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J Innov Cardiac Rhythm Manage. 2021;12(6):1–7
ATRIAL FIBRILLATION
DOI: 10.19102/icrm.2021.120605
AMYLOIDOSIS
ORIGINAL RESEARCH
Clinical Outcomes and Disease Burden in
Amyloidosis Patients with and Without Atrial
Fibrillation—Insight from the National Inpatient
Sample Database
SHAKEEL JAMAL, md,1 ASIM KICHLOO, md,1 BETH BAILEY, phd,1 JAGMEET SINGH, md,2
HAFEEZ VIRK, md,3 RONAK SONI, md,4 FARAH WANI, md,5 MUHAMMAD AJMAL, md,6
SINDHURA ANANTHANENI, md,1 EHIZOGIE EDIGIN, md,7 RAJEEV SUDHAKAR, md,8
and KHALIL KANJWAL, md, facc, fhrs, ccds, ceps(p)9
1Central Michigan University, College of Medicine, Saginaw, MI, USA
2Geisinger Commonwealth School of Medicine, Scranton, PA, USA
3Albert Einstein College of Medicine, Philadelphia, PA, USA
4University of Toledo, College of Medicine, Toledo, OH, USA
5Samaritan Medical Center, Watertown, NY, USA
6University of Arizona, College of Medicine, Tucson, AZ, USA
7John H Stroger Hospital of Cook County, Chicago, IL, USA
8Ascension Medical Group, Central Michigan University, Saginaw, MI, USA
9McLaren Greater Lansing Hospital, Michigan State University, Lansing, MI, USA
Q1
ABSTRACT. Amyloidosis is a systemic illness that affects multiple organ systems, including the
cardiovascular, renal, gastrointestinal, and pulmonary systems. Common manifestations include
restrictive cardiomyopathy, arrhythmias, nephrotic syndrome, and gastrointestinal hemorrhage.
It is unknown whether coexisting atrial fibrillation (AF) worsens the disease burden and out-
comes in patients with systemic amyloidosis. In this study, those with a diagnosis of amyloidosis
with and without coexisting AF were identified by querying the Healthcare Cost and Utilization
Project—specifically, the National Inpatient Sample for the year 2016—based on International
Classification of Diseases, 10th Revision, Clinical Modification codes. During 2016, a total of
2,997 patients were admitted with a diagnosis of amyloidosis, including 918 with concurrent
AF. Greater rates of mortality (7.4% vs. 5.6%); heart block (6.8% vs. 2.8%); cardiogenic shock
(5% vs. 1.6%); placement of an implantable cardioverter-defibrillator, cardiac resynchronization
therapy device, or permanent pacemaker (14.5% vs. 4.5%); renal failure (29% vs. 21%); heart
failure (66% vs. 30%); and bleeding complications (5.7% vs. 2.8%) were observed in patients
with a diagnosis of amyloidosis and coexisting AF when compared with in patients without AF.
Interestingly, patients with amyloidosis without comorbid AF had greater odds of associated stroke
relative to those with concurrent AF (7.9% vs. 3.4%).
KEYWORDS.
ISSN 2156-3977 (print)
ISSN 2156-3993 (online)
CC BY 4.0 license
© 2021 Innovations in Cardiac
Rhythm Management
The Journal of Innovations in Cardiac Rhythm Management, June 2021 1
Introduction
Amyloidosis is a heterogeneous group of inherited or
acquired diseases that results from extracellular systemic
deposition of amyloid, which constitutes 20 different
insoluble fibrillary proteins assembled in an abnormal
β-sheet conformation.1,2 Amyloidosis can result in the
deposition of these proteins in various organ systems,
including the heart, kidneys, central nervous system,
blood vessels, pancreas, and liver, disrupting organ
integrity, structure, and function. This process can lead
to multiple organ system involvement and can manifest
either in the form of a serious illness or just an inciden-
tal finding.3 Treatment strategies are aimed at destabiliz-
ing these fibrillary deposits.4 Systemic amyloidosis can
manifest in the form of amyloid A (AA) amyloidosis and
amyloid light-chain (AL) amyloidosis (most common).
