaÈ ber 1 3 4
David Carballo 1 3
Christian Matter 1 3 5
Thomas LuÈ scher 1 3 5
Stephan Windecker 1 3 4
FrancË ois Mach 1 3
Nicolas Rodondi 1 3
David Nanchen 1 2 3
0 Service of Cardiology, Lausanne University Hospital , Lausanne , Switzerland , 3 Division of Cardiology, Faculty of Medicine, Geneva University Hospitals , Geneva , Switzerland , 4 Institute of Social and Preventive Medicine, and Clinical Trials Unit, Department of Clinical Research, University of Bern , Bern , Switzerland
1 Funding: The SPUM-ACS cohort is supported by the Swiss National Science Foundation [SNSF 33CM30-124112, aInflammation and Acute Coronary Syndromes (ACS)±Novel Strategies for Prevention and Clinical Management,o and SNSF 32473B_163271, aLong-Term Benefit of the Multi- Center, Multi-Dimensional Secondary Prevention Program in Patients With Acute Coronary
2 Department of Ambulatory Care and Community Medicine, University of Lausanne , Lausanne , Switzerland
3 Editor: Marc W. Merx, Klinikum Region Hannover GmbH , GERMANY
4 Department of Cardiology, University Hospital Bern , Bern , Switzerland , 7 Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern , Bern , Switzerland , 8 Institute of Primary Health Care (BIHAM), University of Bern , Bern , Switzerland
5 University Heart Center, Department of Cardiology, University Hospital Zurich , Zurich , Switzerland
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
To examine the prognosis of patients with cardiovascular and non-cardiovascular
multimorbidity after acute coronary syndrome compared to patients without prior multimorbidity.
This multicenter prospective cohort study in Switzerland included 5,635 patients
hospitalized with acute coronary syndrome between 2009 and 2014, with a one-year follow-up
period. We defined cardiovascular and non-cardiovascular multimorbidity as having at least
two prior comorbidities before the index hospitalization. Multivariable adjusted Cox
proportional models were built to assess the one-year risk of recurrent cardiovascular events,
defined as cardiovascular mortality and non-fatal myocardial infarction or stroke. The final
model was adjusted for age, gender, body mass index, tobacco consumption, education,
and family history of cardiovascular disease, prescription of high-dose statinsat discharge
and use of cardiac rehabilitation after discharge.
Overall, 3,664 patients (65%) had no multimorbidity, 1,839 (33%) had cardiovascular
multimorbidity, 62 (1%) had non-cardiovascular multimorbidity, and 70 (1%) had both
cardiovascular and non-cardiovascular multimorbidity. The multivariate risk of recurrent
cardiovascular events was increased among patients with cardiovascular multimorbidity
(hazard ratio (HR) 2.05, 95% CI: 1.54±2.73, p<0.001) and patients with non-cardiovascular
multimorbidity (HR 2.57, 95% CI: 1.04±6.35, p = 0.04) compared to patients without
Syndromesº. None of the funding had any role in
design and conduct of the study; collection,
management, analysis, and interpretation of the
data; and preparation, review, or approval of the
Competing interests: Prof LuÈscher reports
receiving research grants to the institution from
Abbott, Biosensors, Biotronik, Boston Scientific,
Daichi Sankyo, Eli Lilly and Medtronic, and
consultant payments from AstraZeneca,
Boehringer Ingelheim, Bayer, Merck, and Pfizer,
MSD, Roche and Servier. Prof Matter reports
receiving grants from MSD, Eli Lilly, AstraZeneca,
Roche and Bayer; expert testimony from MSD;
payment for lectures from MSD, AstraZeneca, and
Roche; and having patents from Mabimmune, CH.
Prof Windecker reports receiving research
contracts to the institution from Abbott, Biotronik,
Boston Scientific, Biosensors, Cordis, Medtronic,
St. Jude Medical. Prof Mach has received
honoraria for advisory boards and conferences on
dyslipidaemia from Amgen, AstraZeneca, BMS, Eli
Lilly, MSD, Sanofi, and Pfizer. All other authors
report no conflicts of interest. This does not alter
our adherence to PLOS ONE policies on sharing
data and materials.
multimorbidity. Patients with cardiovascular and non-cardiovascular multimorbidity had the
highest risk of recurrence with a HR of 5.19, 95% CI: 2.79±9.64, p<0.001, compared to
patients without multimorbidity.
