Veterans and Agent Orange Update 2010 (2012) / Chapter Skim
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10 Cardiovascular and Metabolic Effects
10 Cardiovascular and Metabolic Effects
Pages 646-707
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From page 646... ...
The change reflects the growth of evidence pertaining to metabolic syndrome and its potential role in the development of cardiovascular disease. Some controversy remains as to whether increases in waist circumference, triglycerides, blood pressure, and fasting glucose and a decrease in high-density lipoprotein cholesterol constitute a "syndrome." But there is little dispute that these physical effects, which are often related to obesity and regarded as indicators of the "metabolic syndrome," are commonly present as comorbidities with adverse conditions of which there is increasing evidence of an association with Agent Orange exposure, and this suggests a possible interrelationship.
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From page 647... ...
The onset of type 2 diabetes can be preceded by a set of clinical findings that are collectively called metabolic syndrome. A number of definitions of the syndrome have been proposed, but it typically includes a combination of high waist circumference, low high-density lipoprotein cholesterol, high triglycerides, high blood pressure, and high fasting glucose.
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From page 648... ...
deaths, all ages) ICD-9 Range Diseases of Circulatory System Men Women Men Women 250 Diabetes nr nr 36,000 36,400 7.9a 7.9a Physician-diagnosed nr nr 3.8a 1.9a Undiagnosed nr nr 35.9a 22.2a Prediabetes nr nr Lipid disorders Total cholesterol ≥ 200 mg/dL 45.2 47.9 nr nr Total cholesterol ≥ 240 mg/dL 15.0 17.2 nr nr LDL cholesterol ≥ 130 mg/dL 33.1 32.0 nr nr HDL cholesterol < 40 mg/dL 25.0 7.9 nr nr 390–459 All circulatory disorders 37.9 35.7 398,600 432,700 390–398 Rheumatic fever and rheumatic nr nr 1,022 2,226 heart disease 401–404b Hypertensive disease 24,400 32,200 401 Essential hypertension nr nr nr nr 402 Hypertensive heart disease nr nr nr nr 403 Hypertensive renal disease nr nr nr nr 404 Hypertensive heart and renal nr nr nr nr disease 410–414, Ischemic, coronary heart disease 9.1 7.0 224,500 200,900 429.2 410, 412 Acute, old myocardial 4.7 2.6 76,100 65,400 infarction 411 Other acute, subacute forms nr nr nr nr of ischemic heart disease 413 Angina pectoris 4.6 4.6 nr nr 414 Other forms of chronic nr nr nr nr ischemic heart disease 429.2 Cardiovascular disease, nr nr nr nr unspecified 415–417b Diseases of pulmonary nr nr nr nr circulation 420-429 Other forms of heart disease nr nr nr nr (such as pericarditis, endocarditis, myocarditis, cardiomyopathy)
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From page 649... ...
deaths, all ages) ICD-9 Range Diseases of Circulatory System Men Women Men Women 430–438b Cerebrovascular disease (such as 2.5 3.2 54,500 82,600 hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in ICD-401)
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From page 650... ...
. In the original assessment, 641 Australian Vietnam veterans in a randomly selected sample of 1,000 from the list of Army veterans deemed eligible for previous studies of Agent Orange responded; 450 responded to the second interview and are the subjects of the recent report.
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From page 651... ...
92 ns et al., 2003 AFHS, AFHS -- 1997 exam cycle (Numerous analyses discussed in 2000b Ranch Hand veterans and comparisons the text of Type 2 Diabetes) Longnecker AFHS -- comparison veterans only, OR by and quartiles of serum dioxin concentration Quartile 1: < 2.8 ng/kg Michalek, 26 1.0 Quartile 2: 2.8– < 4.0 ng/kg 2000b 25 0.9 (0.5–1.7)
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From page 652... ...