AL amyloidosis results from the accumulation of fibrils
derived from monoclonal immunoglobulin light chains,
which can involve any organ system in the body directly,
excluding the brain, and the most common causes of
death in patients with the condition are heart failure,
uremia, and autonomic neuropathy.5,6 AA amyloidosis is
also known as reactive amyloidosis as it is a consequence
of persistent inflammatory, neoplastic, and infective dis-
orders. Hereditary systemic amyloidosis is an autosomal
dominant condition in which amyloid fibrils are formed
from genetic variants of apolipoproteins, transthyretin,
lysozyme, and fibrinogen A-α.7 Amyloidosis is known to
affect any organ system in the body; the purpose of this
study was to understand the outcomes on the cardiovas-
cular system in general and in concert with atrial fibril-
lation (AF) specifically. Cardiac involvement is thought
to be the leading cause of morbidity and mortality in
amyloidosis.8 Fifty percent of patients with AL amyloi-
dosis have an underlying cardiac involvement, which
depends on the type of amyloid.9 Amyloid deposits cause
myocardial cell toxicity by the deposition of amyloid
fibrils in the extracellular space of cardiac myocytes in
the atria, the ventricles, around the coronaries, and in the
valves,10 which leads to restrictive cardiomyopathy, con-
tinuing further to diastolic dysfunction and manifesting
during physical examinations as edema, congestive hepa-
tomegaly, and jugular venous distension, while patients
with progression to advanced forms of the disease pres-
ent with hypotension.11 Atrial arrhythmias occur most
commonly in up to 10% to 15% of patients. AF is known
to be the most common atrial arrhythmia in amyloidosis.8
Deposition of amyloid in the atrial issue leads to altered
conduction, which increases the likelihood of triggering
AF, while AF increases the likelihood of the deposition of
amyloid, creating a vicious cycle.12 Sanchis et al. reported
238 cases of cardiac amyloidosis in a study where 48%
had AL amyloidosis and 52% had transthyretin amy-
loid (ATTR) cardiomyopathy. Forty-two percent of the
238 study participants had AF, 60% had permanent AF,
and 40% had nonpermanent AF.13 Another study looked
at 382 patients with ATTR cardiomyopathy, in which 69%
were found to have AF (stratified as 45% with paroxys-
mal, 27% with persistent, 15% with longstanding persis-
tent, and 13% with permanent AF).14 Krishnappa et al.
studied the cardiac biopsies of 1,083 patients with AF
and found that 3.1% had subclinical cardiac amyloido-
sis.15 Röcken et al. found an association between isolated
atrial amyloidosis and AF irrespective of age and sex
based on biopsies of the right atrial appendage collected
during open-heart surgeries.12 AL amyloidosis can have
a spectrum ranging from no involvement of the heart at
all to a severe form of cardiovascular disease.16 Cardiac
amyloidosis presents with restrictive cardiomyopathic
symptoms (exercise intolerance) followed by systolic
dysfunction, atrial/ ventricular arrhythmias [amyloid
deposits in the sinoatrial/atrioventricular (AV) node
and conduction tissue], myocardial infarction (deposi-
tion of amyloid deposits in coronaries), and outflow tract
obstruction due to asymmetric deposition of amyloid
fibrils in the interventricular septum.8,17–19 Pericardial
and pleural effusion have also been reported.20,21
We queried the National Inpatient Sample (NIS) to
answer the hypothesis that coexisting AF worsens the
clinical outcomes and associated disease burden in
patients with amyloidosis and that appropriate manage-
ment of AF may improve the clinical outcomes and dis-
ease burden. To evaluate our hypothesis, we conducted a
cross- sectional analysis.
Methods
Data source
The NIS has been elaborated on in detail in prior studies.22
The NIS is the largest publicly available database in the
United States (US), which falls under the Healthcare Cost
and Utilization Project (HCUP) and is maintained by the
Agency for Healthcare Research and Quality. It is one of
the most useful databases available to study the outcomes
and trends of various procedures and diseases. It includes
deidentified data collected from 20% of community hos-
pitals of 46 states in the US. Each hospitalization is rep-
resentative of one primary diagnosis, up to 29 secondary
diagnoses, and 15 procedures using the international
Clinical Modification codes [International Classification
of Diseases, ninth revision and 10th revision (ICD-10)].