Multimorbidity increased by two-fold the risk of cardiovascular events over the year after an
acute coronary syndrome. The magnitude of this increased risk was similar for patients with
cardiovascular or non-cardiovascular multimorbidity.
Multimorbidity is a major challenge for health care systems[
]. Multimorbidity is defined as
the presence of two or more chronic medical conditions and is associated with polypharmacy,
a reduced quality of life and higher mortality rates[
]. Among patients with acute coronary
syndrome (ACS), multimorbidity can increase the rate of in-hospital complications and the
length of stay[5±7]. After discharge, patients with multimorbidity frequently receive care from
different specialists, which may impact the achievements of secondary prevention targets.
Further, the risk/benefit ratio of preventive drugs is unclear among patients with multimorbidity,
since scientific evidence is largely based on clinical studies with patients suffering from a single
3, 8, 9
]. While many patients with ACS have multiple comorbidities[
the prognosis role of multimorbidity after ACS has been poorly studied, and it remains
unknown if comorbidities associated with cardiovascular (CV) disease, such as diabetes or
hypertension, have a similar impact than non-CV comorbidities, such as pulmonary disease or
cancer. In a large prospective cohort of patients with ACS, we aimed to assess the prognosis of
multimorbidity after ACS, examining separately CV and non-CV multimorbidity.
We studied patients from the Special Program University Medicine-Acute Coronary
Syndromes (SPUM-ACS) study, a prospective cohort study of patients hospitalized with ACS in
Switzerland in four university centers. The main aim of the SPUM-ACS study was the
identification of new determinants of coronary heart disease. Full methodology of the SPUM-ACS
study has been reported previously[
]. Briefly, all patients hospitalized with ACS in four
university hospitals in Switzerland (Lausanne, Geneva, Bern and Zurich) were invited to
participate. The inclusion period for this study was 2009 to 2014. Exclusion criteria were the
presence of severe physical disability, inability to give consent due to dementia, and life expectancy
of less than one year for non-cardiac reasons. Inclusion criteria were: age 18 years, a main
diagnosis of ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial
infarction (NSTEMI), or unstable angina. The total study population comprised 5,635 patients with
available one-year follow-up information. This study was approved by Swiss ethics (Swiss
Ethics Committees on research involving humans) involving the ethics committees of each local
center (Lausanne, Geneva, Bern and Zurich) and complies with all laws and international
ethics guidelines outlined in the Declaration of Helsinki. All human patients provided written,
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We defined multimorbidity as the presence of two or more chronic disorders, similar to
]. We categorized patients according to the presence of multimorbidity as follows:
no multimorbidity, CV multimorbidity, non-CV multimorbidity and both CV and non-CV
multimorbidity. CV multimorbidity was defined as having 2 or more preexisting
comorbidities associated with CV disease out of: coronary heart disease (defined as prior myocardial
infarction, percutaneous coronary intervention or coronary artery bypass grafting), congestive
heart failure, peripheral arterial disease, cerebrovascular disease (defined as stroke or transient
ischemic attack), diabetes, hypertension, or possible familial hypercholesterolemia. Non-CV
multimorbidity was defined as having 2 or more comorbidities out of pre-existing: cancer
(defined as malignant disease confirmed with a biopsy), chronic obstructive pulmonary
disease, gastrointestinal bleeding, inflammatory systemic disease (defined as lupus erythematosus,
polymyosite, mixed connective tissue disease, polymyalgia rheumatica, rheumatoid arthritis,
or psoriasis), severe renal disease (defined as dialysis or clearance<30 mL/min assessed by the
MDRD method), and liver disease (defined as hepatic cirrhosis or chronic hepatitis). Patients
categorized in the no multimorbidity group could have a maximum of one of the CV, and one
of the non-CV comorbidities listed above (S1 Table: Pre-existing comorbidities in the study
population (N = 5,635).).
