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Department of Ophthalmology, Odense University Hospital, Odense, DenmarkDepartment of Clinical Research, University of Southern Denmark, Odense, DenmarkSteno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, DenmarkSteno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, DenmarkOpen Patient Data Explorative Network, Department of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark
Department of Ophthalmology, Odense University Hospital, Odense, DenmarkDepartment of Clinical Research, University of Southern Denmark, Odense, Denmark
Department of Ophthalmology, Odense University Hospital, Odense, DenmarkDepartment of Clinical Research, University of Southern Denmark, Odense, Denmark
Department of Ophthalmology, Odense University Hospital, Odense, DenmarkDepartment of Clinical Research, University of Southern Denmark, Odense, DenmarkSteno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
To evaluate the proliferative diabetic retinopathy (PDR) progression rates and identify the demographic and clinical characteristics of patients who later developed PDR compared with patients who did not progress to that state.
Design
A national 5-year register-based cohort study including 201 945 patients with diabetes.
Subjects
Patients with diabetes who had attended the Danish national screening program (2013–2018) for diabetic retinopathy (DR).
Methods
We used the first screening episode as the index date and included both eyes of patients with and without subsequent progression of PDR. Data were linked with various national health registries to investigate relevant clinical and demographic parameters. The International Clinical Retinopathy Disease Scale was used to classify DR, with no DR as level 0, mild DR as level 1, moderate DR as level 2, severe DR as level 3, and PDR as level 4.
Main Outcome Measures
Hazard ratios (HRs) for incident PDR for all relevant demographic and clinical parameters and 1-, 3-, and 5-year incidence rates of PDR according to baseline DR level.
Results
Progression to PDR within 5 years was identified in 2384 eyes of 1780 patients. Proliferative diabetic retinopathy progression rates from baseline DR level 3 at 1, 3 and 5 years were 3.6%, 10.9%, and 14.7%, respectively. The median number of visits was 3 (interquartile range, 1–4). Progression to PDR was predicted in a multivariable model by duration of diabetes (HR, 4.66 per 10 years; 95% confidence interval [CI], 4.05–5.37), type 1 diabetes (HR, 9.61; 95% CI, 8.01–11.53), a Charlson Comorbidity Index score of > 0 (score 1: HR, 4.62; 95% CI, 4.14–5.15; score 2: HR, 2.28; 95% CI, 1.90–2.74; score ≥ 3: HR, 4.28; 95% CI, 3.54–5.17), use of insulin (HR, 5.33; 95% CI, 4.49–6.33), and use of antihypertensive medications (HR, 2.23; 95% CI, 1.90–2.61).
Conclusions
In a 5-year longitudinal study of an entire screening nation, we found increased risk of PDR with increasing baseline DR levels, longer duration of diabetes, type 1 diabetes, systemic comorbidity, use of insulin, and blood pressure–lowering medications. Most interestingly, we found lower risk of progression from DR level 3 to PDR compared with that in previous studies.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references.
We offer systematic DR screening to reduce the risk of vision impairment and blindness as a free, tax-funded service in Denmark performed according to evidence-based national guidelines.
Trained ophthalmologists perform the grading, and 2-field or more fundus photography is the standard of care.
Systematic reviews conducted to clarify the risk factors for development of DR and incident proliferative DR (PDR) showed that a longer duration of diabetes, higher levels of blood glucose, type 1 diabetes, and hypertension are most commonly associated.
Few prospective population-based studies have investigated the incidence of and associated risk factors for progression to PDR in both type 1 and type 2 diabetes.
The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years.
The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more.
The study group investigated the existing incidence and risk factors for progression to PDR according to baseline characteristics in a national 5-year cohort of Danish patients with type 1 or type 2 diabetes. Previous studies that included both patients with type 1 and those with type 2 diabetes were either of older date,
The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years.
The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more.