The available data include admission status, demograph-
ics, admitting diagnosis, comorbidities, health care facility
(whether rural or urban), discharge diagnosis, outcomes,
length of stay, and costs during hospitalization. It is
important to mention here the inherent limitations of NIS,
including a lack of distinction between acute and chronic
diagnoses and between comorbidities and complications;
however, we evaluated the disease burden and inpatient
mortality and length of stay as outcomes.23,24
Q2
Dr. Kanjwal is a consultant for Abbott, Johnson and Johnson, and
Biosense Webster. The other authors report no conflicts of interest
for the published content.
Manuscript received January 1, 2021. Final version accepted
February 5, 2021.
Address correspondence to: Khalil Kanjwal MD, FACC, FHRS,
CCDS, CEPS(P), Michigan State University, McLaren Greater
Lansing Hospital, Lansing, MI 48901, USA. Email: khalil.kanjwal@
mclaren.org.
Clinical Outcomes and Disease Burden in Amyloidosis Patients with and Without AF
2 The Journal of Innovations in Cardiac Rhythm Management, June 2021
We examined all adult patients who were hospitalized in
the US during the year 2016 with the diagnosis of amy-
loidosis and with comorbid AF using the NIS. Patients
were filtered using ICD-10 Clinical Modification codes.
We identified all adult patients aged 18 years or more
who were admitted with amyloidosis with and without
a concomitant primary or secondary diagnosis with AF
during the year 2016. We excluded any hospitalizations
with missing demographics (ie, age, sex, admission or
discharge diagnosis, and mortality data). We utilized
NIS variables to identify patients’ age, sex, race, county
location, county income, hospital bed size, and alcohol
abuse. Race was divided into two categories, white and
nonwhite.
Primary outcomes and comorbid conditions
Our objectives were to assess the comorbidities and inpa-
tient outcomes in patients with a diagnosis of amyloidosis
with and without coexisting AF. The primary outcomes
analyzed were inpatient mortality and length of the
hospital stay of all patients admitted with amyloidosis
with and without coexisting AF. Comorbidities associ-
ated with amyloidosis and AF were stroke; heart failure;
bleeding; supraventricular tachycardia; ventricular tach-
ycardia; heart block; cardiac arrest; cardiogenic shock;
implantable cardioverter-defibrillator (ICD), permanent
pacemaker (PPM), or cardiac resynchronization therapy
(CRT) placement; and renal and respiratory failure.
Statistical analysis
We used survey analyses for stratifying and clustering
encounters for all continuous and categorical variables.
The Statistical Package for the Social Sciences software
program (IBM Corporation, Armonk, NY, USA) was used
to perform statistical analyses. We used the chi-squared
test or analysis of variance approach to identify differ-
ences in categorical variables and the two-sample t-test
for the analysis of continuous variables, respectively.
Logistic regression modeling was used to calculate the
odds ratio (OR) for outcomes between the two study
groups. This was followed by multivariate analyses to
account for any confounders in the form of comorbidities
between the two groups. A p-value of less than 0.05 was
considered to be statistically significant. We audited the
analyses using the checklist provided by the NIS to assess
and confirm the data analyses were done according to the
rules recommended by the NIS (https://www.hcupus.
ahrq.gov/db/nation/nis/nischecklist.jsp).
Results
We identified a total of 7,135,090 inpatient hospitaliza-
tions in the year 2016. Among these, we further identified
patients (n = 2,997) with a diagnosis of amyloidosis using
the ICD-10 codes E850, E851, E852, E853, E854, E8581,
E8582, E8589, and E859. We also identified patients (n =
984) with concomitant AF using the ICD-10 codes I48.0,
I48.1, I48.2, I48.3, I48.4, I48.91, and I48.92. The ICD-10
codes for secondary outcomes are presented in supple-
mental documents. Thus, our final sample had two study
groups: patients with amyloidosis without AF (n = 2,013)
and patients with amyloidosis and AF (n = 984). Table 1
presents the background characteristics by study group.
Patients with amyloidosis and AF were significantly
older, with a mean age of 76.3 ± 9.7 years (p < 0.001), and
included a greater proportion of men (66.2% vs. 52.8%;
p < 0.001).
