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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 301-308
Epidemiology of Anemia in Human Immunodeficiency Virus
(HIV)-Infected Persons: Results From the Multistate Adult and
Adolescent Spectrum of HIV Disease Surveillance Project
By
Patrick S. Sullivan,
Debra L. Hanson,
Susan Y. Chu,
Jeffrey L. Jones,
John W. Ward, and
the Adult/Adolescent Spectrum
of Disease Group
From the Division of HIV/AIDS Prevention, National Center for HIV,
STD, and TB Prevention, Atlanta, Georgia.
 |
ABSTRACT |
To study the incidence of, the factors associated with, and the
effect on survival of anemia in human immunodeficiency virus
(HIV)-infected persons, we analyzed data from the longitudinal medical
record reviews of 32,867 HIV-infected persons who received medical care
from January 1990 through August 1996 in clinics, hospitals, and
private medical practices in nine United States cities. We calculated
the 1-year incidence of anemia (a hemoglobin level of <10 g/dL or a
physician diagnosis of anemia); the adjusted odds ratios showing excess
risk of anemia associated with demographic factors, prescribed
therapies, and concurrent diseases; the risk of death for patients who
developed anemia compared with risk for patients who did not develop
anemia; and, of patients who did develop anemia, the risk of death for
those who did not recover from anemia compared with the risk for those
who did recover. The 1-year incidence of anemia was 36.9% for persons
with one or more acquired immunodeficiency syndrome (AIDS)-defining
opportunistic illnesses (clinical AIDS), 12.1% for patients with a CD4
count of less than 200 cells/µm or CD4 percentage of <14 but not
clinical AIDS (immunologic AIDS), and 3.2% for persons without
clinical or immunologic AIDS. Of anemia diagnoses, 22% were identified
by physicians as drug related. Incidence of anemia was associated with
clinical AIDS, immunologic AIDS, neutropenia, thrombocytopenia,
bacterial septicemia, black race, female sex, prescription of
zidovudine, fluconazole, and ganciclovir, and lack of prescription of
trimethoprim-sulfamethoxazole. The increased risk of death associated
with anemia differed by first CD4 count: for patients with a CD4 count
of  200 cells/µL at the beginning of the survival analysis, the
risk of death was 148% (99% confidence interval [CI], 114 to 188)
greater for those who developed anemia; for patients whose first CD4
count was <200 cells/µL, the risk of death was 56% (99% CI, 43 to
71) greater for those in whom anemia developed. For persons in whom
anemia developed, the risk of death was 170% (99% CI, 132 to 203)
greater for persons who did not recover from anemia compared with those
who did recover. Anemia is a frequent complication of HIV infection,
and its incidence is associated with progression of HIV disease,
prescription of certain chemotherapeutics, black race, and female sex.
Anemia, particularly anemia that does not resolve, is associated with
shorter survival of HIV-infected patients.
| |
INTRODUCTION |
ANEMIA IS A FREQUENT complication of
infection with the human immunodeficiency virus type 1 (HIV-1) and may
have multiple causes.1 In different study settings, the
prevalence of anemia in persons with acquired immunodeficiency syndrome
(AIDS) has been estimated at 63% to 95%,2-5 making it
more common than thrombocytopenia or leukopenia in patients with
AIDS.3,6 This high prevalence of anemia may be because of a
high incidence of anemia, a long duration of anemia, or a combination
of both.
HIV infection may lead to anemia in many ways: changes in cytokine
production with subsequent effects on hematopoiesis7-9;
decreased erythropoietin concentrations10,11; opportunistic
infectious agents, such as Mycobacterium avium
complex12 and parvovirus B-1913;
administration of chemotherapeutic agents such as
zidovudine,14 ganciclovir,15 and
trimethoprim-sulfamethoxazole16; and myelophthisis caused
by cancers such as lymphosarcoma. Other mechanisms for HIV-associated
anemia, although uncommon, include vitamin B12
deficiency17 and the autoimmune destruction of red blood
cells.18 Direct infection of marrow precursor
cells19 has been hypothesized, but not proven.
