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Archives of Gerontology and Geriatrics 59 (2014) 491495

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Archives of Gerontology and Geriatrics


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High prevalence of aspirin resistance in elderly patients with


cardiovascular disease (CVD) and hyperhomocysteinaemia
Huaxin Zhang a,1, Xiuying Chen e,1, Lin Liu c, Li Fan b,*, Jian Cao b,**, Xiaoli Li b, Guoliang Hu b,
Yixin Hu b, Bingpo Zhu b, Xianfeng Liu b, Yan Gao b, Cong Ma b, Wenxiu Leng d
a
Department of Clinical Laboratory of South Building, Chinese PLA General Hospital, Beijing, China
b
First Geriatric Cardiology Division, Chinese PLA General Hospital, Beijing, China
c
Department of Respiratory Disease of South Building, Chinese PLA General Hospital, Beijing, China
d
Second Geriatric Cardiology Division, Chinese PLA General Hospital, Beijing, China
e
Pharmacy Department, Hospital of Chinese Peoples Armed Police Forces, Beijing 100039, PR China

A R T I C L E I N F O A B S T R A C T

Article history: Although aspirin resistance is well reported in CVD, little is known about aspirin response in elderly
Received 27 April 2012 patients with hyperhomocysteinaemia. The aim of the present study was to explore the prevalence of
Received in revised form 16 April 2014 aspirin resistance in elderly patients with CVD and hyperhomocysteinaemia. A total of 370 elderly
Accepted 24 April 2014
patients with CVD were recruited. The study included 216 patients with hyperhomocysteinaemia and
Available online 10 May 2014
154 patients with normohomocysteinaemia receiving daily aspirin therapy (75 mg) over 1 month.
The effect of aspirin was assessed using by light transmission aggregometry (LTA). Aspirin resistance
Keywords:
was dened as 20% arachidonic acid induced aggregation according to LTA. Aspirin resistance was
Aspirin resistance
Cardiovascular disease
dened in 48 (13.0%) of 370 patients. The prevalence of aspirin resistance was higher in
Hyperhomocysteinaemia hyperhomocysteinaemic patients than normohomocysteinaemic patients (16.7% vs. 7.8%, odds ratio
(OR) = 2.367; 95% condence interval (CI) = 1.1884.715, p = 0.012). In the multivariate logistic
regression analysis, hyperhomocysteinaemia (OR = 2.406, 95% CI = 1.2014.820, p = 0.013) was a
signicant risk factor for aspirin resistance. A signicant number of CVD patients with
hyperhomocysteinemia are resistant to aspirin therapy. Hyperhomocysteinemia is a signicant risk
factor for aspirin resistance in elderly patients with CVD.
2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction to a Framingham risk score model signicantly improve risk


prediction, especially in the intermediate-risk individuals for
Homocysteine is a sulfhydryl amino acid, resulting from coronary heart disease events (Veeranna et al., 2011).
the metabolism of methionine. Evidence from epidemiological Possible mechanisms of the association between hyperhomo-
studies has demonstrated an association between mild hyperho- cysteinaemia and CVD include promoting smooth muscle growth,
mocysteinemia and an elevated risk of CVD (Collaboration, 2002; impairing the function of endothelial cell, increasing lipid
Wald, Law, & Morris, 2002). The lowering homocysteine concen- peroxidation, stimulating autoimmune response, enhancing in-
trations by 3 mmol/l from current levels is estimated to result in a ammatory cytokine expression, and activating thrombosis
16% lower risk of ischemic heart disease, a 25% lower risk of deep (Austin, Lentz, & Werstuck, 2004; Durand, Lussier-Cacan, & Blache,
vein thrombosis, and a 24% lower risk of stroke (Wald et al., 2002). 1997; Zhang et al., 2009). Hyperhomocysteinaemia has been
Furthermore, one recent study suggests that adding homocysteine associated with increased platelet activation and thromboxane
production, increased sensitivity to agonists, and impaired nitric
oxide formation (Coppola et al., 2000; Signorello, Segantin,
* Corresponding author at: First Geriatric Cardiology Division, Chinese PLA
Passalacqua, & Leoncini, 2009).
General Hospital, 28 Fuxing Road, Beijing 100853, PR China. The prevalence of hyperhomocysteinaemia in elderly subjects
Tel.: +86 010 66876233; fax: +86 010 68212494. is higher than younger subjects (19.2% vs. 10.7%). In addition,
** Co-Corresponding author. higher homocysteine level is found to be independently
E-mail addresses: calvin301@163.com (L. Fan),
associated with an increased risk of death in elderly subjects
calvinisbest@hotmail.com (J. Cao).
1
These authors are equal rst authors. during a 4.3-year follow-up (Gonzalez, Huerta, Fernandez,

