Abstract
The prevalence of both hypertension and diabetes mellitus is increasing worldwide. Both diseases lead to severe complications such as cardiovascular and chronic kidney diseases, which increase the risk of death over a long period of time. Therefore, the prevention and aggravation of hypertension and diabetes mellitus are major challenges. Because few review articles have focused on the epidemiological perspective of hypertension and diabetes mellitus, we reviewed major observational studies mainly from Japan and from Western countries that have reported on the prevalence of hypertension and diabetes mellitus, the binominal risk of hypertension and diabetes mellitus, and the risk of their coexistence. Our investigation found that approximately 50% of diabetic patients had hypertension, and approximately 20% of hypertensive patients had diabetes mellitus. Those with either hypertension or diabetes mellitus had a 1.5- to 2.0-fold higher risk of having both conditions. These results were similar for both Japan and Western countries. Although comparing the results between Japan and Western countries was difficult because the risks were estimated using widely varying statistical analyses, it was revealed that the coexistence of hypertension and diabetes mellitus certainly increased the risk of complications regardless of the country. The definition, prevalence and medical treatment of hypertension and diabetes mellitus will change in the future. For early intervention based on the latest evidence to prevent severe complications, it is important to accumulate epidemiological knowledge of hypertension and diabetes mellitus and to update the evidence for both Japan and other countries.
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Introduction
Hypertension and diabetes mellitus are characterized by different pathophysiologies, but they have much in common. Both are categorized as non-communicable diseases caused by similar unhealthy lifestyles, such as heavy alcohol consumption,1, 2 physical inactivity3, 4 and obesity5, 6 in addition to genetic factors. Insulin resistance is also well known as an intermediate factor between unhealthy lifestyles and incidences of both hypertension and diabetes mellitus.7 Therefore, strategies for prevention and target populations overlap. In addition, complications are similar because both diseases influence whole-body circulation. Furthermore, both hypertension and diabetes mellitus are globally prevalent and increase the risk of complications, which lead to severe diseases such as cardiovascular diseases (CVDs) and chronic kidney disease (CKD) that lead to the risk of death over a long period.8, 9, 10
The prevalence of both hypertension and diabetes mellitus is increasing worldwide, and from 1975 to 2015, diabetes increased by 4.5%.11 Although the age-standardized percentage of hypertension decreased from 1975 to 2015, the number of hypertensive individuals increased from 594 million in 1975 to 1.13 billion in 2015 because of population growth and increasingly aging population.12 The Non-communicable Disease Risk Factor Collaboration has estimated the age-standardized prevalence of hypertension (systolic blood pressure ⩾140 mm Hg or diastolic blood pressure ⩾90 mm Hg) in 2015 by region, sex and age groups in 5-year increments among adults aged 18 years or older.12 The report stated that the prevalence of hypertension in men and women aged 50–54 years was, respectively, 32.8% and 29.7% worldwide, 26.3% and 14.0% in high-income Asia-Pacific countries including Japan, 37.1% and 39.5% in South Asia, 27.1% and 17.7% in high-income Western countries, and 46.2% and 35.0% in Central and Eastern Europe.12 The prevalence of diabetes mellitus in 2015 by region has been reported by the International Diabetes Federation; the diabetes global prevalence was 8.8% among adults aged 20–79 years, and the age-adjusted comparative diabetes prevalence by region was 8.8% in Western Pacific countries including Japan, 7.3% in Europe and 11.5% in North America and the Caribbean.13
Consequently, the prevention of the incidence and aggravation of hypertension and diabetes mellitus are major challenges. Although there are review articles discussing hypertension and diabetes mellitus, few studies have focused on the epidemiological perspective of the two diseases.14, 15, 16 Furthermore, no study has focused on ethnic differences. In Asia, stroke incidence is more frequent than the incidence of coronary heart disease (CHD). Because hypertension has a stronger impact on stroke than CHD, the linear relationship between blood pressure and risk of CVD is steeper in Asia than in Western countries.17 Therefore, this study discusses the epidemiological perspective of the coexistence of hypertension and diabetes mellitus by reviewing observational studies of Asia (mainly Japan) and comparing the findings to major studies of Western countries.
