Abstract
Background
1,5-Anhydroglucitol (1,5-AG) is a novel biomarker of glycemic control proposed to monitor recent hyperglycemic excursions in persons with diabetes. The clinical utility of 1,5-AG outside of diagnosed diabetes is unclear, but it may identify people at high risk for diabetes and its complications. We compared associations of 1,5-AG with 2-h glucose for risk of major clinical complications.
Research Design and Methods
We prospectively followed 6644 Atherosclerosis Risk in Communities (ARIC) Study participants without diagnosed diabetes for incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality for ∼20 years. We assessed associations of 1,5-AG and 2-h glucose (modeled categorically and continuously with restricted cubic splines) with adverse outcomes using Cox models and evaluated improvement in risk discrimination using Harrell’s c-statistic.
Results
1,5-AG <10 µg/mL was statistically significantly associated with incident diabetes (HR: 2.70, 95% CI 2.31, 3.15), and showed suggestion of association with the other outcomes compared to 1,5-AG ≥10 µg/mL. Continuous associations of 1,5-AG with outcomes displayed a clear threshold effect, with risk associations generally observed only <10 µg/mL. Comparing associations of 1,5-AG and 2-h glucose with outcomes resulted in larger c-statistics for 2-h glucose than 1,5-AG for all outcomes (difference in c-statistic [2-h glucose -1,5-AG] for diagnosed diabetes: 0.17 [95%CI, 0.15, 0.19]; chronic kidney disease 0.02 [95%CI 0.00, 0.05]; cardiovascular disease 0.03 [95%CI, 0.00, 0.06]; and all-cause mortality 0.04 [95%CI, 0.02, 0.06]).
Conclusions
In this community-based population without diagnosed diabetes, low 1,5-AG was modestly associated with major clinical outcomes and did not outperform 2-h glucose.
Impact Statement
People at high risk for diabetes would benefit from the convenience of the 1,5-AG test if it proves to be an accurate diagnostic. This study characterizes associations of 1,5-AG and long-term outcomes to assess the utility of 1,5-AG for diabetes screening in a community-based population. This evidence advances our understanding of the clinical utility of 1,5-AG by demonstrating that it is unlikely to be a successful screening test in the general population and that its use may be limited to those with overt diabetes.
Introduction
Diabetes poses a substantial burden on patients, providers, and the health care system (1). Persons with diabetes are at increased risk for microvascular and macrovascular disease and at high risk of death (2). There is widespread screening for diabetes in the US, with the aim of identifying and intervening early in the disease process to prevent major complications. Routine measurement of biomarkers of hyperglycemia is used to screen and diagnose diabetes (3) and identify those at increased risk for its associated outcomes.
Glucose measured after the administration a 75-g oral glucose load (simulated carbohydrate-rich meal) is a well-established test used to diagnose diabetes. In the setting of insulin resistance and/or impaired insulin secretion, blood glucose concentrations will remain elevated (≥200 mg/dL) 2 h following the oral glucose load. 1,5-Anhydroglucitol (1,5-AG) is a less common measure of hyperglycemia that reflects glycemic excursions, although through a different mechanism. 1,5-AG is a monosaccharide that remains stable in blood at normal levels of glycemia. However, when circulating plasma glucose exceeds the renal threshold for glucose reabsorption (∼160-180 mg/dL), 1,5-AG and glucose compete for reabsorption in the renal proximal tubule, resulting in increased excretion of 1,5-AG in the urine and lower 1,5-AG concentrations in the blood. 1,5-AG is attractive as an alternative measure of hyperglycemia as it is a non-fasting test, does not involve administration of a carbohydrate challenge, and can be measured in a single blood sample. Some investigators have suggested the utility of 1,5-AG for diabetes screening (4–6).
Elevated 2-h glucose and low 1,5-AG concentrations are both associated with future outcomes including microvascular and macrovascular events, and all-cause mortality (7–11). However, prior studies have not compared associations of 2-h glucose to 1,5-AG in the same study population. We therefore evaluated and compared the associations of 1,5-AG and 2-h glucose with risk for future diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality in adults in the Atherosclerosis Risk in Communities (ARIC) Study, a US-based prospective cohort.