Table 2 summarizes the results of logistic regression
analyses used for adjusted OR calculations to control for
variables in Table 1. Patients with amyloidosis and AF
had a higher inpatient mortality rate [adjusted OR: 1.39,
95% confidence interval (CI): 1.01–1.91]. Patients with
amyloidosis and AF had a greater odds of heart failure
(adjusted OR: 4.61, 95% CI: 3.88–5.47), bleeding compli-
cations (adjusted OR: 2.31, 95% CI: 1.55–3.42), supraven-
tricular tachycardia (adjusted OR: 2.02, 95% CI: 1.31–
3.12), ventricular tachycardia (adjusted OR: 2.40, 95% CI:
1.68–3.41), heart block (adjusted OR: 2.36, 95% CI: 1.61–
3.46), restrictive cardiomyopathy (adjusted OR: 2.66, 95%
CI: 1.77–4.00), renal failure (adjusted OR: 1.59, 95% CI:
1.33–1.91), cardiogenic shock (adjusted OR: 3.77, 95% CI:
2.34–6.09), and ICD/CRT/PPM placement (adjusted OR:
3.30, 95% CI: 2.47–4.40). After controlling for confounding
Q3
Q4
Q5
Table 1: Background Characteristics by Study Group
Amyloidosis
Alone (n = 2,013)
Amyloidosis
with AF (n = 984)
p-value
Age (years) 71.3 ± 12.1 76.3 ± 9.7 < 0.001
Sex (% male) 52.8% 66.2% < 0.001
Race (% non-white) 35.5% 33.3% 0.469
County location* (% completely rural) 5.1% 4.5% 0.268
County income (% lowest quartile) 27.5% 36.3% 0.036
Hospital bed size** (% small) 11.1% 13.0% 0.322
AF: atrial fibrillation.
*Based on the National Center for Health Statistics Urban–Rural Code; % non-
metropolitan, non-micropolitan.
**Definitions of hospital bed size categories vary by geographic region of the
country, rural or urban setting, and whether the facility is a teaching hospital.
S. Jamal, A. Kichloo, B. Bailey, et al.
The Journal of Innovations in Cardiac Rhythm Management, June 2021 3
variables, disease severity was significantly higher in the
amyloidosis with AF population, with the exceptions of
stroke (adjusted OR: 0.34, 95% CI: 0.23–0.50), respiratory
failure (adjusted OR: 1.08, 95% CI: 0.82–1.41), and cardiac
arrest (adjusted OR: 1.57, 95% CI: 0.80–3.07). Figures 1
and 2 present comparisons of outcomes of amyloidosis
in terms of percentage of population subset in two series.
Discussion
The principal findings of this study were as follows: (1)
there was a greater associated inpatient mortality rate in
patients with amyloidosis and coexisting AF; (2) there
was a higher associated cardiovascular morbidity burden
in patients with amyloidosis and AF; (3) patients with
amyloidosis and AF had a significantly increased odds
of bleeding, but the prevalence of ischemic stroke was
significantly higher in patients with amyloidosis without
AF; (4) coexisting AF was associated with renal failure in
patients who had compromised renal functions at base-
line; (5) patients with amyloidosis and AF were found to
have a higher prevalence of heart block and ICD/CRT/
PPM placement when compared to patients without AF;
and (6) age and male sex are important and significant
predictors of outcomes in patients with amyloidosis and
AF.
Morbidity and mortality rates in systemic amyloidosis
depend upon the extent and type of amyloid fibril dep-
osition in the organ systems and vary from milder forms
of disease to very severe forms of nephrotic syndrome,
infiltrative cardiomyopathies, autonomic neuropathies
leading to hypotension and diarrhea, soft tissue infiltra-
tion resulting in carpal tunnel syndrome, macroglossia,
bleeding (gastrointestinal), malnutrition, and pulmo-
nary involvement.25–27 AF, in general, is known to lead
to a fourfold increased risk of mortality when compared
to the general population after adjusting for cardiovas-
cular comorbidities.28,29 AF is known to increase the risk
Figure 2: AF: atrial fibrillation.