Our aim was to evaluate the rate of progression to PDR and identify the demographic and clinical characteristics of patients with subsequent progression to PDR compared with patients who did not progress to that state. We based the study on data from the Danish Registry of Diabetic Retinopathy (DiaBase) between 2013 and 2018.
Methods
This was a cohort study based on data from Danish national registers that investigated eyes from patients with and without progression to PDR. Data from all patients with diabetes aged > 18 years who attend the Danish national screening program for DR are collected in DiaBase, which is a national clinical-quality database.
It contains information on the level of DR, visual acuity, date for screenings, indication for screening, and recommended time interval to next eye screening. Selected hospital departments and practicing opthalmologists offer the screening service performed in accordance with Danish guidelines for DR.
We included data on DR level and dates for screening.
The Danish National Patient Register includes all patient contacts within all Danish hospital facilities. It contains codes in the form of International Classification of Diseases 10 and Related Health Problems codes,
operations codes, treatment codes, date of admission, hospital codes, and geographical information; of these, we included data on diagnostic and treatment codes along with the date of admission.
The Danish National Prescription Registry holds information on medical prescriptions coded according to Anatomical Therapeutic Chemical Classification System codes.
includes the unique identification numbers assigned to all individuals living in Denmark, which allows for the linking of data between registers. From this register, we extracted data on sex, age, marital status, death, and migration.
Our study population (Figure 1) included all Danish patients with diabetes aged > 18 years who attended the Danish screening program. The patients needed a registration in DiaBase with their first visit between January 2, 2013, and December 30, 2018. We allowed the inclusion of data from both eyes if eligible; however, these data are not shown in Tables 1 and 2, in which the patients were represented by the level of DR in their worst eye.
Figure 1A flowchart displaying the selected study population. DiaBase = The Danish Registry of Diabetic Retinopathy; DR = diabetic retinopathy; PDR = proliferative diabetic retinopathy.
Table 1Baseline Characteristics of Patients in the Danish Registry of Diabetic Retinopathy According to the Level of Diabetic Retinopathy in the Worst Eye
We used the first screening episode as the index date, and each patient contributed, from the first screening episode to their last episode of screening, reach of the end point (PDR), death, or emigration, which could be at any time between January 2, 2013, and December 30, 2018.
The distribution of diabetes types in the population was determined by combining diagnostic codes (International Classification of Diseases 10 codes) for diabetes and codes for prescription (Anatomical Therapeutic Chemical Classification System codes) of insulin. Pedersen et al
published supplementary material with a detailed description of the diabetes distribution.
The definition of progression to PDR (level 4) was set as a progression to DR level 4 in DiaBase from any other DR level (levels 0–3) at baseline according to the International Clinical Diabetic Retinopathy disease severity scale.
Increased severity is indicated with higher numbers, with no DR indicating level 0, mild nonproliferative DR (NPDR) indicating level 1 (microaneurysms and/or dot hemorrhages only), moderate NPDR indicating level 2 (more than just microaneurysms and/or dot hemorrhages but less than severe NPDR), severe NPDR indicating level 3 (> 20 intraretinal hemorrhages in each of 4 quadrants or prominent intraretinal microvascular abnormalities in ≥ 1 quadrant and no PDR), and PDR indicating level 4 (neovascularization [active or treated] or vitreous/preretinal hemorrhage).
We measured progression in both eyes separately. Consequently, some patients contribute with 1 eye and some with 2 eyes. We excluded eyes with the presence of PDR at baseline, with subsequent regression from PDR, and if DR level assessment was absent at all screening visits.
We included a number of covariates that originated from the aforementioned databases and registers. They were measured at the index date and comprised sex (female or male), age at the index date (in years), duration of diabetes (in years), type of diabetes (type 1, type 2, or unknown), marital status (never married or married), patient comorbidity according to Charlson Comorbidity Index score
(0 = low, 1 = moderate low, 2 = moderate high, or ≥ 3 = high), and use of medication (insulin, noninsulin glucose-lowering treatment, antihypertensives, and cholesterol-lowering medications).