Prevalence of coexistence
We selected major studies from the literature and reviewed the prevalence of the coexistence of hypertension and diabetes mellitus reported in Japanese and Western cohort studies with large sample sizes. Table 1 shows the percentages of hypertension, diabetes mellitus and their coexistence.18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 The table also includes our newly calculated percentages using the number of participants and the percentages shown in the studies. For example, in the report showing the prevalence of hypertension according to diabetes categories, the percentage of diabetes mellitus in hypertensive patients was calculated as follows: (number of hypertensive patients in the diabetes category)/(the sum of hypertensive patients in each category) × 100 (Figure 1). We rounded the calculated number of participants to whole numbers. However, we did not calculate the percentages of hypertension or diabetes mellitus in studies involving only participants with hypertension or diabetes mellitus.25, 26, 27, 31, 33 The ages of participants shown in Table 1 are presented as ranges or averages according to the description in the original studies. The terms for blood glucose and hypertension, such as fasting glucose level or fasting blood glucose and white coat hypertension or isolated office hypertension, are also presented according to the term used in the original studies.
Method for calculating percentages of diabetes mellitus in hypertensive patients.
Hypertension in diabetes mellitus
Among seven Japanese studies reporting the prevalence of hypertension,18, 19, 20, 21, 22, 23, 24 four reported approximately 50% of diabetic patients had hypertension.18, 19, 20, 21 The Hisayama study reported lower percentages than the others, which was due to using higher levels of blood pressure (⩾160/95 mm Hg) to define hypertension than in the other studies.22 Meanwhile, the National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 80 (NIPPON DATA80) and the Tanno-Sobetsu study that collected data ~1980 reported a higher prevalence of hypertension.23, 24 Because the mean systolic blood pressure decreased during the past few decades in Japan,36 it may be that these two studies would report higher prevalence of hypertension than the later studies.
In other studies mainly conducted in Western countries, the Strong Heart Study and Honolulu Heart Study reported close to 50% prevalence of hypertension.28, 29 The population of the Honolulu Heart Study was of Japanese ancestry, which may be the reason for the similar prevalence to the Japanese study.29 The Framingham study reported a slightly higher prevalence because hypertension was defined as a lower level of blood pressure (⩾130/80 mm Hg) for diabetic patients.30 Other studies reported higher than 50% prevalence of hypertension in diabetic patients.31, 32, 33, 34, 35 Possible explanations for the difference may be the additional ambulatory measurement of blood pressure for defining hypertension or a high prevalence of hypertension in the study population.
In addition, it is hypothesized that the duration of hypertension or diabetes mellitus is associated with the prevalence of coexistence. Because changes caused by hypertension and diabetes mellitus, such as microvascular damage, sympathetic damage, an enhanced renin–angiotensin system and decreased insulin sensitivity, all aggravate hypertension and diabetes mellitus,37, 38, 39 the longer the duration increases the risk of coexistence. As discussed later, high risks of the future coexistence of hypertension and diabetes mellitus in hypertensive or diabetic patients may indicate that patients with long duration of one or the other condition are more likely to acquire the other disease.