Incidence of CV events during the first year after hospitalization for ACS was obtained by a
telephone call at 30 days post discharge, and in a clinical face-to-face visit at 1 year post ACS.
When patients could not be reached for the one-year follow-up visit, medical information
was obtained from primary care physicians, family members, hospital records or registry
Three certified cardiologists adjudicated all CV events, unaware of the allocation status of
multimorbidity. CV events were defined as the composite of: incident myocardial infarction,
ischemic stroke, transient ischemic attack, or cerebrovascular or CV mortality, as already
]. Coronary events were defined as the composite of: incident cardiac
death or non-fatal myocardial infarction[
Covariables. The presence of pre-existing comorbidities at the time of ACS was collected
by study nurses and medical doctors on standardized, web-based case report forms and stored
in a central database, as reported previously[
]. Information on medication at baseline and
one year included use of aspirin, anti-hypertensive drugs, clopidogrel, prasugrel, ticagrelor,
anticoagulants, statins, amiodarone, digoxin, nitrates, insulin, antidiabetic drugs, NSAID,
proton pump inhibitors, immunosuppressive drugs, antiretroviral drugs, hormonotherapy and
antidepressants. Polymedication was defined as 6 or more out of the aforementioned drugs.
Men younger than 55 years old and women younger than 60 years old at the time of their first
ACS were considered as having a personal history of premature CHD. Family history of
premature coronary heart disease was based on patient reports of a coronary event in a brother or
father younger than 55 years old, or a mother or sister younger than 60 years old[
Education status was dichotomized as having graduated from high school or university or having a
lower-level education. Hypertension was defined as a systolic blood pressure 140 mmHg or
diastolic blood pressure 90 mmHg or use of blood pressure lowering drugs. Smoking status
was categorized into current, former and never-smokers. Former smokers were those who
smoked at least one cigarette a day during at least one-year, and were non-smokers for more
than one month before inclusion. Diabetes was either self-reported or diagnosed by the use of
antihyperglycemic medication, or a haemoglobin A1c of 6.5% or greater at admission. Familial
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hypercholesterolemia was defined as possible or probable using the Dutch Lipid Clinic
definition (3 points or more), which includes the LDL-cholesterol levels along with personal or
family history of premature coronary heart disease[
]. Total cholesterol, HDL-cholesterol and
triglycerides levels were measured within 24 hours of admission, and immediately processed
locally using standardized and certified dosage methods.
Statistical analysis. We described the baseline characteristics of the patients according to
the presence of pre-existing CV and non-CV multimorbidity before the index event. Analysis
of variance and chi-squared tests were used for the comparison of categorical and continuous
variables, as appropriate. We assessed the associations between multimorbidity and CV and
coronary outcomes using unadjusted and multivariable adjusted Cox proportional hazard
models, with the no multimorbidity group as the reference group. The first model was adjusted
for age and sex. In the second model, we additionally adjusted for body mass index, current
smoking, higher education and family history of premature CHD. In the third model, we
further adjusted for attendance to cardiac rehabilitation and use of high-dose statins at discharge.
In the fourth model, we additionally adjusted for the GRACE score for 6 months mortality.
The GRACE risk score was computed with age, heart rate, systolic blood pressure, initial
serum creatinine, history of congestive heart failure, history of myocardial infarction, elevated
cardiac markers (conventional troponins as per local laboratories), ST-segment depression
and in-hospital revascularization, as previously described[
]. For the CV events analysis,
patients were censored at the occurrence of myocardial infarction, stroke, death, or 365 days
after the index hospitalization for ACS[
]. For the coronary events analysis, patients were
censored at the occurrence of myocardial infarction, death, or 365 days after the index
hospitalization. Kaplan-Meier curves were built to estimate the CV and coronary events rates over
one year by the presence of multimorbidity. All hypothesis tests were two-sided and the
significance level was set at 5%. Statistical analyses were performed using Stata 141 (Stata Corp,
College Station, TX, USA).