We compared the clinical and demographic baseline characteristics (Table 1) of patients who had subsequent progression to PDR (cases) with those of patients who did not have progression, defined as International Clinical Retinopathy Disease Severity Scale level 0 to 3 (controls). Descriptive data are presented as medians with interquartile ranges for continuous variables and counts with proportions for categorical variables.
We used the k-sample test for the equality of medians and chi-square test for continuous and categorical variables to test for differences between groups (Table 2).
The principal end points were defined as the adjusted hazard ratios (HRs) of markers of incident PDR according to baseline differences between patients with and without progression to PDR and 1-, 3-, and 5-year incidence rates of PDR according to the level of DR at baseline.
We displayed the HR for subsequent progression to PDR in Figure 2, estimated for all independent variables using the Cox proportional hazard model. We fitted a crude model as a semiadjusted (sex and age) and a multivariable model adjusted for sex, age, civil status, type of diabetes, blood pressure-lowering medications, cholesterol-lowering medications, and a modified Charlson Comorbidity Index score (excluding diabetes). Patients entered the analyses at the index date and were observed until progression to PDR, death, emigration, or their last screening episode, whichever occurred first. We accounted for the presence of patients with progression in 2 eyes using the robust standard errors.
Figure 2Forrest plots of the hazard ratio for subsequent progression to proliferative diabetic retinopathy according to baseline characteristics. The figure shows a semiadjusted (sex and age) and a multivariable Cox proportional hazard model. Cholesterol lowering refers to all types of cholesterol-lowering medications. Glucose lowering refers to glucose-lowering medications exclusive of insulins. CCI = Charlson Comorbidity Index; HR = hazard ratio; ref. = reference.
We modeled a competing risk analysis (Fine-Gray subdistribution hazard methods) with death as a competing cause of progression to PDR among patients registered with DR level 3 at baseline compared with patients with DR level 2 at baseline. This was consequently done because of the findings in the study.
We used Stata 17 (StataCorp) for statistical analyses, with P values of < 0.05 and 95% confidence intervals (CIs) that did not include 1.0 considered statistically significant.
The study is a part of the Ocular and Systemic complications in DR project that originates from the Danish Excellence Centre in Ophthalmic Epidemiology Study.
Interactions between ocular and systemic disease using national register-based data in the Danish Excellence Centre in Ophthalmic Epidemiology (DECODE-EYE): study perspective.
We performed the study in accordance with the preconditions of the Declaration of Helsinki. We obtained all relevant permissions from the Region of Southern Denmark’s record of data processing activities (Journal nr. 18/61231) and the Danish Clinical Registries (DIABASE-2018-12-11). The requirement of individual consent from each patient was not applicable.
Results
We found that 201 945 patients were eligible for inclusion, of which we identified 1780 (0.9%) patients and 2384 (0.6%) eyes with progression to PDR in 5 years of follow-up. There were 510, 1041, 535, and 298 eyes with progression from baseline DR levels 0, 1, 2, and 3, respectively, which equaled to rates of 0.1%, 2.7%, 4.7%, and 14.7%, respectively. The median number of visits was 3 (interquartile range, 1–4).