Serum insulin abnormalities 18 3.4 (1.9–6.1) AFHS, AFHS -- 1987 examination cycle -- elevation in 1991b blood glucose with serum TCDD Significance of slope Ranch Hand veterans and comparisons 85 p = 0.001, p = 0.028 AFHS, 1984 AFHS -- 1982 examination cycle -- elevation in blood glucose with serum TCDD Ranch Hand veterans and comparisons 158 p = 0.234 US VA Cohort of Army Chemical Corps All COIs Cypel and US ACC personnel Kang, 2010 Deployed vs nondeployed 27 1.79 (0.71–4.39)
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From page 653... ...
et al., 1992 Preliminary NIOSH Cross-Sectional Medical Study Dioxin/phenoxy herbicides 1.1, p < 0.003 Sweeney Dioxin-exposed workers in two chemical plants et al., 1997/1998 NIOSH/Ranch Hand Comparison Steenland Ranch Hand veterans, workers exposed to et al., 2001 TCDD-contaminated products compared with nonexposed comparison cohorts Ranch Hands 147 1.2 (0.9–1.5) Workers 28 1.2 (0.7–2.3)
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From page 654... ...
1994 German Production Workers Dioxin/phenoxy herbicides Von Benner West German chemical production workers nr nr et al., 1994 United Kingdom Production Workers Dioxin/phenoxy herbicides May, 1982 TCP production workers 2 nr United States Production Workers Dioxin/phenoxy herbicides Calvert Workers exposed to 2,4,5-T, derivatives 26 1.5 (0.8–2.9) et al., 1999b Serum TCDD pg/g of lipid < 20 7 2.1 (0.8–5.8)
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From page 655... ...
et al., 1989 ENVIRONMENTAL Seveso, Italy Residential Cohort TCDD Consonni Seveso residents (men and women) -- 25-yr et al., 2008 mortality follow-up Zone A 3 1.0 (0.3–3.1)
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From page 656... ...
OCDD > 90th percentile vs nondetectable 31 2.1 (0.9–5.2) Other Environmental Studies dl PCBs Turyk et al., Great Lakes sport fish consumers -- cross– 2009 sectional study Sum of dioxin-like PCBs Adjusted prevalence OR < Limit of detection Reference 0.2–0.3 ng/g lipid 1.2 2.1 (p < 0.05)
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From page 657... ...
propionic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; AHS, Agricultural Health Study; BMI, body mass index; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzop-dioxin; HxCDD, 1,2,3,6,7,9-hexachlorodibenzo-p-dioxin; IARC, International Agency for Research on Cancer; IU, international unit; MI, Michigan; NHANES, National Health and Nutrition Examina tion Survey; NIOSH, National Institute for Occupation Safety and Health; nr, not reported; ns, not significant; NZ, New Zealand; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo- p-dioxin; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/Fs, chlorinated dioxins and furans combined; PCP, pentachlorophenol; SEA, Southeast Asia; TCDD, 2,3,7,8-tetra chlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TCP, trichlorophenol; TEF, toxicity equiva lency factor; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs; VES, Vietnam Experience Study; WV, West Virginia.
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From page 658... ...
. The report included additional workers, refined dose estimates based on serum dioxin evaluations, and additional followup.
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From page 659... ...
Given the likelihood that fisherman are high fish consumers and therefore may have high ingestion of persistent organic pollutants that may accumulate in fish, this group was expected to have a higher exposure to dioxin and dioxin-like compounds. In a small substudy of 161 cohort members, dioxin total toxic equivalents (TEQs; pg/g lipid)
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From page 660... ...
(2009) associated metabolic syndrome with a large number of persistent organic pollutants in a sample of 1,374 Japanese residents who had no history of occu pational exposure to polychlorinated dibenzodioxins (PCDDs)
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From page 661... ...
Using data from the third National Health and Nutrition Examination Survey, Schreinemachers (2010) related urinary 2,4-D concentrations to fasting insulin, glucose, and C-peptide concentrations, a measure of endogenous insulin produc tion.
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From page 662... ...
Although the study subjects were Vietnam veterans, several important weaknesses render the result unreliable. Disease ascertainment was by self-report, which may be inaccurate.
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From page 663... ...
However, the study was cross-sectional so, in addition to potential selection bias, it cannot be certain whether the PCBs concentrations were increased because they cause diabetes or whether some feature of the diabetic phenotype predisposes to the accumulation of dioxin-like PCBs. The study of Great Lakes sport fishermen (Turyk et al., 2009)
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From page 664... ...
. Coronary heart disease is related specifically to atherosclerosis; ischemic heart disease is broader and typically includes atherosclerosis and its symptoms.
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From page 665... ...
The committee responsible for Update 2006 reviewed new studies and intensively revisited all the studies related to ischemic heart disease and hypertension that had been discussed in previous updates and concluded that there is limited or suggestive evidence to support an association between exposure to the herbicides used in Vietnam and hypertension. That committee was unable to reach a consensus as to whether that was also the case for ischemic heart disease, so that outcome remained in the category of inadequate evidence.