Anemia has been associated with progression to AIDS20 and
shorter survival times21,22 for HIV-infected patients. No
published data have shown whether, given that anemia has developed,
recovery from anemia is associated with improved survival.
Understanding the association between anemia and survival is important
because treatments for anemia are available including recombinant human
erythropoietin (r-huEPO),23 blood transfusion, and, in
drug-induced anemia, cessation of myelosuppressive therapies.
To study the occurrence, associations, and effect of anemia on the
survival of HIV-infected patients, we analyzed data from the medical
records of 32,867 persons enrolled in a project that provided
surveillance for opportunistic illnesses, other clinical conditions,
drugs prescribed, and laboratory data for persons infected with HIV.
| |
METHODS |
Adult and Adolescent Spectrum of HIV Disease Surveillance Project.
We analyzed data from January 1990 (when the project began) through
August 1996 from the records of patients in the Adult and Adolescent
Spectrum of HIV Disease Surveillance Project, a multicenter medical
record review in nine United States cities.24 Each project
site developed procedures to ensure patient confidentiality and
conducted the project according to guidelines of local human subjects
review committees. Depending on the project site, either all patients
infected with HIV who attended participating clinics or a systematic
sample of patients who attended were eligible for observation, and
HIV-infected patients with and without AIDS were observed. A
standardized instrument was used to collect information on the
patient's clinical conditions, laboratory values, and treatments
during the year preceding the first medical record abstraction
(baseline review); similar information was collected by medical record
review every 6 months until the patient's death or last contact
(semester abstractions). For each semester abstraction, we used the
most recent hemoglobin determination in the semester.
Definitions.
Prevalent hemoglobin concentration was defined as the first recorded
hemoglobin concentration recorded after first observation in Adult and
Adolescent Spectrum of HIV Disease Project (ASD).
Univariate statistics were calculated on prevalent hemoglobin
concentrations stratified by sex. Strata of hemoglobin concentrations
were created based on sex-specific reference ranges.25 For
men strata were <10, 10 to 14, and 14 g/dL; for women strata were
<10, 10 to 12, and 12 g/dL. Stratified hemoglobin concentrations
are presented by stage of HIV disease.
For all other analyses, anemia was defined as a hemoglobin
concentration of less than 10 g/dL or an International Classification
of Diseases (ICD-9) diagnosis code of 280 to 281.99
(iron deficiency anemia and other deficiency anemias), 283 to 284.79
(acquired hemolytic anemias), 648.2 to 648.29 (anemia complicating
pregnancy or childbirth), or 284.9 to 285.99 (aplastic anemia, other
than drug related, and other unspecified anemias). Drug-related anemia
was defined as a diagnosis of anemia for which the physician specified
a drug-related cause in the medical record or for which an ICD-9 code
of 284.8 (aplastic anemia caused by drugs) was recorded; all other
diagnoses were considered unrelated to drugs.
To determine whether a person with anemia recovered from anemia,
hemoglobin levels measured during two semesters after the semester of
anemia diagnosis (or one semester, if there was only one semester of
follow-up) were compared with the level from the semester of anemia
diagnosis. If both hemoglobin levels determined after anemia diagnosis
were more than 10.0 g/dL and were at least 1.0 g/dL more than the level
at the time of anemia diagnosis, the person was considered to have
recovered.
Incidence of anemia.
To calculate the incidence of anemia, all anemia diagnoses in the
1-year period from 6 months to 18 months after baseline review
(semesters 2 and 3, defined as the study year) were counted; the
analysis included all patients who were observed through the end of the
study year, died during the study year, or had anemia during the study
year. Patients who had only one semester of follow-up, prevalent anemia
(defined as anemia during the semester before the study year), or no
CD4 count or hemoglobin level during the study year were excluded
(Table 1). Multiple
logistic regression was performed to describe the associations of
demographic variables (sex, age < or 45 years, race, and HIV
exposure mode), stage of disease (CD4 T-lymphocyte count of < or
200 cells/µL, and diagnosis of any AIDS-defining opportunistic
illness), illnesses (bacterial septicemia, lymphoma, and
Mycobacterium avium complex), laboratory data (neutropenia and
thrombocytopenia), and chemotherapeutic agents (zidovudine, didanosine,
dideoxycytidine, trimethoprim-sulfamethoxazole, ganciclovir, and
fluconazole) with the occurrence of anemia during the study year. Drug
prescriptions during the semester preceding the semester of anemia
incidence, and clinical conditions present during the semester of
anemia incidence were examined. Because of the large numbers of
observations available, all covariates were kept in the regression
model regardless of statistical significance. Separate regression
models were constructed for the outcomes of anemia related to drugs and
anemia unrelated to drugs. For persons who did not develop anemia,
semester 2 was considered the referent semester to determine
covariates. The results are reported as adjusted odds ratios (AORs),
with 99% confidence intervals (CIs). We used 99% CIs because we
performed a large number of tests of significance.