The population (Table 1) consisted predominantly of men (56.5%) and elderly individuals (median age, 65.8 years). Type 2 diabetes (75.6%) was more prevalent than type 1 diabetes (7.8%), and the last proportion (16.6%) had an unknown type of diabetes. The duration of diabetes at baseline was longer in patients with type 1 diabetes (median, 15.4 vs. 5.3 years) than in those with type 2 diabetes. The duration of diabetes increased with higher DR levels at baseline for type 2 diabetes (5.0 vs. 10.5 vs. 11.0 vs. 11.2 vs. 12.9 years), but this was not consistent for type 1 diabetes (9.7 vs. 19.6 vs. 19.7 vs. 19.5 vs. 20.2 years). Patients with higher DR levels at baseline were more likely to have never been married (14.3% vs. 17.9% vs. 18.9% vs. 24.4% vs. 16.6%). Increasing DR levels (4.8% vs. 7.3% vs. 8.1% vs. 7.2% vs. 10.6%) were associated with higher Charlson Comorbidity Index scores (≥ 3). Insulin treatment was more prevalent (25.2% vs. 68.1% vs. 75.5% vs. 78.9% vs. 82.7%), whereas use of noninsulin glucose-lowering medications (79.4% vs. 59.0% vs. 60.6% vs. 57.3% vs. 43.6%) was lower with increasing levels of DR. There was no consistent decrease or increase in the use of antihypertensives and cholesterol-lowering drugs in relation to increasing DR levels.
Baseline differences between patients with and without subsequent progression to PDR (Table 2) showed that male sex (60.3 vs. 56.5%, P = 0.001) and lower age (59.6 vs. 65.8 years, P = 0.001) were associated with incident PDR. Furthermore, progression to PDR was associated with longer duration of diabetes (type 1 diabetes: 19.9 vs. 14.9 years, P < 0.001; type 2 diabetes: 11.7 vs. 5.3 years, P < 0.001), type 1 diabetes (28.7% vs. 7.6%, P < 0.001), never being married (21.9 vs. 14.8%, P <0.001), and use of insulin (86.3 vs. 31.5%, P < 0.001) and blood pressure–lowering medication (80.0 vs. 74.6%, P < 0.001).
We compared patients without PDR progression with patients with subsequent progression to PDR in a Cox proportional hazard model, and the latter (Figure 2) had a longer duration of diabetes at baseline (HR, 4.66 per 10 years; 95% CI, 4.05–5.37) and a Charlson Comorbidity Index score of > 0 (score 1: HR, 4.62; 95% CI, 4.14–5.15; score 2: HR, 2.28; 95% CI, 1.90–2.74; score ≥ 3: HR, 4.28; 95% CI, 3.54–5.17) and were more likely to never have been married (HR, 1.36; 95% CI, 1.19–1.56), to have type 1 diabetes (HR, 9.61; 95% CI, 8.01–11.53), to receive insulin (HR, 5.33; 95% CI, 4.49–6.33), and to be treated with blood pressure–lowering medication (HR, 2.23; 95% CI, 1.90–2.61).
There was a decreased risk with age at first eye screening per 10-year increment (HR, 0.87; 95% CI, 0.83–0.91) and noninsulin glucose-lowering treatment (HR, 0.51; 95% CI, 0.45–0.57) but no differences in risk regarding cholesterol-lowering drugs (HR, 1.10; 95% CI, 0.97–1.26) and sex (HR, 1.07; 95% CI 0.97–1.19).
Patients with DR level 3 at baseline had an increased risk of progression to PDR when compared with that in those with DR level 2 (HR, 3.25; 95% CI, 2.74–3.87), and when death was examined as a competing cause to PDR, the findings indicated no effect of death on the risk of progression (HR, 3.25; 95% CI, 2.74–3.87).
We performed temporal analysis (Table 3), which showed the incidence rates of PDR within 1, 3, and 5 years according to the patients’ baseline DR level. One-, 3- and 5-year incidence rates were 0.6, 0.6, and 0.7 events per 1000 person-years for patients with DR level 0; 8.3, 10.8, and 11.6 events per 1000 person-years for patients with DR level 1; 13.9, 17.9, and 19.9 events per 1000 person-years for patients with DR level 2; and 52.7, 67.9, and 72.7 events per 1000 person-years for patients with DR level 3, respectively.