Methods
Study Population
The ARIC Study was initiated in 1987, enrolling 15 792 participants from four communities (Washington County, Maryland; Minneapolis, Minnesota; Jackson, Mississippi; and Forsyth County, North Carolina) in the first study visit (12). Since the baseline visit (Visit 1), there have been 6 subsequent completed or ongoing visits (Visit 2: 1990-92, Visit 3:1993-95, Visit 4:1996-98, Visit 5: 2011-13, Visit 6: 2016-17, and Visit 7: 2018-19). Investigators obtained study approvals from institutional review boards and written informed consent from all participants.
Our study population included the 11 656 participants who attended the fourth visit (1996-98) when both 1,5-AG and 2-h glucose were measured. We then excluded participants ineligible for the oral glucose tolerance test or missing glycemic markers (n = 3587), those with prevalent diagnosed diabetes, chronic kidney disease, or cardiovascular disease (n = 1299), those who were not black or white or who were black from the Washington Country or Minneapolis sites (n = 43), and those missing covariates of interest (n = 81; see Supplemental eFig. 1 for more details). We followed the resulting 6644 participants over ∼20 years for incident disease, including diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality.
Exposure Measurements
1,5-AG, 2-h glucose, and fasting glucose were all measured in plasma at the Baylor College of Medicine. 1,5-AG was measured using the GlycoMark assay in 2015-2016 from stored samples kept at -70 °F obtained from ARIC participants at the fourth study visit (inter-assay CV, 4.54%). Blood samples were collected in the fasting state and 2 h following administration of 75-g glucose load among those without diagnosed diabetes or currently taking medications for diabetes at the study visit. The oral glucose tolerance test protocol also excluded participants who had prior stomach or intestinal surgery, those on dialysis, those who were fasting for less than 10 h (13) (see Supplemental eFig. 1 for detail). Glucose was measured in plasma using the hexokinase method with the Roche Hitachi 911 autoanalyzer.
Assessment of Outcomes
We followed participants prospectively from baseline (Visit 4: 1996-98) for incident diabetes and major clinical outcomes (incident chronic kidney disease, cardiovascular disease, and all-cause mortality) for nearly 20 years (end of follow-up: December 31, 2013 for chronic kidney disease; December 31, 2015 for all other outcomes). We defined incident diabetes as self-report of physician diagnosis or glucose-lowering medication use during a study visit or annual or semi-annual telephone call (14); chronic kidney disease as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (from CKD-EPI equation (15) using creatinine) at Visit 5 (2011-13) and a decline from Visit 4 of at least 25%, a chronic kidney disease-related hospitalization or death (16), or end stage renal disease event identified by linkage to the United States Renal Data System; cardiovascular disease as an adjudicated hospitalization or death from coronary heart disease or ischemic stroke (12); and all-cause mortality as identified from surveillance of all ARIC participants.
Covariate Measurement
Participants reported demographic characteristics (age, sex, race, parental history of diabetes, and education level) at cohort initiation (Visit 1). Because race may be confounded by study center (12), we defined race-center as Washington County, Maryland-White; Minneapolis, Minneapolis-White; Forsyth County, North Carolina-White; Forsyth County, North Carolina-Black; Jackson, Mississippi-Black.
Other covariates were measured at baseline of the present study (Visit 4). Height, weight, waist-to-hip ratio, total cholesterol, HDL cholesterol, and triglycerides were measured using standard anthropometric and phlebotomy protocols (17, 18). Body mass index was calculated from weight and height (kg/m2). Mean systolic and diastolic blood pressure were calculated by averaging two measurements (19). We defined hypertension as self-report of hypertensive medications, mean systolic blood pressure ≥140 mmHg, or mean diastolic blood pressure ≥90 mmHg. Participants self-reported whether they were currently, formerly, or never smokers and/or drinkers (17). eGFRcr was calculated from creatinine using the CKD-EPI equation (15). We derived albumin-to-creatinine ratio from albumin and creatinine measurements in urine samples (20).