Diabetes mellitus in hypertension
Among nine Japanese studies,18, 19, 20, 21, 23, 24, 25, 26, 27 the Japan Public Health Center-based Prospective Study, NIPPON DATA80 and the Suita study used a single blood test for the definition of diabetes mellitus and reported a prevalence of approximately 10% with diabetes mellitus in hypertensive patients.19, 21, 23 The Funagata,18 Ohasama20 and Toyama et al.25 studies of hypertensive patients used a 75 g oral glucose tolerance test to define diabetes (which was only partially used in the Ohasama study) and reported approximately 20% with diabetes mellitus. Although the Tanno-Sobetsu study also used an oral glucose tolerance test, the prevalence of hypertension was lower than in the other three studies possibly because the amount of glucose used in the tolerance test was 50 g.24 The prevalence of diabetes mellitus reported in treated hypertensives studies, that is, the Home blood pressure measurement with Olmesartan-Naive patients to Establish Standard Target blood pressure (HONEST) study and the Japan Home vs. Office blood pressure Measurement Evaluation (J-HOME) study, did not differ from the previously mentioned studies, even though the definitions of diabetes mellitus were based on information from physicians.26, 27
In other studies, mainly conducted in Western countries, the Swiss Hypertension and Risk Factor Program, the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO) and the study by Banegas et al.33 reported a similar prevalence of diabetes compared with Japanese studies with a similar definition of diabetes mellitus.31,32 The study by Hu et al.34 and the Honolulu study29 using self-reporting for the definition of diabetes mellitus reported relatively low percentages. In the two studies, undiagnosed diabetes mellitus might have been overlooked. Despite the definition of diabetes mellitus by a single blood test or by self-reported medication, the Framingham study reported a high prevalence of diabetes mellitus in hypertensive patients.30 In addition to a relatively high prevalence of hypertension in the Framingham study population, there was a considerable difference in the mean age between those with diabetes mellitus (61.8 years) and those without diabetes mellitus (45.9 years) among hypertensive patients.30 Because the prevalence of diabetes mellitus increases with age, this finding might be a reason for the high prevalence of diabetes mellitus in hypertensive patients. The Strong Heart Study, whose participants were American Indians living in Arizona, reported a remarkably high percentage (53.7%).28 Pima Indians who reside on the eastern position of the Gila River Indian Reservation in Central Arizona are well known for having an enormously high prevalence of diabetes mellitus; the prevalence was approximately 50% among those aged 35 years and older.40, 41 This population has a 19-fold higher incidence of diabetes compared with the white population of Rochester, Minnesota.42 Therefore, the high percentage reported by the Strong Heart Study might have been a reflection of the characteristics of the region. The Jackson Heart Study involving blacks and including glycated hemoglobin (HbA1c) levels as well as fasting glucose levels for the definition of diabetes mellitus also reported a relatively high percentage of diabetes mellitus in hypertensive patients.35 Because individuals with high fasting glucose levels and high HbA1c are not often overlapped,43 the number of diabetes mellitus increased when using the two indices. In addition, blacks had a higher prevalence of diabetes compared with whites in the United States, which may be a reason for the high prevalence of diabetes in the Jackson Heart Study.44
Bidirectional risk
Many studies have investigated the risk of hypertension for diabetes incidence45, 46, 47, 48, 49, 50, 51, 52, 53, 54 (Table 2). In Asian studies, Japanese and Korean studies have reported a significantly (1.3–1.8 times) higher risk of hypertension for diabetes incidence compared with normotensive individuals, whereas the Chinese study did not report a high risk.45, 46, 47 Possible explanations for the inconsistency are the inclusion of many more variables and the inclusion of younger individuals in the Chinese study47 compared with the Japanese45 and Korean46 studies. In addition, the participants at risk in the Chinese study did not include individuals with prediabetes, who are at high risk of developing diabetes.
In other studies mainly conducted in Western countries,48, 49, 50, 51, 52, 53, 54 many have reported 1.4–2.2 times higher risk of hypertension for diabetes incidence. Although the risk of hypertension might be slightly higher in Western countries than in Asian countries, it is difficult to confirm the ethnic difference because there are other differences such as the methods of hypertension categorization or adjustment variables. The Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) is the only study to have reported close to a 2.0 times higher risk of masked hypertension for diabetes incidence compared with those without white coat hypertension and masked hypertension.49 If a high risk of masked hypertension for diabetes incidence is considered, the risk of hypertension reported by other studies that used office blood pressure alone might be underestimated because other studies included masked hypertension in the reference group.