Out of 5,635 patients with ACS, 1,839 (33%) had CV multimorbidity, 62 (1%) had non-CV
multimorbidity and 70 (1%) had both CV and non-CV multimorbidity. Baseline
characteristics of the study population, with respect to the presence of CV and non-CV multimorbidity,
are shown in Table 1. Compared to patients with no multimorbidity, patients with both CV
and non-CV multimorbidity were older, had lower education, were more frequently
polymedicated, and were less frequently smokers. There were no differences in gender or ethnicity
across the groups.
Out of the 5,635 patients included in the SPUM-ACS cohort, there were 154 patients lost to
follow-up at one-year and 132 deaths (S1 Fig: Study flow chart).
Patients with both CV and non-CV multimorbidity had a high incidence rate of CV events
at one year, reaching 23.9 per 100 person-years compared to patients with no multimorbidity,
for whom the incidence rate was 4.52 per 100 person-years (Fig 1). The risk of recurrent CV
events after ACS with respect to the presence of multimorbidity is shown in Table 2. In the age
and sex-adjusted model, hazard ratios (HR) for incident CV events were 1.87 (95% confidence
interval (CI) 1.50±2.33) in patients with CV multimorbidity, and 2.27 (95% CI 1.11±4.63) in
patients with non-CV multimorbidity, compared to patients with no multimorbidity. Similar
results were found in the fully adjusted model, with HR of 2.05 (95% CI 1.54±2.73) in patients
with CV multimorbidity, and 2.57 (95% CI 1.04±6.35) in patients with non-CV
multimorbidity, compared to patients with no multimorbidity. Patients with both CV and non-CV
multimorbidity had the highest risk of CV events as compared to patients with no multimorbidity
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Data are given as number (percentage) or mean (standard deviation).
1Defined as a high school or university graduation or higher
2Defined as more than 14 units alcohol/week
3Self-reported history of a major cardiovascular event in a brother or father younger than 55 years old, or a mother or sister younger than 65 years old
4Include angiotensin converting enzyme inhibitors, or angiotensin II receptor blockers, or beta-blockers, or calcium-channel blockers, or diuretics
Abbreviations: LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate; ACS, acute coronary syndrome; STEMI,
STsegment elevation myocardial infarction; NSTEMI, non ST-segment elevation myocardial infarction
5Include age, heart rate, systolic blood pressure, initial serum creatinine, history of congestive heart failure, history of myocardial infarction, elevated cardiac markers
(conventional troponins as per local laboratories), ST-segment depression and in-hospital revascularization.
with a HR of 5.19 (95% CI 2.79±9.64) in the fully adjusted model. After further adjustment for
the GRACE risk score, there were no major changes in point estimates, but statistical
significance was not reached for patients with non-cardiovascular morbidity only. The type of ACS,
either STEMI, NSTEMI or unstable angina, did not modify the association between
multimorbidity and recurrence of cardiovascular events (S2 Table: Association between multimorbidity
PLOS ONE | https://doi.org/10.1371/journal.pone.0195174
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Fig 1. Cardiovascular events rates after acute coronary syndrome, by presence of cardiovascular and non-cardiovascular multimorbidity.
and recurrence of cardiovascular events for each category of patients with acute coronary
syndrome, STEMI, NSTEMI and unstable angina.). Similar estimates of risk were found for
incidence of coronary events (Table 2 and Fig 2).
Comparison of clinical management after ACS according to presence of multimorbidity is
shown in Table 3. Compared to patients with no multimorbidity, patients with multimorbidity
attended less frequently a cardiac rehabilitation program and used less frequently high-dose
statins one-year after discharge. Despite using more drugs, patients with multimorbidity had
also higher blood pressure levels one-year after discharge, as compared to patients without
In a large population of patients hospitalized with ACS, pre-existing multimorbidity was
associated with a two-fold higher risk of recurrence of CV events after discharge, compared to
patients without multimorbidity. The magnitude of the increased risk was similar for patients
with CV multimorbidity than for patients with non-CV multimorbidity. The combination of
CV and non-CV multimorbidity further increased the risk of cardiovascular recurrence
compared to patient with no multimorbidity. We also reported that patients with multimorbidity
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1Adjusted for age, sex, body mass index, current smoking, higher education, and family history of cardiovascular disease.