Statistical Analysis
We compared participants’ baseline characteristics by 1,5-AG categories (≥10 µg/mL, <10µg/mL) within 2-h glucose categories (<200 mg/dL, ≥200 mg/dL). We used Cox proportional hazards models to characterize associations with incident outcomes, using categories of each biomarker (1,5-AG ≥10 µg/mL, <10µg/mL; 2-h glucose <200 mg/dL, ≥200 mg/dL; and fasting glucose <126 mg/dL, ≥126 mg/dL) and using restricted cubic splines with four knots located at the 5th, 35th, 65th, and 95th percentiles to more flexibly model each of the biomarkers. We graphed the continuous associations of 1,5-AG, 2-h glucose, and fasting glucose with incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality. To assess whether 1,5-AG helped further risk stratify those in addition to 2-h glucose and/or fasting glucose, we used Harrell’s c-statistic to compare continuous spline models of 2-h glucose and fasting glucose to 1,5-AG.
We primarily present unadjusted results, given the importance in understanding the comparative overall (crude) associations, which would be most relevant for informing diabetes screening. We also conducted two supplementary analyses evaluating the associations after adjustment for potential confounding variables. In these analyses, Model 1 included age, sex, race-center, and Model 2 included all variables in Model 1 plus body mass index, systolic blood pressure, hypertension medication use (no, yes), total cholesterol, HDL, triglycerides, education (less than high school, high school/vocational school, college or higher), smoking status (current, former, never), drinking status (current, former, never), parental history of diabetes (no, yes), eGFRcr, and log transformed albumin-to-creatinine ratio). We also assessed whether the discrimination of 1,5-AG for diagnosed diabetes compared to 2-h glucose and fasting glucose improved when limiting follow-up time to 5 or 10 years. For all of our analyses, we used Stata 15.1 (StataCorp, College Station, TX).
Results
At baseline, participants were a mean of 63 years old, 60% female, and 17% black. Mean (SD) 2-h glucose, fasting glucose, and 1,5-AG were 136 (51.8) mg/dL, 101 (17.7) mg/dL, and 20.0 (6.2) µg/mL. Participants with 2-h glucose ≥200 mg/dL were more likely to be obese, had higher fasting glucose, lower HDL, higher triglycerides, were more likely to have hypertension, and were more likely to have a parental history of diabetes compared to those with 2-h glucose <200 mg/dL (Table 1). Among those with 2-h ≥200 mg/dL, participants with 1,5-AG <10 µg/mL were less likely to be female, more likely to be black, had higher 2-h and fasting glucose, lower HDL, and higher triglycerides, were less likely to have hypertension, and had higher albumin-to-creatinine ratio compared to those with 1,5-AG ≥10 µg/mL (Table 1).
Table 1.
Baseline risk factors by hyperglycemia and 1,5-AG concordance categories among those without prevalent diabetes, chronic kidney disease, or cardiovascular disease, n = 6644.