http://dx.doi.org/10.1016/j.archger.2014.04.005
0167-4943/ 2014 Elsevier Ireland Ltd. All rights reserved.
492 H. Zhang et al. / Archives of Gerontology and Geriatrics 59 (2014) 491495

Patterson, & Lasheras, 2007). Homocysteine concentrations 2.4. Platelet aggregation by LTA
are higher among patients with CVD and than controls. CVD
patients with hyperhomocysteinaemia are common (Selhub, The last dose of aspirin was administered within 212 h before
2006). Thus aspirin therapy is important in these patients. blood sampling. Two tubes of whole blood, anticoagulated with
Although aspirin resistance is well reported in CVD, little is 3.2% sodium citrate were used for Platelet aggregation. Blood
known about aspirin response in elderly patients with hyperho- samples were centrifuged at 800 rpm for 5 min to obtain native
mocysteinaemia. The aim of the present study was to explore the platelet-rich plasma and further centrifuged at 4000 rpm for 8 min
prevalence of aspirin resistance in elderly patients with CVD and to obtain platelet-poor plasma. The addition of arachidonic acid
hyperhomocysteinaemia. (AA; 0.5 mM) to platelet-rich plasma enhanced platelet aggrega-
tion. Aggregation was assessed with a ChronoLog Aggregometer
2. Subjects and methods (Chronolog, Havertown, PA, USA).

2.1. Ethical approval of the study protocol 2.5. Denition of aspirin resistance

This study complied with the Declaration of Helsinki. It was The denition of aspirin resistance was 20% AA-aggregation
approved by the Scientic and Ethics Review Board of Chinese PLA according to LTA (Gurbel et al., 2007; Lordkipanidze et al., 2007).
General Hospital (Beijing, PR China). All patients provided written
informed consent prior to inclusion in the study. 2.6. Statistical analyses