Mortality.
Analyses of mortality were conducted from the first CD4 T-lymphocyte
count after baseline review ("first CD4 count") to the date of
death, last contact, or loss to follow-up. For 75% of patients, the
first CD4 count was done in the first semester after baseline review;
for 90%, the first CD4 count was done in the first two semesters after
baseline review. Patients were excluded if they (1) did not have a
blood hemoglobin level and CD4 count at any time after baseline review,
(2) developed anemia before the first CD4 count, or (3) had no
follow-up after the date of the first CD4 count
(Table 2).
The Kaplan-Meier method was used to describe the median survival of
patients after the first CD4 count, and the log rank test was used to
determine differences in survival between those persons who had (1) no
anemia, (2) drug-related anemia, or (3) anemia unrelated to drugs.
Proportional hazards regression was conducted to evaluate the effect of
anemia on survival from the first CD4 count. The time-dependent
regressors were clinical AIDS, antiretroviral therapy (at least one
therapy of zidovudine [ZDV], didanosine, or dideoxycytidine),
Pneumocystis carinii pneumonia prophylaxis (at least one
therapy of aerosolized pentamidine, trimethoprim-sulfamethoxazole
[TMP-SMX], or dapsone), neutropenia (white blood cell count of
<2,500/µL), thrombocytopenia (platelet count of <50,000/µL or
physician diagnosis), and anemia. Non-time-dependent regressors were
sex, age (<25, 25 to 44, or 45 years), and HIV exposure mode.
Separate analyses were conducted for subgroups stratified by first CD4
counts. The results of these analyses are reported as risk ratios with
99% CIs.
Effect of recovery from anemia on mortality.
In analyses to describe the effects of recovery from anemia on
mortality, patients were excluded if they (1) did not have a diagnosis
of anemia after first CD4 count, (2) did not have at least one
measurement of hemoglobin level in a semester after the incident
semester, or (3) had no follow-up after the date of the first CD4
count. The Kaplan-Meier method and proportional hazards regression were
conducted as already described to determine the effect of recovery from
anemia on mortality after the first CD4 count. Separate analyses were
conducted for subgroups stratified by first CD4 counts. The results of
these analyses are reported as median survival of patients after first
CD4 count and as risk ratios with 99% CIs.
| |
RESULTS |
Data from the medical records of 32,867 patients were analyzed. Of
these, 31,534 (96%) had at least one hemoglobin concentration
abstracted. The distribution of the first abstracted value (prevalent
concentration) is shown in Table 3. The
distribution of hemoglobin strata varied dramatically with stage of HIV
disease: For HIV-infected persons with no AIDS, 72% and 69% of men
and women, respectively, had hemoglobin concentrations within the
reference range (greater than 14 or 12 g/dL, respectively). However,
for persons with clinical AIDS, only 13% and 23% of men and women,
respectively, had hemoglobin concentrations within the reference range.
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Table 3.
Distribution of Prevalent (first observed) Hemoglobin
Concentrations Among HIV-Infected Persons, by Sex and
Stage* of HIV Disease
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A total of 13,315 had sufficient follow-up time and all information
required for analysis of incidence; the characteristics of persons who
were included and those who were excluded were similar (Table 1).