2Adjusted for model 1 and attendance to cardiac rehabilitation and high-dose statin at discharge
Abbreviations: HR, hazard ratio; CI, confidence interval; LDL, low-density lipoprotein
3Adjusted for model 2 and results of the 6-months GRACE risk score.
used less frequently high-dose statins or cardiac rehabilitation after ACS compared to patients
with no multimorbidity. Thus, clinical management differed according to the presence of
Previous studies have examined the short-term impact of different comorbidities among
patients suffering from an ACS[
]. Overall, they show that patients with multiple cardiac
comorbidities tended to experience lower survival and higher length of stay during the
]. After hospital discharge for ACS, multimorbidity was shown to be associated
with reduced one-year survival.[
6, 17, 18
]However, to our knowledge, there is no previous
data on the association between multimorbidity and recurrence of coronary and CV events
after ACS. It remains debated why patients with multiple comorbidities have a poorer
prognosis. The increased risk of multimorbidity may be attributable to a less effective clinical
management or alternatively multimorbidity itself may confer a poorer prognosis. Our study adds
particular novel information by showing that non-CV multimorbidity may confer a similar
CV risk than CV multimorbidity. Hence, the presence of non-CV multimorbidity should
not be neglected for the secondary prevention of CV disease. Reasons why non-CV
multimorbidity might confer a risk for CV recurrence remain unclear. One possible explanation is
that non-CV comorbidities influence the CV risk by common pathological underlying
mechanisms such as low-grade systemic inflammation[
]. The role of inflammation in the
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Fig 2. Coronary events rates after acute coronary syndrome, by presence of cardiovascular and non-cardiovascular multimorbidity.
pathogenesis of CV disease has been already demonstrated both in clinical and experimental
We also reported in our study that the clinical management of patients with ACS differed
according to the presence of multimorbidity, with poorer attendance to cardiac rehabilitation,
similar to previous reports.[
] These results highlight the challenge that clinicians meet to
stick with CV prevention guidelines for patients with multimorbidity, who often have
psychosocial deprivation.. In our study, we further reported that patients with multiple diseases
were at higher risk of CV outcomes, independently of the prescription of preventive drugs or
participation to cardiac rehabilitation. Clinical practice guidelines are usually made for a single
disease condition, since clinical trials usually include patients with a single disease entity.[
Strategies are being implemented in order to account for comorbidities in the management of
patients with CV disease[
]. More studies are needed to test specific secondary prevention
programmes for ACS patients with multiple comorbidities.
Limitations of our study must be recognized. First, we classified patients according to
presence of multimorbidity, and not comorbidity, so that patients included in the no
multimorbidity group could still suffer from one of the CV or/and non-CV comorbidities. Although this
classification may lead our results to a null finding due to the dilution of differences between
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Lipid lowering drugs at discharge
(n = 5,563)
Lipid lowering drugs at one year
(n = 5,185)
Clinical management at one year
Cardiac rehabilitation (n = 5,566)
LDL-cholesterol levels at one-year,
mmol/L(n = 2,810)
SBP at one-year, mmHg(n = 4,296)
DBP at one-year, mmHg(n = 4,296)
Polymedication (> 5) at one-year
(n = 5,635)
Data are given as number (percentage) or mean (standard deviation).
1High-dose statins included atorvastatin 40-80mg or rosuvastatin 20-40mg.
Abbreviations: LDL, low-density lipoprotein; SBP systolic blood pressure; DBP diastolic blood pressure.
groups, our results still showed statistical differences between groups, confirming the role of
multimorbidity as an important prognosis variable. Second, even though using a large study
sample there were few patients classified in the non-CV multimorbidity group, which may
limit the power of the study to detect differences. However, differences between groups were
still statistically significant and robust after multiple adjustments. Finally, we did not have the
information about the grade of severity of the different comorbidities included, except for the
severe renal disease. Consequently, the specific role and weight of each comorbidity in the CV
risk recurrence, especially for the non-CV comorbidities, could not be assessed.