2.2. Participants Continuous variables are mean value  standard deviation.


Categorical data and proportions were compared using the x2 test,
Initially, we enrolled 405 patients from the Wangshoulu area of if small expected cell frequencies, exact tests. Students t-test or
Beijing during between April 2008 and June 2010. After enroll- MannWhitney U two-sample tests (if the distribution was not
ment, patients with poor compliance (n = 17), inadequate dose normal) were used to compare the continuous variables between the
(75 mg) (n = 12), taking other antiplatelet medications (n = 6) two groups. p < 0.05 was considered signicant. Parameters signi-
were excluded during the follow-up. Thus, 370 patients were cantly related with the presence of aspirin resistance were deter-
eventually included in the present study. mined using binary logistic regression analyses. Pearson correlation
There were 216 patients (74.72  7.58 years old) in the or Spearman correlation (if the distribution was not normal) were
hyperhomocysteinemic group, which was dened as a homocysteine used to evaluate the association between platelet aggregation
concentration >15.0 mmol/L (Balogh et al., 2012). In this group, there induced by AA and homocysteine. Parameters signicantly related
were 155 males and 61 females. The normohomocysteinemic group with homocysteine were determined using multiple linear regression
included 154 CVD patients (73.98  8.41 years old). In this group, analyses (SPSS, Windows, version 14.0, Chicago, IL, USA).
there were 102 men and 52 women.
All patients were aged 65 years and were being treated for 3. Results
coronary heart disease, hypertension, peripheral arterial disease or
stroke; patients were on regular aspirin treatment (75100 mg 3.1. Patient characteristics
daily over 1 month). The exclusion criteria included: ingestion of
clopidogrel, ticlopidine, dipyridamole or other non-steroidal anti- As shown in Table 1, there were no signicant differences
inammatory drugs; administration of heparin or low-molecular- between the hyperhomocysteinaemic group and the normoho-
weight heparin; a major surgical procedure within 1 week of study mocysteinaemic group when comparing: age; being female; being
enrolment; family or personal history of bleeding disorders; a current smoker; having hypertension or peripheral arterial
platelet count <150  103/mL or >450  103/mL; hemoglobin occlusive disease; medications taken; and baseline platelet count.
<8 g/dL; history of myeloproliferative disorders; or a history of The number of patients with diabetes among patients with
drug-induced thrombocytopenia. Follow-up of patients was hyperhomocysteinaemia was lower than patients with normoho-
performed 36 months after the rst visit, which was completed mocysteinaemia (p = 0.011). The group with hyperhomocystei-
in all patients by telephone interviews and review of medical naemia had higher levels of homocysteine, CD62P, and creatinine
records. We documented medications and clinical events such as compared the group with normohomocysteinaemia (P < 0.001,
death, myocardial infarction, stroke, transient ischemic attack, and P = 0.032 and P = 0.001, respectively). Moreover, there were fewer
unstable angina. patients in normohomocysteinaemic patients with receiving