Incidence of anemia was associated with clinical stage of disease:
1-year incidence was 3.2% for 6,094 persons with HIV infection but not
AIDS, 12.1% for 2,579 persons with immunologic AIDS (CD4 of
<200/µL or CD4 percentage of <14), but not clinical AIDS, and
36.9% for 4,642 persons with clinical AIDS. In all groups there were
2,222 anemia diagnoses, of which 494 (22.2%) were drug related. Most
diagnoses (1,311, 59%) were based only on low hemoglobin level; 505
diagnoses (23%) were based only on ICD-9 codes and 406 diagnoses
(18%) were based both on hemoglobin level and ICD-9 codes. The
incidence of anemia differed by race/ethnicity, stage of disease,
presence of concurrent illnesses, and prescription of chemotherapeutic
agents (Table 4). Anemia, whether
drug-related or unrelated to drugs, was positively associated with
clinical AIDS, a CD4 count of <200, bacterial septicemia,
neutropenia, thrombocytopenia, prescription of ganciclovir, and
prescription of fluconazole and negatively associated with the
prescription of TMP-SMX. Additionally, drug-related anemia was
positively associated with prescription of ZDV
(Table 5). Anemia unrelated to drugs was
also associated with black race, female sex, and lymphoma and was
negatively associated with prescription of ZDV (Table 5).
Of 19,213 persons included in survival analysis (Table 2), 6,632 (35%)
died during follow-up. Median follow-up time for all persons included
was 17 months. Survival did not differ significantly for persons with a
diagnosis of drug-related anemia versus those with a diagnosis of
anemia unrelated to drugs (P = .3 by log rank test), so all
anemic persons were considered together in the mortality analysis.
Median survival was significantly shorter for persons with anemia than
for those without anemia, regardless of first CD4 count
(Table 6). Proportional hazards regression
was used to control for CD4 count, clinical AIDS, age, neutropenia,
thrombocytopenia, antiretroviral therapy, and Pneumocystis
carinii pneumonia (PCP) prophylaxis. After
controlling for these factors, anemia was significantly associated with
increased risk of death at all levels of first CD4 count (Table 6).
Stratified proportional hazards regression analysis showed that the
effect of anemia on survival differed by first CD4 counts; for persons
with a first CD4 count of <200 cells/µL, the risk ratio was 1.56
(99% CI, 1.43 to 1.71; summary data not shown in Table 6), but for
persons with a first CD4 count of 200 cells/µL, the risk ratio was
2.48 (99% CI, 2.14 to 2.88).
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Table 6.
Results of Kaplan-Meier, Log Rank, and Proportional
Hazards Regression Analyses Describing Survival From First CD4
T-Lymphocyte Count, by CD4 Count, of HIV-Infected Persons Who Did and
HIV-Infected Persons Who Did Not Develop Anemia
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There were 7,261 anemic persons in the initial mortality analysis, of
whom 3,203 (44%) had subsequent hemoglobin level determinations and
were, thus, also included in analyses of the effect of recovery from
anemia on mortality. The results of mortality analyses were not
different for persons recovering from drug-related anemia or anemia
unrelated to drugs, so all persons with anemia were considered together
for these analyses. Of these, 1,341 (42%) were treated with either
erythropoietin or blood transfusion and 1,208 (38%) recovered from
anemia. Median survival was significantly longer for persons who
recovered than for those who did not recover, regardless of first CD4
count (Table 7). When clinical AIDS, CD4
count, neutropenia, thrombocytopenia, antiretroviral therapy, and PCP
prophylaxis were controlled, recovery from anemia was significantly
associated with decreased risk of death (Table 7); there was no
interaction with first CD4 count, and the combined risk ratio was 0.37
(99% CI, 0.33 to 0.43).
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Table 7.
Results of Kaplan-Meier, Log Rank, and Proportional
Hazards Regression Analyses Describing Survival From First CD4 Count,
by CD4 Count, for Anemic HIV-Infected Persons Who Did Recover From
Anemia and Anemic HIV-Infected Persons Who Did Not Recover From
Anemia
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DISCUSSION |
We found that anemia is a frequent complication of HIV infection that
is associated with an increased risk of death and that recovery from
anemia is associated with decreased risk of death for HIV-infected
persons who do develop anemia. According to our analysis, for most CD4
strata the median survival for persons who never became anemic was
similar to the median survival for those who became anemic but later
recovered (Tables 6 and 7).