Table 2: Outcomes and Comorbidities of Amyloidosis with and Without AF
Amyloidosis
Alone (n = 2,013)
Amyloidosis
with AF (n = 984)
OR (95% CI) aOR* (95% CI)
Stroke 7.9% 3.4% 0.39 (0.27–0.58) 0.34 (0.23–0.50)
Heart failure 30.4% 66.0% 4.47 (3.80–5.27) 4.61 (3.88–5.47)
Bleeding 2.8% 5.7% 2.10 (1.44–3.07) 2.31 (1.55–3.42)
Ventricular tachycardia 3.5% 7.5% 2.28 (1.63–3.20) 2.40 (1.68–3.41)
Heart block 2.8% 6.8% 2.60 (1.80–3.75) 2.36 (1.61–3.46)
Cardiac arrest 1.1% 1.6% 1.42 (0.75–2.71) 1.57 (0.80–3.07)
Restrictive cardiomyopathy 2.6% 5.6% 2.22 (1.51–3.27) 2.66 (1.77–4.00)
Cardiogenic shock 1.6% 5.0% 3.16 (2.01–4.98) 3.77 (2.34–6.09)
ICD/CRT/PPM placement 4.5% 14.5% 3.59 (2.71–4.74) 3.30 (2.47–4.40)
Renal failure 20.8% 29.1% 1.59 (1.33–1.90) 1.59 (1.33–1.91)
Respiratory failure 9.5% 9.8% 1.03 (0.80–1.34) 1.08 (0.82–1.41)
Inpatient mortality 5.6% 7.4% 1.34 (0.99–1.83) 1.39 (1.01–1.91)
Length of stay (includes only those
patients who survived to discharge)
7.4 ± 9.2 days 7.8 ± 12.9 days —†—
AF: atrial fibrillation; aOR: adjusted odds ratio; CI: confidence interval; CRT: cardiac resynchronization
therapy; ICD: implantable cardioverter-defibrillator; OR: odds ratio; PPM: permanent pacemaker.
*Adjusted for age, sex, and county income.
†Continuous variable; t-test nonsignificant (p = 0.301).
Figure 1: AF: atrial fibrillation; CRT: cardiac resynchronization
therapy; ICD: implantable cardioverter-defibrillator; PPM:
permanent pacemaker.
Q6
Clinical Outcomes and Disease Burden in Amyloidosis Patients with and Without AF
4 The Journal of Innovations in Cardiac Rhythm Management, June 2021
of thromboembolism and stroke, the risk of congestive
heart failure and pulmonary/renal complications, and
the health care costs and to affect the quality of life.30–34
We found a higher inpatient mortality with an adjusted
OR of 1.39 in patients with amyloidosis and coexisting
AF. This observation is thought to be due to the cumula-
tive effects on adverse outcomes like heart failure, heart
block, renal failure, respiratory failure, and bleeding com-
plications. The overall length of stay was not statistically
different between the groups.
Age is considered an independent risk factor for amy-
loidosis and AF.16 Amyloid deposits in the atria with
increasing age are considered a triggering factor for atrial
arrhythmias and AF.12 These trends are consistent with
our study results, as age contributed to an increased
prevalence of AF in patients with amyloidosis. In previ-
ous studies, female sex was found to be protective against
myocardial involvement in transthyretin-related amyloi-
dosis.35 This is consistent with our study results, with an
increased propensity for male sex among patients with
cardiovascular involvement.
Our analyses revealed statistically significant increased
prevalence rates of heart failure (66% vs. 30%; adjusted
OR: 4.61, 95% CI: 3.88–5.47), restrictive cardiomyopathy
(5.6% vs. 2.6%; adjusted OR: 2.66, 95% CI: 1.77–4.00),
supraventricular tachycardia (4.4% vs. 2.5%; adjusted
OR: 2.02, 95% CI: 1.31–3.12), ventricular tachycardia
(7.5% vs. 3.5%; adjusted OR: 2.40, 95% CI: 1.68–3.41),
heart block (6.8% vs. 2.8%; adjusted OR: 2.36, 95% CI:
1.61–3.46), requirement for ICD/CRT/PPM placement
(14.5% vs. 4.5%; adjusted OR: 3.30, 95% CI: 2.47–4.40),
and cardiogenic shock (5% vs. 1.6%; adjusted OR: 3.77,
95% CI: 2.34–6.09) in patients with amyloidosis and coex-
isting AF.