Although there have been many studies investigating the risk of hypertension for diabetes incidence, there have been few studies investigating the risk of diabetes mellitus for the incidence of hypertension. The Tehran Lipid and Glucose Study is the only one to have reported the risk of diabetes in relation to the incidence of hypertension (n=7329, median follow-up of 10.1 years); the multivariable adjusted hazard ratios (HRs) and 95% confidence interval (CI) for incidence of hypertension were 1.25 (1.02–1.54) in prediabetics and 1.92 (1.47–2.51) in diabetics compared individuals with normal glucose tolerance.52 In addition, Janghorbani et al.55 reported that those with prediabetes had a high risk for the incidence of hypertension; multivariable adjusted HRs and 95% CI for the incidence of hypertension were 1.54 (1.33–1.77) in those with impaired glucose tolerance (fasting glucose level <126 mg dl−1, 2 h glucose level after a 75 g oral glucose tolerance test 140–199 mg dl−1) and 1.23 (1.01–1.50) in those with impaired fasting glucose (fasting glucose level 100–126 mg dl−1, 2- h glucose level after 75- g oral glucose tolerance test <140 mg dl−1) compared with normal glucose tolerance (fasting glucose level <100 mg dl−1, 2- h glucose level after 75- g oral glucose tolerance test <140 mg dl−1). There was no difference in the risk for prediabetes between the two studies. Further studies are needed to confirm the risk of diabetes for hypertension incidence.
Risk for macrovascular and microvascular diseases
It is well known that both hypertension and diabetes mellitus increase the risks for macrovascular disease such as CVD, stroke and CHD, and microvascular diseases such as kidney disease and retinopathy. The coexistence of hypertension and diabetes mellitus is naturally supposed to increase risk. The UK Prospective Diabetes Study involving diabetic patients estimated the risk of an increase in systolic blood pressure for incidence of any diabetic complications, including both macrovascular (stroke, myocardial infarction, sudden death, heart failure or angina) and microvascular diseases (renal failure, lower extremity amputation or death from peripheral vascular disease, death from hyperglycemia or hypoglycemia, vitreous hemorrhage, retinal photocoagulation and cataract extraction): the HR was 1.12 (P<0.001) per 10 mm Hg increments of systolic blood pressure.56 The UK Prospective Diabetes Study also reported that patients with an HbA1c ⩾8% and a systolic blood pressure ⩾150 mm Hg had a 16.3 times higher risk of microvascular disease, including retinal photocoagulation, vitreous hemorrhage and fatal or non-fatal renal failure, compared with patients with HbA1c <6% and systolic blood pressure <130 mm Hg.57 Other studies have shown the risk of the coexistence of hypertension and diabetes mellitus with respect to each complication.21, 26, 30, 34, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 To estimate the risk of the coexistence of hypertension and diabetes mellitus, some studies analyzed the combination categories of hypertension and diabetes mellitus, and other studies analyzed via stratifications. Tables 3, Tables 4, 5 show the risks of hypertension and diabetes mellitus for macrovascular disease reported by the cohort studies. Incidence rates are shown for the studies that did not estimate the risk. Because the number of studies investigating the risk for microvascular disease was smaller than that for macrovascular disease, the results for microvascular disease are not shown.
Risk of the coexistence for CVD
Table 3 shows the risk for the coexistence of hypertension and diabetes mellitus for CVD. As reported by the Suita study, which is a population-based cohort study, the risk of the coexistence of hypertension and diabetes mellitus for CVD incidence was approximately 5 times higher than for the population without hypertension and diabetes mellitus.21 The HONEST study, involving hypertensive patients, estimated an approximately 2.8 times higher risk for CVD incidence among those with uncontrolled hypertension and diabetes compared with those with controlled hypertension and without diabetes mellitus.26 In the study reported by Iso et al.,58 although it may be an overestimation because confounding factors were not adjusted, the crude incidence rate of the coexistence for ischemic stroke was approximately 6.5 times higher than for those without hypertension and diabetes mellitus (1.2 vs. 7.9).
In other studies, mainly conducted in Western countries, the multivariable adjusted risk of the coexistence of hypertension and diabetes mellitus for ischemic stroke was reported as 3.0–4.5 times higher compared with those without hypertension and diabetes mellitus by the Greater Cincinnati/Northern Kentucky Stroke Study59 and the study by Hu et al.60 The risk for CHD was reported by Hu et al.34 as approximately 2–3 times higher in men and 6–7 times higher in women compared with those without hypertension and diabetes mellitus. According to the Atherosclerosis Risk in Communities study, age- and race-adjusted CHD incidence rates of those with hypertension and diabetes mellitus were approximately 3 times higher in men (9.9 vs. 28.4) and 7 times higher in women (2.7 vs. 18.7) compared with those without hypertension and diabetes mellitus.61 Although the statistical methods for risk estimation were different in these two studies, the degrees of risk seemed to be similar.