The incidence of anemia was strongly and consistently associated with
the progression of HIV disease as measured by diagnosis of an
AIDS-defining opportunistic illness and measurement of a CD4 count of
<200 cells/µL. This association is most likely explained by the
increasing viral burden as HIV disease progresses, which could cause
anemia by increased cytokine-mediated myelosuppression. Alternatively,
anemia may be a surrogate marker for some aspect of disease progression
not captured by controlling for CD4 count and clinical AIDS diagnosis.
When adequate data are available for viral load measurements,
quantitative RNA measurements should be included as a covariate in
analyses like the ones presented here.
The administration of ZDV is recognized to cause anemia because of
myelosuppression.14 In our analysis, the prescription of
ZDV was positively associated with a diagnosis of drug-related anemia
but was protective against a diagnosis of anemia unrelated to drugs.
This protective effect may occur because patients in whom anemia
develops while they are prescribed ZDV are likely to be given a
diagnosis of drug-related anemia, and the diagnoses of drug-related
anemia and anemia unrelated to drugs were mutually exclusive in our
analysis. The protective effect may also be explained by the fact that
for patients who do not develop anemia related to ZDV and continue to
take the drug, ZDV treatment may slow the progression of the HIV
disease and the HIV replication rate. Lower viral burden, in turn, may
be associated with a decreased incidence of anemia because of less
cytokine-mediated myelosuppression. The prescription of ganciclovir,
known to cause myelosuppression, was also associated with the incidence
of anemia, whether identified as drug related or unrelated to drugs.
This suggests that anemia associated with prescription of ganciclovir
may be less likely to be recognized or recorded in medical records as
drug-related than anemia associated with ZDV prescription. Fluconazole
may cause myelosuppression when taken concurrently with ZDV, because
taking both reduces the serum half life of ZDV and increases its serum
concentrations.26
An unexpected finding was the negative association between prescription
of TMP-SMX and anemia. Although administration of TMP-SMX can cause
drug-associated aplastic anemia or immune-mediated destruction of
specific populations of blood cells, this effect would not be expected
to have a significant influence on the AOR in this analysis because the
effect is sporadic.16 It is likely that the protective
effect of TMP-SMX is associated with the prevention of other
conditions, such as Mycobacterium avium complex27
or bacterial septicemia, which are more predictable causes of anemia,
or other infections that could promote the development of the anemia
associated with chronic disease or with inflammation.
An increased incidence of anemia not recognized as drug related was
observed in black persons, although black race was not associated with
drug-related anemia. This association could be because of several
factors or a combination of these factors. A small percentage of black
persons have sickle cell anemia. The prevalence of glucose-6-phosphate
dehydrogenase (G-6-PD) deficiency may be 4% to 13% for black
men28,29 and 3% for black women.29 For persons
with G-6-PD deficiency, dapsone30 or
sulfamethoxazole,31 both of which are prescribed for
prophylaxis for P carinii pneumonia in patients with HIV
infection, may cause hemolytic anemia. Persons with G-6-PD deficiency
may also develop hemolytic anemia after infection with certain bacteria
(including Salmonella).32 The diagnoses of sickle
cell anemia and G-6-PD were not consistently collected in the Adult and
Adolescent Spectrum of HIV Disease Project, so a direct evaluation of
these hypotheses was not possible. It is also possible that black race
is a marker for other factors that are associated with increased
incidence of anemia but that were not included in our analysis.
Anemia was also associated with thrombocytopenia and neutropenia,
perhaps because myelosuppression caused by chemotherapeutics may affect
production of all the cell lineages. The association of anemia with
lymphoma may be because of myelophthisis, the secondary effects of
therapies administered for lymphoma, or anemia associated with chronic
disease. Myelosuppression is commonly observed in patients with
bacterial septicemia, regardless of HIV infection status.