Table 3Risk of Progression to Proliferative DR within 1, 3, and 5 Years According to the Level of DR at the Time of the First Registration in the Danish Registry of Diabetic Retinopathy
A total of 4237 (2.1%) patients with DR levels 0 to 3 at baseline had VEGF inhibitor injections at any time from 2007 to 2018. The treatment was distributed as 2260 (1.3%), 1100 (5.5%), 631 (10.6%), and 246 (26.9%) patients with DR levels 0, 1, 2, and 3, respectively, at baseline.
Discussion
This was a national 5-year prospective cohort study of 201 945 patients with type 1 or type 2 diabetes who attended the national screening program for DR. We identified type 1 diabetes, duration of diabetes, and insulin treatment as the most prevalent risk factors for subsequent progression to PDR.
We found that 0.9% of the cohort progressed to PDR over a 5-year period. A meta-analysis, performed by Wong et al,
included 27 120 patients with diabetes (48% with type 2 diabetes) and reported a 5-year risk of progression to PDR of 6.4% on the basis of studies from 1986 to 2008. Thus, they reported substantially higher rates of progression to PDR than those in our study. This study contributes new knowledge about the rate of progression in well-controlled patients with diabetes. The study was performed nationwide and consisted of both patients with type 1 diabetes and patients with type 2 diabetes, of which a large proportion were relatively healthy patients with type 2 diabetes. Older studies consisted of poorly regulated high-risk populations with diabetes, as in the meta-analysis by Wong et al,
among which, some studies solely investigated patients with type 1 diabetes. Our results indicate that good systemic control helps with reducing diabetic eye complications.
It was difficult to compare our study with others because of differences in the follow-up time, method, and study population. A prospective cohort study from 2007 to 2014 by Romero-Aroca et al
of 15 396 patients with type 1 (6.6%) and type 2 (93.4%) diabetes reported 19 PDR progression patient cases (0.1%) from any baseline DR level in 8 years of follow-up time. In comparison, we reported 1780 patients (0.9%). They included 6.6% of patients with type 1 diabetes compared with 9.5% in our study.
A 5-year (2005–2009) prospective study from Scotland
Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the Diabetic Retinopathy Screening Service for Wales: retrospective analysis.
reported a 17-year (1990–2006) PDR progression rate of 0.9% from any baseline DR level, including both type 1 (1%) and type 2 diabetes (99%).
The current study found lower 1-, 3-, and 5-year PDR progression rates for individuals with baseline DR level 3 (severe NPDR) compared with those in earlier reports.
Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group.
The ETDRS Research Group, which laid the foundation for the development of the International Clinical Retinopathy Disease Severity classification scale,
found 1-, 3-, and 5-year risks of progression to high-risk PDR to be 17.1%, 44.4%, and 57.8%, respectively. We found the 1-, 3- and 5-year risks to be 3.6%, 10.9%, and 14.7%, respectively. Although the current recommendations
Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group.
The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years.
our study indicates that screening intervals can be reconsidered if all systemic factors (blood pressure and hemoglobin A1c) are known and can be taken into account. Our results strengthen the notion that clinicians should control systemic factors appropriately (hemoglobin A1c and blood pressure), treat diabetic macular edema, and care for patients in need of special care (pregnancy, bariatric surgery, and mental or physical vulnerability) when proposing individual screening intervals.
We performed a competing risk analysis with mortality as a competing outcome for individuals with DR level 3 (compared with DR level 2) to assess whether the low incidence rates were due to death occurring before the individuals had progression to PDR. The HR from the competing risk analysis was compared with the HR for progression to PDR between DR levels 2 and 3 and could not explain the low incidence rates. These findings add further substance to the trend that PDR progression rates are declining compared with those in previous decades in populations with relatively good control and well-characterized and cared for risk factors.
This seems particularly true for those with DR level 3 at baseline, which gives a strong argument for better prevention, monitoring, and treatment of diabetes to reduce the risk of PDR.