calcium-channel blockers therapy than hyperhomocysteinaemic
2.3. Laboratory measurements patients (P = 0.001).
As shown in Table 2, aspirin resistance, and aspirin sensitivity
Blood samples were obtained by trained personnel from all as measured by LTA were associated with no signicant difference
patients via antecubital venipuncture. The platelet counts were with regard to age; being a current smoker; having hypertension,
performed on a SYSMEX-XE2100 analyzer (SYSMEX, Kobe, diabetes, cerebrovascular disease, or peripheral arterial occlusive
Japan). Serum homocysteine levels were measured with a disease; and baseline platelet count. The number of patients with
chemiluminescent enzyme immumetric assay in a cobas 6000 hyperhomocysteinaemia among aspirin-resistant patients was
analyzer series (Roche Diagnostic). Platelet surface expression of higher than aspirin-sensitive patients (p = 0.012).
PAC-1 and CD62P after natural activation, which was tested by
ow cytometry (BD Biosciences, San Jose, CA, USA). The 3.2. Aspirin resistance in patients with or without
percentage activity of antithrombin III and protein C was hyperhomocysteinaemia
analyzed by a STA-R Evolution coagulation analyzer (Stago,
Paris, France). Serum creatinine, blood lipid, high-sensitivity C- Aspirin resistance was dened in 48 (13.0%) of 370 patients.
reactive protein, type-B natriuretic peptide and uric acid, as well Aspirin resistance was detected in 36 patients with hyperhomo-
as other basic biochemical blood tests, were carried out using cysteinaemia and 12 patients with normohomocysteinaemia. The
standard methods. prevalence of aspirin resistance was higher in the group with
H. Zhang et al. / Archives of Gerontology and Geriatrics 59 (2014) 491495 493

Table 1
Demographic characteristics of hyperhomocysteinaemic and normohomocysteinaemic groups.

Hyperhomocysteinaemia (n = 216) Normohomocysteinaemia (n = 154) P

Age (years) 74.72  7.58 73.98  8.41 0.337


Female, n (%) 61(28.2) 52(33.8) 0.255
Hypertension, n (%) 149(70.0) 109(70.7) 0.711
Coronary artery disease, n (%) 128(59.3) 86(55.8) 0.512
Cerebrovascular disease, n (%) 86(39.8) 53(34.4) 0.290
PAOD, n (%) 20(9.3) 10(6.5) 0.337
Diabetes, n (%) 56(25.9) 59(38.3) 0.011
Current smoker, n (%) 18(8.3) 17(11) 0.381
Aspirin resistance, n (%) 36(16.7) 12(7.8) 0.012
BMI (kg/m2) 25.25  3.12 24.64  3.31 0.075
Homocysteine (mmol/L) 21.02  5.77 12.31  6.48 <0.001
hs-CRP (mg/dL) 0.51  1.14 0.35  0.31 0.194
CD62P (%) 20.50  24.95 15.23  20.11 0.032
PAC-1 (%) 42.33  28.31 47.52  27.63 0.085
Protein C activity (%) 124.88  36.84 114.93  33.67 0.410
Antithrombin III activity (%) 103.74  14.21 104.76  13.04 0.493
Creatinine (mmol/L) 87.05  26.62 74.16  17.66 0.001
Fasting serum glucose (mmol/L) 5.95  1.23 6.06  1.24 0.419
Total cholesterol (mmol/L) 4.84  1.04 4.93  1.34 0.474
Triglyceride (mmol/L) 1.57  0.72 1.63  0.72 0.441
HDL cholesterol (mmol/L) 1.30  0.33 1.31  0.39 0.751
LDL cholesterol (mmol/L) 2.83  0.83 2.87  0.78 0.648
Uric acid (mmol/L) 335.68  84.98 319.78  82.00 0.113
Platelet count (103/mL) 207.52  62.22 205.03  54.30 0.696
Medications taken
Statins, n (%) 64(29.6) 46(29.9) 0.960
ACEIs/ARBs, n (%) 47(21.8) 33(21.4) 0.939
CCBs, n (%) 96(44.4) 43(27.9) 0.001
Daily aspirin dose, n (%)
75 mg 94(43.5) 68(44.2) 0.903
100 mg 122(56.5) 86(55.8) 0.903