For an analysis of factors associated with incidence of anemia, the
outcomes of drug-related anemia and anemia unrelated to drugs were
evaluated separately because the effect of ZDV prescription, one of the
most recognized causes of anemia in HIV-infected persons, differed by
type of anemia. Because these two types of anemia were distinguished
only on the basis of physician diagnosis as recorded in the medical
record, there was no standard criterion for drug-related anemia. The
condition may have been under diagnosed or under documented in medical
records or the association between ZDV prescription and drug-related
anemia could be overestimated if physicians assume a drug-related cause
for anemia in a patient who is taking ZDV.
In all analyses, some patients were excluded because of prevalent
anemia, inadequate length of follow-up, or missing data that were
necessary for our analysis. In general, the characteristics of the
patients excluded from the analyses were similar to the characteristics
of those who were included (Tables 1 and 2). A possible bias is
introduced in the analysis of incidence by including persons who
developed anemia during the second semester after baseline review but
had no further semester reviews, but not including persons with two
semesters of review and no anemia. This tends to cause an overestimate
of the incidence of anemia.
The main limitation of our analysis is that outcomes and exposures in
this project are reported only as occurring or not occurring in each
6-month interval of chart abstraction, and the exact dates of
drug-related anemia diagnosis, concurrent illnesses, or specific drug
administration were not collected. Therefore, our ability to define
exact temporal relationships between exposures and anemia is limited.
Exposures to drugs could occur from 1 day to 12 months before anemia,
and this decreases our ability to detect associations between anemia
and a drug. This should result in conservative estimates of excess
risk. Data that would allow the classification of the cause of anemia,
such as reticulocyte counts, erythropoietin levels, and parvovirus IgM
titers, were not collected in this project.
The Adult and Adolescent Spectrum of HIV Disease Project includes
diverse study sites and populations,24 but these data are
not necessarily representative of all HIV-infected persons in the
United States. Because HIV-infected patients must have been receiving
medical care at a clinic for at least 12 months to be included in our
analysis, there may be a selection bias for asymptomatic people with
earlier knowledge of HIV infection status or with more access to care.
The definition of anemia chosen for this study (hemoglobin <10 g/dL)
was different from clinical reference ranges for hemoglobin
concentration in men and women. We chose this cutoff for defining
anemia to exclude hereditary causes for mild anemia, such as
thalassemia trait, and to allow for use of a single cutoff that would
clearly exclude normal hemoglobin concentrations for both men and
women. As a result, our estimates of anemia incidence underestimate the
true impact of anemia in this population. Physicians should consult
their local laboratories to determine appropriate reference ranges for
clinical interpretation of hemoglobin concentrations, and any anemia in
HIV-infected persons, regardless of severity, should be investigated.
Anemia in HIV-infected patients, if persistent, is associated with
substantially decreased survival. Although our analyses cannot show
whether this relationship is causal, our findings are consistent with
those of other studies of anemia as a prognostic factor in HIV
infection,20,21 and consideration should be given to
evaluating the effects of treating anemia in a prospective study
design. If recovery from anemia is shown to directly increase survival,
screening for anemia should be aggressive and patients with anemia
should be treated.
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FOOTNOTES |
Submitted June 10, 1997;
accepted August 25, 1997.
Address reprint requests to Patrick S. Sullivan, DVM, PhD, Centers for
Disease Control and Prevention, 1600 Clifton Rd NE, Mail Stop E47,
Atlanta, GA 30333.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
APPENDIX |
The Adult/Adolescent Spectrum of HIV Disease Group includes Susan
Burkham, MPH, Texas Department of Health, Austin, TX; Susan Buskin,
PhD, Seattle-King County Department of Public Health, Seattle, WA;
Arthur Davidson, MD, Denver Department of Health and Hospitals, Denver,
CO; A.D. McNaghten, PhD, Michigan Department of Public Health, Detroit,
MI; Kaye Reynolds, Department of Health and Human Services, Houston,
TX; Frank Sorvillo, PhD, Los Angeles County Department of Health
Services, Los Angeles, CA; Melanie Thompson, MD, AIDS Research
Consortium of Atlanta, Atlanta, GA; and Susan Troxler, RN, MPH,
Louisiana Department of Health, New Orleans, LA.
| |
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Abstract
Introduction
Abstract