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From page 666... ...
Update of the Epidemiologic Literature The practice of evaluating the evidence on hypertension separately from that of other circulatory diseases, established in Update 2008, is continued in the present update. Hypertension Vietnam-Veteran Studies Hypertension was considered in two new publications on cohorts of Vietnam veterans.
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From page 667... ...
411 Stroke or transient ischemic attack 17 1.26 (0.78–2.03) Model 3: All subjects with serum TCDD readings (RH group vs comparisons)
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From page 668... ...
755 Stroke or transient ischemic attack 1.04 (0.76–1.44) Ketchum and AFHS -- circulatory disease -- mortality Michalek, 2005 Ranch Hand subjects vs all SEA veterans 66 1.3 (1.0–1.6)
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From page 669... ...
9 1.5 (0.7–3.3) US VA Cohort of Army Chemical Corps All COIs Cypel and Kang, Vietnam veterans vs non-Vietnam veterans -- mortality Deaths and causes 2010 Circulatory system disease 184 1.21 (0.93–1.58)
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From page 670... ...
Discharged after 1970 125 1.43 (1.02–1.99) Ischemic heart diseases 0–15 yrs since discharge 8 0.77 (0.31–1.55)
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From page 671... ...
US VA Cohort of Female Vietnam Veterans All COIs Cypel and Kang, Female US Vietnam-era veterans -- mortality (through 2004) Adjusted for 2008 Circulatory system diseases duration of service, year Vietnam vs non-SEA veterans 129 0.8 (0.6–1.0)
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From page 672... ...
Other circulatory diseases nr 2.39 (1.61–3.17) Roster of Australian Vietnam Veterans vs Australian Population All COIs ADVA, 2005b Mortality Circulatory disease 1,767 0.88 (0.84–0.92)
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From page 673... ...
Not adjusted for known Ischemic heart disease 1.04 (0.94–1.14) risk factors Cerebral hemorrhage 0.80 (0.53–1.22)
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From page 674... ...
588 0.86 (0.79–0.93) Ischemic heart disease (ICD 410–414)
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From page 675... ...
456 1.09 (1.00–1.20) risk factors Ischemic heart disease (ICD 410–414)
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From page 676... ...
Dioxin, phenoxy herbicides Suskind and Workers exposed to 2,4,5-T production (204) vs nonexposed Hertzberg, 1984 (163)
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From page 677... ...
No adjustment discussed 2009a Ischemic heart disease 218 1.1 (0.9–1.2) Cerebrovascular disease 37 1.0 (0.7–1.4)
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From page 678... ...
of exposure TCDD > 124 ng/kg Ischemic heart diseases (ICD 410–414)
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From page 679... ...
Janys, 1997/1998; Flesch-Janys et al., 1998 p-trend < 0.01 Ischemic heart disease (ICD 410–414)
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From page 680... ...
New Zealand Production Workers -- Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, phenoxy, herbicides McBride et al., New Zealand phenoxy herbicide workers -- ischemic heart disease 2009a mortality Ever-exposed workers -- stroke 15 1.1 (0.6–1.9)
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From page 681... ...
(0.8–1.2) Ischemic heart disease 38 1.0 (0.7–1.4)
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From page 682... ...
Other ischemic heart diseases 72 0.41 (0.32–0.52) Stroke 155 0.96 (0.81–1.12)
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From page 683... ...
6 0.6 (0.3–1.4) Chronic ischemic heart diseases (ICD 412, 414)
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From page 684... ...
447 1.0 (0.9–1.1) Chronic ischemic heart diseases (ICD 412, 414)
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From page 685... ...
1.3 (0.9–1.9) > 46.4 Ha et al., 2007 NHANES, 1999–2002 -- self-reported cardiovascular disease Adjusted for age, ≥ 75th percentile vs < 25th percentile race, income, BMI, (excluding hypertension)
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From page 686... ...
1.3 (0.9–1.9) > 46.4 Lee et al., 2007c NHANES, 1999–2002 -- 721 nondiabetics ≥ 20 yrs old with fasting blood samples and measured POPs high blood pressure (≥ ≥ 75th percentile vs those 130/85 mmHg)
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From page 687... ...