| 2-h glucose <200 mg/dL |
2-h glucose ≥200 mg/dL |
|||
|---|---|---|---|---|
| 1,5-AG ≥10 µg/mL | 1,5-AG <10 µg/mL | 1,5-AG ≥10 µg/mL | 1,5-AG <10 µg/mL | |
| N = 5747 | N = 223 | N = 544 | N = 130 | |
| Age (years) | 62.6 (5.5) | 63.3 (6.0) | 64.7 (5.6) | 63.4 (5.5) |
| Female, % | 59.0 | 65.9 | 66.9 | 52.3 |
| Black, % | 16.1 | 22.4 | 17.6 | 21.5 |
| Body mass index (kg/m2) | 28.2 (5.3) | 27.6 (5.2) | 30.3 (5.8) | 30.8 (5.7) |
| Obese, % | 30.3 | 28.7 | 47.8 | 50.8 |
| 1,5-AG (µg/mL) | 20.9 (5.5) | 7.5 (2.2) | 18.8 (5.4) | 6.0 (2.9) |
| 2-hour glucose (mg/dL) | 123.5 (33.3) | 125.3 (31.4) | 233.5 (32.3) | 302.6 (86.2) |
| Fasting glucose (mg/dL) | 98.4 (9.4) | 98.5 (10.1) | 118.2 (21.9) | 168.6 (62.4) |
| Total cholesterol (mg/dL) | 202.5 (35.6) | 199.0 (36.1) | 203.7 (38.6) | 206.5 (37.4) |
| HDL cholesterol (mg/dL) | 51.9 (16.6) | 55.1 (18.1) | 47.4 (15.4) | 43.1 (14.2) |
| Triglycerides (mg/dL) | 135.2 (75.5) | 123.1 (60.4) | 172.8 (97.3) | 200.8 (143.2) |
| Hypertension, % | 38.3 | 38.6 | 61.9 | 46.9 |
| Less than high school, % | 14.3 | 15.2 | 21.3 | 18.5 |
| Current smoker, % | 14.1 | 13.9 | 11.0 | 10.0 |
| Current drinker, % | 55.6 | 58.7 | 46.7 | 50.8 |
| Parent history of diabetes, % | 21.1 | 25.1 | 30.9 | 37.7 |
| eGFRcr (ml/min/1.732 m2) | 90.1 (78.9, 96.1) | 89.2 (78.5, 95.0) | 89.1 (78.1, 95.7) | 92.2 (85.2, 98.5) |
| ACR (Median, IQR; ug/mg) | 3.4 (1.8, 6.4) | 3.9 (1.9, 7.1) | 3.8 (1.7, 7.5) | 5.1 (2.0, 10.6) |
Data are means (SD) unless otherwise noted.
1,5-AG, 1,5-Anhydroglucitol; eGFRcr, estimated glomerular filtration rate (creatinine); ACR, albumin-to-creatinine ratio.
In total, there were 1750 cases of incident diagnosed diabetes (median follow-up of 15.8 years), 1334 chronic kidney disease events (median follow-up of 15.7 years), 808 cardiovascular disease events (median follow-up of 17.7 years), and 1788 deaths (median follow-up of 17.8 years). Categorical analyses suggested that compared to 1,5-AG ≥10 µg/mL, 1,5-AG <10 µg/mL was associated with increased risk of incident diabetes, and may be associated with future chronic kidney disease, cardiovascular disease, and all-cause mortality (Table 2). 2-h glucose ≥200 mg/dL and fasting glucose ≥126 mg/dL were statistically significantly associated with increased risk of all outcomes compared to their reference categories (Table 2). Adjustment for additional covariates did not alter the overall inferences of these results (Supplemental eTable 1).
Table 2.
Unadjusted hazard ratios and 95% CI of categories of 1,5-AG, 2-h glucose, and fasting glucose for risk of incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality, n = 6644.