The risk of progression to PDR within 1, 3, and 5 years was found to increase with higher DR levels at baseline (Table 3). The findings from a population-based 5-year cohort study by Janghorbani et al
align with our findings showing that baseline DR level is the main risk factor for incident PDR regardless of diabetes type. They also found that insulin-treated diabetes compared with noninsulin-treated diabetes, duration of diabetes, and poor glycemic control were all risk factors for subsequent progression to PDR, with the first 2 being statistically significant risk factors in this study as well.
Although it is well known that duration of diabetes is a strong risk factor for DR and that every patient with onset of diabetes before the age of 15 years will develop PDR,
we were encouraged by the observation that duration of diabetes as a risk factor was mostly driven by the larger difference in patients with type 2 diabetes (Table 2).
The study represents an entire national screening population, which is considered a major strength; however, we need to address the limitations. First, the reports of DR grading in DiaBase rely on data input from many different sources. To address this, the accuracy has recently been validated by Thykjær et al.
In 458 randomly chosen eyes, there was a full 5-step DR grading agreement of 93% between ophthalmologists reporting to DiaBase and a certified expert grader, corresponding to an overall agreement of 96% (κ, 0.89) and 90% (κ, 0.76) for practicing ophthalmologists and hospital-based grading centers, respectively. Likewise, a virtual ocular learning platform has been nationally launched to support training in DR grading of Danish ophthalmologists.
Second, data on glycaemic control, hypertension, body mass index, smoking, and physical activity were not included because of unavailability. Third, it was not possible to include data on diabetic macular edema because of inconsistent reporting in DiaBase. As a sensitivity analysis, we used intravitreal treatment with VEGF inhibitors as a proxy marker for diabetic macular edema. Only 2.1% of patients received intravitreal injections between 2007 and 2018, with the highest number administered to patients with severe NPDR at baseline, of which 26.9% subsequently received intravitreal treatment. Hence, we cannot exclude the possibility of a potential causal pathway between diabetic macular edema and PDR for a minority of patients.
This 5-year longitudinal study of a national cohort consisted of patients with diabetes attending the screening program for DR. We identified, with the first screening episode as the baseline, that patients with subsequent progression to PDR differed from patients with no or minimal progression. Duration of diabetes, type of diabetes, and use of insulin were all identified as the most important risk factors for incident PDR. Finally, the incidence rates of progression to PDR were lower than those reported previously and in particular for patients with DR level 3 at baseline.
References
Carstensen B.
Rønn P.F.
Jørgensen M.E.
Prevalence, incidence and mortality of type 1 and type 2 diabetes in Denmark 1996-2016.
The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years.
The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more.
Interactions between ocular and systemic disease using national register-based data in the Danish Excellence Centre in Ophthalmic Epidemiology (DECODE-EYE): study perspective.
Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the Diabetic Retinopathy Screening Service for Wales: retrospective analysis.
Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group.
The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years.
All authors have completed and submitted the ICMJE disclosure form.
The authors have made the following disclosures: R.K.: Grant – Topcon, Senju, Novartis, Nanolux, Tamron, and WHILL, outside the submitted work; Personal fees – Novartis, Bayer, Office Future, Nanolux, Kowa, Santen, and Bausch Lomb, outside the submitted work.
J.G.: Grant – VELUX FONDEN; Personal fees – Bayer, Novartis, Roche, Allergan, and Santen, outside the submitted work.
Supported by Steno Diabetes Center Odense, Odense, Denmark, and the Region of Southern Denmark, Denmark. The funding organizations had no role in the design or conduct of this research.
Preliminary data presented at The European Association for the Study of Diabetes (EASD) Eye Complications 31st Conference. Presented at the Eye Complication Study Groups Annual Meeting, October 30, 2021.
HUMAN SUBJECTS: Human subjects were included in this study. The study was performed in accordance with the tenets of the Declaration of Helsinki. All relevant permissions were obtained from the Region of Southern Denmark’s record of data processing activities (Journal nr. 18/61231) and the Danish Clinical Registries (DIABASE-2018-12-11). The requirement of individual consent from each patient was not applicable.
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