AF is the most common arrhythmia seen in patients
with amyloidosis. An increased prevalence of ischemic
stroke was recorded in patients with amyloidosis with-
out AF; however, the association of bleeding complica-
tions was higher in patients with coexisting AF. Cardiac
thrombi have been reported in cardiac amyloidosis even
before the development of AF, which could be because of
changes in both systolic and diastolic dynamics due to
amyloid deposits.36 These deposits can embolize, result-
ing in stroke as an initial manifestation of the disease.37
Anticoagulation can be challenging in these patients
and patients with systemic amyloidosis as they are at
an increased risk of bleeding (eg, gastrointestinal hem-
orrhage, factor X deficiency).38 Patients with amyloidosis
without concurrent AF had a higher prevalence of stroke
(combined ischemic and hemorrhagic shock) relative to
patients with coexisting AF.
Patients with amyloidosis without concurrent AF had
a greater prevalence of stroke (combined ischemic and
hemorrhagic shock) as compared with patients with coex-
isting AF. Amyloidosis increases the risk of intra-atrial
and intracardiac thrombi, even without coexisting AF.36,37
This could possibly explain the increased prevalence
of stroke in patients without concurrent AF. Moreover,
patients with amyloidosis and coexisting AF, irrespec-
tive of their CHADS2VASc score, are supposed to be on
anticoagulation; this could very well explain the reduced
risk of stroke in this group, who are likely receiving anti-
coagulation, in our study. Patients with amyloidosis are
at an increased risk of bleeding, including mainly gastro-
intestinal bleeding and factor X deficiency.39 Moreover,
patients with coexisting AF were also found to exhibit
an increased risk of bleeding as they were on anticoagu-
lation for thromboembolic prevention. This could possi-
bly explain the increased risk of bleeding in amyloidosis
patients with coexisting AF.
Cardiac involvement in amyloidosis can cause infiltra-
tion of the conduction system and result in heart blocks
requiring ICD/CRT/PPM placement as evident from our
results; however, concurrent refractory AF can worsen
the prevalence of ICD/CRT/PPM implantation due to
procedures such as AV nodal ablation, making patients
PPM-dependent and resulting in cardiomyopathies,
heart failure, and increased mortality rates.8,9,40–42
Renal amyloid deposition manifests as albuminuria
and progresses to nephrotic-range proteinuria, which
is almost always diagnosed in advanced forms of the
disease. Amyloidosis manifesting clinically with renal
involvement is considered very rare.26,43–25 AF with a
loss of atrial kick, which contributes to 20% to 25% of
the cardiac output, can lead to a fall in blood pressure
and decreased perfusion to the kidneys, further worsen-
ing the renal dysfunction.45 Our analyses showed that
coexisting AF is associated with worse renal outcomes in
patients with amyloidosis (29% vs. 20.8%) as compared
with in those without coexisting AF.
Limitations
The inherent nature of a cross-sectional study did not
allow us to calculate incidence and rate ratios. Reliance
on the HCUP database can also have limitations of its
own, eg, due to the select group of patients in the data-
base. It could not be determined whether the patients
had paroxysmal versus persistent AF. Moreover, antico-
agulation status in both the groups could not be deter-
mined either. Another limitation to the study was that
there was not a single case with a primary diagnosis of
transthyretin cardiomyopathy during the years 2016 and
2017 and this resulted in the limitation of not being able
to conduct a subgroup analysis of patients with transthy-
retin cardiomyopathy. Additionally, we took a composite
of ischemic and hemorrhagic stroke, but it would have
been ideal to have considered them as separate entities.
Moreover, the NIS has inherent limitations of a lack of
distinction between new and chronic diagnoses and
between comorbidities and complications.22,23 Still, the
increased mortality rates and significant trend toward
other outcomes in the AF and amyloidosis groups can
serve as a platform for further research. Given the under-
diagnosed nature of amyloidosis, new ideas and man-
agement strategies should be formulated to enhance
future practice.
Q7
S. Jamal, A. Kichloo, B. Bailey, et al.
The Journal of Innovations in Cardiac Rhythm Management, June 2021 5
Conclusion
Amyloidosis with AF is associated with a higher inpa-
tient mortality rate and other adverse clinical outcomes.
Optimizing the management of AF in patients with amy-
loidosis may help to improve outcomes. Further studies
in the future can help us to understand the underlying
pathogenesis of these outcomes and also help devise
strategies to improve outcomes.
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The Journal of Innovations in Cardiac Rhythm Management, June 2021 7
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