2008 Ischemic heart disease Standardized mortality Men 269 0.73 (0.65–0.81) analysis -- age adjusted Women 62 0.65 (0.50–0.83)
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From page 688... ...
0.9 (0.2–3.7) smoking, BMI ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; BMI, body mass index; CDC, Centers for Disease Control and Prevention; CHD, coronary heart disease; COI, chemical of interest; HDL, high-density lipoprotein; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HpCDF, 1,2,3,4,6,7,8-heptachlorodibenzofuran; HxCDD, 1,2,3,6,7,8-hexachlorodibenzo- pdixion; HxCDF, 1,2,3,4,7,8-hexachlorodibenzofuran; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; MI, Michigan; NZ, New Zealand; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo- p-dioxin; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/F, dioxins and furans combined; PCDF, polychlorinated dibenzofuran; PCP, PeCDF, 2,3,4,7,8-pentachlorodibenzofuran; pentachlorophenol; PMR, proportional mortality ratio; POP, persistent organic pollutant; RH, Ranch Hand; SEA, Southeast Asia; SMR, standard ized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dixoin; TCP, trichlorophenol; TEF, toxicity equivalency factor for individual congener; TEQ, (total)
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From page 689... ...
Deaths from coronary or ischemic heart disease, heart failure, and to a lesser extent stroke will predominate. Many of the reports also break out subcategories (such as cerebrovascular disease and hypertension)
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From page 690... ...
. Workers exposed in the 1963 accident were at an even higher risk of ischemic heart disease death (RR = 1.60, 95% CI 0.72–3.55)
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From page 691... ...
Workers in the two middle categories of dose had statistically nonsignificant increases in ischemic heart disease mortality (RR = 1.24, 95% CI 0.58–2.64 and RR = 1.32, 95% CI 0.60–2.90) compared with the low exposure category.
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From page 692... ...
(2008) found that Finnish fishermen and their spouses had lower 12-year mortality from ischemic heart disease than expected (SMR = 0.73, 95% CI 0.65–0.81 and SMR = 0.65, 95% CI 0.50–0.83, respectively)
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From page 693... ...
Because circulatory diseases constitute a broad group of diverse conditions, hypertension and ischemic heart disease are discussed separately from other circulatory diseases so that the new studies can be adequately synthesized and integrated with the earlier studies.
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From page 694... ...
The additional supporting evidence and the strong biologic rationale affirm the present committee's placement of hypertension in the limited and suggestive category. Ischemic Heart Disease Circulatory diseases comprise a group of diverse conditions, of which hypertension, coronary heart disease, and stroke are the most prevalent and account for
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From page 695... ...
The committee responsible for Update 2008 revisited the entire body of evidence on TCDD exposure and heart disease and concluded that the evidence supported moving ischemic heart disease to the limited and suggestive category. That conclusion was based on evidence of a dose–response relationship in the occupational cohorts, evidence of increased risk of MI in Vietnam veterans, sup porting cross-sectional survey data, and a strong biologic rationale.
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From page 696... ...
did not show a dose–response relationship between TCDD exposure and mortality from ischemic heart disease. Workers involved in the production of herbicides in the Netherlands (Boers et al., 2010)
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From page 697... ...
and ischemic heart disease (ICD-9 410–414) in the limited and suggestive category but that other forms of circulatory disease should remain in the inadequate or insufficient category.
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From page 698... ...
The committee for Update 2006 added the cardiovascular condition hypertension to the list of health outcomes in the category of limited or suggestive evidence. The committee for Update 2008 confirmed the finding of limited or suggestive evidence of an association between the exposures of interest and hy pertension and reached consensus that another cardiovascular outcome, ischemic heart disease, belonged in this category.
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From page 699... ...
1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins.
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From page 700... ...
1997b. Mortality of National Service Vietnam Veterans: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans.
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From page 701... ...
2001. Dioxin exposure is an environmental risk factor for ischemic heart disease.
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From page 702... ...
2009. Association between serum concentrations of persistent organic pollutants and prevalence of newly diagnosed hypertension: Results from the National Health and Nutrition Examination Survey 1999–2002.
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From page 703... ...
2006. Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam.
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From page 704... ...
1996. The Australian Vietnam Veterans Health Study: II.
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From page 705... ...
1991. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols.
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From page 706... ...
1990. Mortality and morbidity among Army Chemical Corps Vietnam veterans: A preliminary report.
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From page 707... ...
1980. The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident.
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