| Biomarker categories | Diagnosed diabetes |
Chronic kidney disease |
|||
|---|---|---|---|---|---|
| n | Events | HR (95% CI) | Events | HR (95% CI) | |
| 1,5-AG ≥10 µg/mL | 6291 | 1575 | 1 (REF) | 1253 | 1 (REF) |
| 1,5-AG <10 µg/mL | 353 | 175 | 2.70 (2.31, 3.15) | 81 | 1.19 (0.95, 1.49) |
| 2-h glucose <200 mg/dL | 5970 | 1275 | 1 (REF) | 1163 | 1 (REF) |
| 2-h glucose ≥200 mg/dL | 674 | 475 | 6.68 (6.00, 7.43) | 171 | 1.46 (1.25, 1.72) |
| Fasting glucose <126 mg/dL | 6315 | 1458 | 1 (REF) | 1250 | 1 (REF) |
| Fasting glucose ≥126 mg/dL | 329 | 292 | 13.8 (12.1, 15.7) | 84 | 1.48 (1.19, 1.85) |
|
Cardiovascular disease |
All-cause mortality |
||||
| n | Events | HR (95% CI) | Events | HR (95% CI) | |
| 1,5-AG ≥10 µg/mL | 6291 | 756 | 1 (REF) | 1685 | 1 (REF) |
| 1,5-AG <10 µg/mL | 353 | 52 | 1.27 (0.96, 1.68) | 103 | 1.12 (0.92, 1.37) |
| 2-h glucose <200 mg/dL | 5970 | 690 | 1 (REF) | 1544 | 1 (REF) |
| 2-h glucose ≥200 mg/dL | 674 | 118 | 1.64 (1.35, 1.99) | 244 | 1.51 (1.32, 1.73) |
| Fasting glucose <126 mg/dL | 6315 | 745 | 1 (REF) | 1660 | 1 (REF) |
| Fasting glucose ≥126 mg/dL | 329 | 63 | 1.79 (1.39, 2.32) | 128 | 1.63 (1.36, 1.95) |
Bold indicates P < 0.05.
When modeled with restricted cubic splines, values of 1,5-AG below the tenth percentile (12.3 µg/mL) tended to be associated with incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality in the primary unadjusted analysis (Fig. 1, Panel A). The lowest levels of 1,5-AG were associated with the highest risk of future outcomes, although risk was not linear across the entire distribution. Higher values of 2-h glucose (200 mg/dL) and fasting glucose (116 mg/dL) were strongly associated with incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality (Fig. 1, Panels B and C). When comparing the models using Harrell’s c-statistic, 2-h glucose and fasting glucose provided more prognostic value for future adverse events than 1,5-AG (Table 3). These comparisons remained irrespective of adjustment for most covariates (Supplemental eTable 2). While shortening follow-up time (to 5 and 10 years) resulted in more prognostic value for 1,5-AG for diagnosed diabetes, the predictive power of 2-h glucose and fasting glucose also improved (Supplemental eTable 3). The differences between the markers were quite consistent over time.
Fig. 1.
Distributions and unadjusted associations of 1,5-AG, 2-h glucose, and fasting glucose with incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality modeled with restricted cubic splines, n = 6644.
Table 3.
C-statistics for discrimination of 1,5-AG, 2-h glucose, and fasting glucose for incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality from unadjusted Cox modelsa, n = 6644.
| Diagnosed diabetes | Chronic kidney disease | Cardiovascular disease | All-cause mortality | |
|---|---|---|---|---|
| C-statistic (95% CI) | ||||
| 1,5-AG | 0.56 (0.55, 0.58) | 0.52 (0.50, 0.53) | 0.52 (0.49, 0.53) | 0.51 (0.50, 0.53) |
| 2-h glucose | 0.73 (0.72, 0.75) | 0.54 (0.53, 0.56) | 0.55 (0.53, 0.57) | 0.55 (0.54, 0.57) |
| Fasting glucose | 0.75 (0.73, 0.76) | 0.54 (0.52, 0.56) | 0.56 (0.54, 0.58) | 0.55 (0.54, 0.56) |
| 2-h glucose + 1,5-AG | 0.73 (0.72, 0.75) | 0.55 (0.53, 0.56) | 0.51 (0.49, 0.53) | 0.51 (0.50, 0.53) |
| Fasting glucose + 1,5-AG | 0.74 (0.73, 0.76) | 0.54 (0.53, 0.56) | 0.55 (0.53, 0.57) | 0.56 (0.54, 0.57) |
| Δ C-statistics (95% CI) | ||||
| 2-h glucose – 1,5-AG | 0.17 (0.15, 0.19) | 0.02 (0.00, 0.05) | 0.03 (0.00, 0.06) | 0.04 (0.02, 0.06) |
| Fasting glucose – 1,5-AG | 0.18 (0.17, 0.20) | 0.02 (0.00, 0.04) | 0.05 (0.02, 0.07) | 0.04 (0.02, 0.06) |
| (2-h glucose + 1,5-AG) – 1,5-AG | 0.17 (0.15, 0.19) | 0.03 (0.01, 0.05) | 0.04 (0.01, 0.06) | 0.04 (0.03, 0.06) |
| (Fasting glucose + 1,5-AG) – 1,5-AG | 0.18 (0.17, 0.20) | 0.02 (0.01, 0.04) | 0.05 (0.02, 0.07) | 0.04 (0.02, 0.06) |
Bold indicates P < 0.05 for differences.