PAOD: peripheral arterial occlusive disease; BMI: body mass index; Hs-CRP: high-sensitivity C-reactive protein; BNP: type-B natriuretic peptide; ACEIs: angiotensin-
converting enzyme inhibitors; ARBs: angiotensin receptor blockers; CCBs: calcium-channel blockers.

Table 2
Demographic characteristics of aspirin-resistant and aspirin-sensitive groups. hyperhomocysteinaemia compared with the group with normo-
Aspirin Aspirin P homocysteinaemia (16.7% vs. 7.8%, odds ratio (OR) = 2.367; 95%
resistant sensitive condence interval (95% CI) = 1.1884.715).
(n = 48) (n = 322)

Age (years) 75.18  8.66 74.30  7.82 0.476 3.3. Multivariate logistic regression analysis
Female, n (%) 14(29.2) 99(30.7) 0.825
Hypertension, n (%) 36(75.0) 222(68.9) 0.394 In the multivariate logistic regression analysis, adjusting for
Coronary artery disease, n (%) 32(66.7) 182(56.5) 0.184
Cerebrovascular disease, n (%) 20(41.7) 119(37.0) 0.530
age, sex and body mass index, hyperhomocysteinaemia
PAOD, n (%) 5(10.4) 25(7.8) 0.568 (OR = 2.406, 95% CI: 1.2014.820, p = 0.013) was a signicant risk
Current smoker, n (%) 5(10.4) 30(9.3) 0.792 factor for aspirin resistance. Additionally, the multivariate logistic
Diabetes, n (%) 11(22.9) 104(32.3) 0.190 regression was performed to assess the association of homocyste-
Hyperhomocysteinaemia, n (%) 36(75.0) 180(55.9) 0.012
ine level (grouped by quintile) and aspirin resistance. However,
BMI (kg/m2) 24.81  2.90 25.02  3.26 0.679
Homocysteine (mmol/L) 18.87  6.82 17.32  8.92 0.686 this did not reach signicant difference (Table 3).
hs-CRP (mg/dL) 0.31  0.28 0.46  1.16 0.372
CD62P (%) 15.20  20.54 14.33  19.22 0.774 3.4. Correlation and multiple linear regression analysis
PAC-1 (%) 41.48  30.20 44.93  27.80 0.434
Protein C activity (%) 115.68  40.86 120.74  69.81 0.806
Antithrombin III activity (%) 103.15  15.09 104.31  13.54 0.595
Homocysteine was positively correlated with platelet aggre-
Creatinine (mmol/L) 94.25  23.54 79.82  20.14 0.825 gation induced by AA, but this difference did not reach statistical
Fasting serum glucose (mmol/L) 5.97  1.18 6.00  1.24 0.884 signicance (r = 0.030, p = 0.565). With homocysteine as the
Total cholesterol (mmol/L) 4.76  1.01 4.89  1.20 0.488 dependent variable, analyses revealed that homocysteine was
Triglyceride (mmol/L) 1.71  0.83 1.57  0.71 0.220
positively correlated with Creatinine (b = 0.145, p = 0.018), Age
HDL cholesterol (mmol/L) 1.29  0.38 1.31  0.36 0.664
LDL cholesterol (mmol/L) 2.79  0.81 2.85  0.81 0.589 (b = 0.137, p = 0.025), and BMI (b = 0.124, p = 0.037) (Table 4).
Uric acid (mmol/L) 316.03  95.51 331.14  82.61 0.338
Platelet count (103/mL) 214.13  82.35 205.30  54.57 0.336
Medications taken Table 3
Statins, n (%) 18(37.5) 92(28.6) 0.207 Multivariate analysis of homocysteine (by quintile) in aspirin-resistant patients,
ACEIs/ARBs, n (%) 8(16.7) 72(22.4) 0.371 adjusted for age, sex and body mass index.
CCBs, n (%) 22(45.8) 117(36.3) 0.205
Homocysteine (mmol/L) Odds ratio 95% Condence P
Daily aspirin dose, n (%)
intervals (CI)
75 mg 22(45.8) 137(42.5) 0.668
100 mg 26(54.2) 185(57.5) 0.668 First quintile (<11.4 mmol/L)
Second quintile (11.414.8 mmol/L) 0.629 0.2231.773 0.380
PAOD: peripheral arterial occlusive disease; BMI: body mass index; Hs-CRP: high-
Third quintile (14.817.7 mmol/L) 0.451 0.1461.397 0.168
sensitivity C-reactive protein; BNP: type-B natriuretic peptide; ACEIs: angiotensin-
Fourth quintile (17.721.5 mmol/L) 1.594 0.6613.847 0.299
converting enzyme inhibitors; ARBs: angiotensin receptor blockers; CCBs: calcium-
Fifth quintile (>21.5 mmol/L) 1.119 0.4412.844 0.813
channel blockers.
494 H. Zhang et al. / Archives of Gerontology and Geriatrics 59 (2014) 491495