Patients suffering from CV or non-CV multimorbidity who are hospitalized for ACS have a
two-fold increased risk of CV events after discharge than patients with no prior
multimorbidity. Presence of both CV and non-CV multimorbidity was associated with the poorest
prognosis, along with a poorer control of CV risk factors, lower use of high-dose statins and lower
attendance of cardiac rehabilitation. Since the prevalence of patients suffering from multiple
comorbidities tends to increase, clinical trials and clinical practice guidelines should be
redesigned to account for these covariates as they impact on outcome. Further studies are needed
to explore the effects of more effective clinical management of patients with multimorbidity
S1 Table. Pre-existing comorbidities in the study population (N = 5,635).
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S2 Table. Association between multimorbidity and recurrence of cardiovascular events for each category of patients with acute coronary syndrome, STEMI, NSTEMI and unstable angina.
S1 Fig. Study flow chart.
The SPUM-ACS cohort is supported by the Swiss National Science Foundation [SNSF
33CM30-124112, ªInflammation and Acute Coronary Syndromes (ACS)–Novel Strategies for
Prevention and Clinical Management,º and SNSF 32473B_163271, ªLong-Term Benefit of the
Multi-Center, Multi-Dimensional Secondary Prevention Program in Patients With Acute
Coronary Syndromes. We acknowledge the cooperation of all participating centers, practicing
physicians, referring doctors and institutions. None of the funding had any role in design and
conduct of the study; collection, management, analysis, and interpretation of the data; and
preparation, review, or approval of the manuscript.
Conceptualization: Silvia Canivell, David Nanchen.
Data curation: Silvia Canivell, Olivier Muller, Baris Gencer, Roland Klingenberg, Thomas
LuÈscher, David Nanchen.
Formal analysis: Silvia Canivell.
Funding acquisition: Olivier Muller, Baris Gencer, Roland Klingenberg, Lorenz RaÈber, David
Carballo, Christian Matter, Stephan Windecker, FrancËois Mach, Nicolas Rodondi, David
Investigation: Silvia Canivell, Olivier Muller, Baris Gencer, Roland Klingenberg, David
Carballo, Thomas LuÈscher, David Nanchen.
Methodology: Silvia Canivell, Olivier Muller, Baris Gencer, Dik Heg, Roland Klingenberg,
Project administration: Olivier Muller, Baris Gencer, Dik Heg, Roland Klingenberg,
Christian Matter, Thomas LuÈscher, Stephan Windecker, Nicolas Rodondi, David Nanchen.
Resources: Olivier Muller, Baris Gencer, Dik Heg, Roland Klingenberg, Lorenz RaÈber,
Christian Matter, Thomas LuÈscher, FrancËois Mach, Nicolas Rodondi, David Nanchen.
Software: Christian Matter, Thomas LuÈscher.
Supervision: Olivier Muller, Dik Heg, Lorenz RaÈber, Christian Matter, FrancËois Mach, Nicolas
Rodondi, David Nanchen.
Validation: Silvia Canivell, Dik Heg, Lorenz RaÈber, David Carballo, Christian Matter, Stephan
Windecker, FrancËois Mach, Nicolas Rodondi, David Nanchen.
Visualization: Silvia Canivell, Baris Gencer, Dik Heg, Lorenz RaÈber, David Carballo, Stephan
Windecker, FrancËois Mach, Nicolas Rodondi, David Nanchen.
Writing ± original draft: Silvia Canivell.
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Writing ± review & editing: Silvia Canivell, Olivier Muller, Baris Gencer, Dik Heg, Roland
Klingenberg, Lorenz RaÈber, David Carballo, Christian Matter, Thomas LuÈscher, Stephan
Windecker, FrancËois Mach, Nicolas Rodondi, David Nanchen.
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