Biomarkers modeled continuously using restricted cubic splines.
Discussion
In our comparison of 1,5-AG and 2-h glucose for risk of future adverse outcomes among persons without diagnosed diabetes, we observed that low values of 1,5-AG were indicative of increased risk of incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality. Consistent with prior studies (9, 10) and the biology of 1,5-AG, the signal for adverse outcomes seemed to be largely driven by those persons with 1,5-AG concentrations <10 µg/mL, meaning risk associations for 1,5-AG demonstrated a clear threshold effect, with virtually no risk associations observed at higher 1,5-AG values. Nonetheless, the prognostic value of 1,5-AG was less than that of 2-h or fasting glucose for the same outcomes.
We also tested whether 1,5-AG provided more prognostic information than fasting or 2-h glucose, but found that traditional glucose measures outperformed 1,5-AG for risk discrimination for all outcomes. In general, our results support that the utility of 1,5-AG outside the setting of diabetes—for instance, as a screening test alone or in combination with glucose to identify individuals at high risk of future outcomes—is likely to be limited (21).
Our study was among the first, to the best of our knowledge, to directly compare associations of 1,5-AG and 2-h glucose in a large, community-based US population with rigorous ascertainment of major clinical outcomes. Additional strengths included the detailed phenotypic characterization of the population and long duration of follow-up. Some limitations of this study that should be considered in the interpretation of our results include that we only had a single measure of each biomarker. And although 1,5-AG was measured in samples from the same visit as 2-h glucose, these assays were conducted in stored samples, many years later. Cases of incident diagnosed diabetes during the follow-up period in this study would have been identified largely on the basis of glucose (HbA1c was not recommended for diagnosis of diabetes until 2010 (22)), and elevated values of glucose (2-h ≥300 mg/dL; fasting glucose ≥200 mg/dL) were reported back to participants. Therefore, it was likely that glucose measures would be more strongly associated with incident diabetes. Additionally, our results are limited to black and white individuals.
In summary, we observed that associations of 1,5-AG with adverse outcomes were not as strong as 2-h or fasting glucose among persons without diagnosed diabetes. Specifically, 1,5-AG did not outperform 2-h glucose or fasting glucose for prediction of future adverse outcomes. It is unlikely that 1,5-AG is a feasible routine screening test for undiagnosed diabetes in the general population. The utility of 1,5-AG appears limited to those individuals with overt diabetes.
Supplementary Material
Author Contributions
All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.
B. Warren and E. Selvin researched the data and wrote the manuscript. All other authors reviewed and edited the manuscript.
E. Selvin is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts: HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, and HHSN268201700002I. B. Warren, NIH/NHLBI grant T32HL007024; A.K. Lee, NIH/NHLBI grant T32HL007024; A. Köttgen, DFG KO 3598/3-1; E. Selvin, NIH/NIDDK grants K24DK106414 and R01DK089174. Reagents for the 1,5-anhydroglucitol assays were donated by the GlycoMark Corporation. Expert Testimony: None declared. Patents: None declared. Other Remuneration: M.E. Grams, Dialysis Clinics Incorporated - travel support.
Role of Sponsor: The funding organizations played no role in the design of study, choice of included participants, review and interpretation of data, preparation of manuscript, or final approval of manuscript.
Acknowledgments: The authors thank the staff and participants of the ARIC Study for their important contributions.
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