Table 4 higher CD62P levels and more collagen-induced CD62P surface


Linear regression analyses of clinical data, echocardiographic data and homocysteine.
expression than control subjects Additionally, another study
Beta t Sig. (Andersen, Hurlen, Arnesen, & Seljeot, 2002) showed that
Creatinine 0.145 2.386 0.018 the levels of CD62P were signicantly higher in the aspirin-
Age 0.137 2.255 0.025 resistant group as compared to the aspirin-sensitive group
BMI 0.124 2.099 0.037 by evaluating 129 patients with acute myocardial infarction.
Constant 0.396 0.693 These results suggest that increasing platelet reactivity in
hyperhomocysteinemic patients may be associated with
aspirin resistance. Recently, one study revealed that patients
with chronic renal failure had higher frequency of aspirin
4. Discussion resistance than controls (34.7% vs. 16.9%, P < 0.001) (Tanrikulu
et al., 2011). Similarly, another study showed that creatinine
In the present study, we demonstrated, for the rst time, that level was signicantly higher in the aspirin-resistant group, and
the prevalence of aspirin resistance by LTA in CVD patients was an independent predictor of aspirin resistance (Ozben,
with hyperhomocysteinaemia was 16.7%, which was higher Tanrikulu, Ozben, & Caymaz, 2010). The present study also
than patients with normohomocysteinaemia. Several studies demonstrated a high trend in aspirin-resistant patients. These
have investigated the prevalence of aspirin resistance using results imply that we should not ignore CVD patients with
LTAAA in patients with CVD. A low prevalence (02%) of impaired renal function.
aspirin resistance was investigated in 120 patients with The present study showed that homocysteine was positively
stable coronary artery disease (DiChiara et al., 2007). Another correlated with Creatinine, Age, and BMI. Hyperhomocysteinemia
study demonstrated that 8 patients (4%) were aspirin resistant in may result from the genetic variation of enzymes involved in its
201 patients with stable coronary artery disease (Lordkipanidze metabolism. Acquired elevated level of homocysteine may be a
et al., 2007). In a third study, aspirin resistance was present in result of various factors, such as lifestyle, Unbalanced diet, the
5% of 80 patients with peripheral arterial disease (Saunders et al., decline of the glomerular ltration rate, medications, sex and age
2011). In addition, the frequency of aspirin resistance was 9% in (Bamashmoos, Al-Nuzaily, Al-Meeri, & Ali, 2013; Davies et al.,
59 stroke patients (Zytkiewicz, Gielwanowska, Wojtasinska, 2001; Malinowska, Kolodziejczyk, & Olas, 2012).
Psuja, & Zawilska, 2008). However, the prevalence of aspirin Previous study reported that 33.6% of cardiovascular patients
resistance was 5.560% in CVD patients as measured with discontinued their medications in a study of 1521 patients
different methods (Gasparyan, Watson, & Lip, 2008). Considering discharged on a combination of aspirin, statin and a b-blocker.
these studies, there was a relatively high frequency of aspirin A multivariable survival analysis showed that patients stopping
resistance in hyperhomocysteinaemic patients according to aspirin medication were associated with an 82% higher risk of
LTAAA. having mortality (Ho et al., 2006). Additionally, one study found
The present study showed that hyperhomocysteinaemia was that 9% of 191 patient with a history of myocardial infarction were
a signicant risk factor for aspirin resistance. Furthermore, there aspirin resistant because of noncompliance (Schwartz, Schwartz,
were more hyperhomocysteinaemic patients among aspirin- Barber, Reeves, & De Franco, 2008). Furthermore, another study
resistant patients than aspirin-sensitive patients. However, reported that the frequency of patients dened as aspirin
homocysteine levels were similar between the aspirin-resistant resistance using the PFA-100 dropped from 18.4% to 1.4% in 212
and aspirin-sensitive group in the present study. Similar results post-MI patients by reinforcing compliance and increasing aspirin
were observed by other studies (Akoglu et al., 2011; Kahraman dosage (von Pape, Strupp, Bonzel, & Bohner, 2005). In the present
et al., 2007). This could be associated with a relatively small study, 4.7% of patients were aspirin resistant due to non-
sample of the aspirin-resistant group. In these studies (including compliance and were excluded from this study. Compliance
the present study), patients with aspirin resistance were less to aspirin therapy was ascertained by telephone reviews and
than 50. Hyperhomocysteinemia is associated with atheroscle- review of medical records, and we also contacted patients doctors
rosis and thrombosis (Cacciapuoti, 2011). Hyperhomocysteine- in community and obtained their conditions by telephone. We
mia may cause increased platelet aggregation due to decrease should take much attention to noncompliance in CVD patients
nitric oxide bioavailability (Signorello et al., 2009). However, taking aspirin treatment.
there is no consensus about homocysteine-lowering therapy The present study had one important limitation. The
(Abraham & Cho, 2010). A Meta-Analysis proposes a hypothesis prevalence of aspirin resistance in CVD patients with hyperho-
to explain why the trials of lowering homocysteine using folic mocysteinemia was valid for the dose of 75100 mg/day of
acid have been negative because almost all patients in them aspirin, but we did not investigate the other suggested doses of
were taking aspirin. The result also suggests that folic acid would 162 mg/day and 325 mg/day.
have a role in the primary prevention of ischemic heart disease,
when there is not concomitant use of aspirin, but not in 5. Conclusions
secondary prevention, when aspirin is taken routinely (David,
Wald, & Nicholas, 2011). Currently, we should pay more In the present study, these ndings suggest that a signicant
attention to CVD patients with hyperhomocysteinemia and number of CVD patients with hyperhomocysteinemia are resistant
further studies are needed to focus on the relationship to aspirin therapy. Hyperhomocysteinemia is a signicant risk
between aspirin resistance and hyperhomocysteinemia. In factor for aspirin resistance in patients with CVD. Further
the future, we will clarify whose homocysteine levels should studies are needed to explore the epidemiology and mechanisms
be measured and understand who should receive homocysteine- of aspirin resistance in hyperhomocysteinemic patients and
lowering therapies. provide additional information for preventing ischemic events.
Interestingly, hyperhomocysteinaemic patients had higher
levels of CD62P, and creatinine than patients with normohomo- Conict of interest of statement
cysteinaemia. CD62P is used as markers of platelet activation.
One study (Holven, Aukrust, Pedersen, Ose, & Nenseter, 2007). No authors report any conicts of interest relevant to this
demonstrated that hyperhomocysteinemic subjects had manuscript.
H. Zhang et al. / Archives of Gerontology and Geriatrics 59 (2014) 491495 495

Gurbel, P. A. B., DiChiara, K. P., Newcomer, J., Weng, J., Neerchal, W., Gesheff, N. K.,
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