Risk of hypertension for CVD in diabetic patients
Table 4 shows the risk of hypertension for CVD in patients with diabetes mellitus. According to the Japan Diabetes Complications Study (JDCS) involving Japanese diabetic patients, the risk for stroke incidence increased 1.18 times higher per 10 mm Hg increments of systolic blood pressure.62 Although the JDCS also estimated the risk for CHD per 10 mm Hg increments of systolic blood pressure in diabetic patients, the risk was not significantly increased, probably because of the small number of events.62 The Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study involving Japanese hypertensive patients with impaired glucose metabolism showed that the risk for CVD incidence and death increased 1.68 times per 1 s.d. increment of the home systolic blood pressure.63 The Asia-Pacific Cohort Studies Collaboration involving Asians, Australians and Maorilanders showed that risk for ischemic and hemorrhagic stroke incidence increased 1.29 and 1.56 times higher, respectively, per 10 mm Hg increments of systolic blood pressure in those with diabetes mellitus.64 In addition, the risk for CHD in Asians increased 1.27 times higher per 10 mm Hg increments of systolic blood pressure.64 Because the risk estimated by Asia-Pacific Cohort Studies Collaboration was adjusted only by age, sex and cohort, this value may be an overestimation.
In other studies, mainly conducted in Western countries, the risk of hypertension or an increase in blood pressure for CVD incidence or death among diabetic patients was assessed.30, 65, 66, 67 From the Framingham study and the study by Henry et al.,66 it was reported that hypertension was associated with approximately 2- or 3-fold increased risk for CVD.30 From the NDR-BP II and IDACO studies, it was shown that an increase in both systolic and diastolic blood pressure was associated with a high risk for CVD.65, 66 For stroke incidence, the NDR-BP II and Framingham studies showed that the risk increased approximately 1.5–2.5 times higher in diabetic patients with hypertension compared with diabetic patients without hypertension.30, 65 With regard to CHD, the Framingham study reported that the risk for incidence of myocardial infarction and heart failure increased 1.89 and 1.76 times higher in diabetic patients with hypertension compared with diabetic patients without hypertension.30 The NDR-BP II and IDACO studies showed that an increase in blood pressure, especially diastolic blood pressure, was associated with increased risk for CHD.65, 66 In contrast to the Japanese studies, the high risk of hypertension for heart diseases was observed among diabetic patients in Western studies.30, 65, 66
Risk of diabetes for CVD in hypertensive patients
Table 5 shows the risk of diabetes mellitus for CVD in those with hypertension. In Japan, although it may be an overestimation because confounding factors were not adjusted, HOMED-BP reported an approximately 2-fold increased risk for CVD in patients with impaired glucose metabolism compared with normal glucose metabolism (incidence rates per 1000 person-years: 4.88 vs. 9.95).63 Iso et al.58 showed that the risk of stroke among those with hypertension and diabetes mellitus was 1.2 times higher, although without significance, than those with only hypertension. The multivariable adjusted risk of diabetes mellitus for CVD incidence or death among hypertensive patients was assessed by the Alderman et al.68 study and the Multiple Risk Factor Intervention Trial (MRFIT).69 These two studies reported that diabetes mellitus was associated with approximately 2–3-fold increased risk for CVD. In Japan and other countries, the number of studies investigating the risk of diabetes compared with non-diabetes mellitus for CVD in hypertensive patients was smaller than that of studies investigating the risk of hypertension for CVD in diabetic patients.
Risk of hypertension and diabetes mellitus for kidney disease
In Japan, the JDCS reported that the risk for progression to proteinuria was 2.55 (95% CI: 0.98–6.33) times higher in diabetic patients with systolic blood pressure ⩾140 mm Hg compared with diabetic patients with systolic blood pressure <120 mm Hg.70 In addition, the Japanese hospital-based prospective study (median follow-up of 11.9 years) by Takao et al.,71 involving 516 diabetic patients, reported that the risk for development of microalbuminuria was 1.39 (95% CI: 1.15–1.67) times higher per time-dependent 10 mm Hg increments of systolic blood pressure. In other countries, the Associazione Medici Diabetologi (AMD)-Annuals Study72 involving diabetic patients in Italy (n=12 995, follow-up of 4 years) reported that patients with hypertension had 1.38 (95% CI: 1.24–1.54) times higher risk for diabetic kidney disease compared with normotensive patients. The Tehran Lipid and Glucose Study in Iran (n=8059, median follow-up of 11.0 years) reported that participants with hypertension and diabetes mellitus had 1.45 (95% CI: 1.22–1.73) times higher risk for CKD compared with those without hypertension and diabetes mellitus.52
Risk of hypertension and diabetes mellitus for retinopathy
In Japan, Takao et al.71 reported that the risk for mild–moderate non-proliferative diabetic retinopathy was 1.18 (95% CI: 1.01–1.37) times higher per time-dependent 10 mm Hg increments of systolic blood pressure. The JDCS, which followed 1630 diabetic patients for 8 years, reported that the systolic blood pressure per 10 mm Hg increments was associated with a 1.09 (95% CI: 1.02–1.17) times higher risk for retinopathy.73 As a result of the German/Austrian Diabetes Prospective Documentation Initiative database, hypertension (blood pressure ⩾140/80 mm Hg) had 1.15 (95% CI: 1.11–1.20) times higher risk for retinopathy.74 In addition, the cohort study of the Genetics of Diabetes Audit and Research in Tayside Scotland reported that the risk for mild background diabetic retinopathy increased 1.20 (95% CI: 1.11–1.30) times for 1 s.d. increments of systolic blood pressure among diabetic patients.75 The meta-analysis investigating the prevalence of diabetic retinopathy, diagnosed by retinal photographs among diabetic patients from 35 population-based studies, reported that the percentages of diabetic retinopathy were 31% among those with normal blood pressure and 40% among those with hypertension (>140/90 mm Hg or treatment for hypertension).76 Consequently, although the statistical methods were different, the high blood pressure was likely to be associated with 1.1–1.3 times higher risk for retinopathy among diabetic patients. However, no study has investigated the risk of diabetes mellitus for retinopathy among hypertensive patients.
Conclusions
We summarized major observational studies conducted in Japan and other countries (mainly Western countries) reporting the prevalence of hypertension and diabetes mellitus, binominal risk of hypertension and diabetes mellitus, and risk of coexistence for complications.
Among individuals with diabetes mellitus, approximately 50% had hypertension defined as a blood pressure ⩾140/90 mm Hg or the use of antihypertensive medication. Among those with hypertension, approximately 20% had diabetes mellitus, including postprandial hyperglycemia. These prevalence was similar between Japan and Western countries. Bidirectional risk of hypertension and diabetes mellitus were also similar between Japan and other countries. Individuals with either hypertension or diabetes mellitus had 1.5–2.0 times higher risk of having both conditions.
Many studies have investigated the risk of hypertension and diabetes mellitus for macrovascular and microvascular diseases. Although it was difficult to compare the results of Japan with other countries because the risks were estimated using widely varying statistical analyses, it was demonstrated that the coexistence of hypertension and diabetes mellitus clearly increased the risk for complications regardless of the country. In Japan, few studies have investigated the risk of CHD, which might be due to a small number of CHD patients for analysis using a high-power statistical test in each Japanese cohort study. Because CHD is a major disease related to cause of death in Japan, further investigations with larger sample sizes are needed.
The definition, prevalence and medical treatment of hypertension and diabetes mellitus will change in the future. For early intervention based on the latest evidence to prevent severe complications, it is important to accumulate epidemiological knowledge of hypertension and diabetes mellitus and update the evidence for both Japan and other countries.
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This study was supported by a grant-in-aid for Young Scientists from the Japan Society for the Promotion of Science (15H06913).
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Tatsumi, Y., Ohkubo, T. Hypertension with diabetes mellitus: significance from an epidemiological perspective for Japanese. Hypertens Res 40, 795–806 (2017). https://doi.org/10.1038/hr.2017.67
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DOI: https://doi.org/10.1038/hr.2017.67
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