Service Utilization for Parent Management of Early Childhood Behavior Problems in a Private Outpatient Behavioral Clinic: The Impact of Out-of-Pocket Cost, Travel Distance, and Initial Treatment Progress.

Poorly-managed early childhood disruptive behavior disorders (DBDs) have costly psychological and societal burdens. While parent management training (PMT) is recommended to effectively manage DBDs, appointment adherence is poor. Past studies on influential factors of PMT appointment adherence focused on parental factors. Less well studied are social drivers relative to early treatment gains. This study investigated how financial and time cost relative to early gains influence PMT appointment adherence for early childhood DBDs in a clinic of a large behavioral health pediatric hospital from 2016 to 2018. Using information obtained from the clinic's data repository, claims records, public census and geospatial data, we assessed how owed unpaid charges, travel distance from home to clinic, and initial behavioral progress influences total and consistent attendance of appointments for commercially- and publicly-insured (Medicaid and Tricare) patients, controlling for demographic, service, and clinical differences. We further assessed how social deprivation interacted with unpaid charges to influence appointment adherence for commercially-insured patients. Commercially-insured patients had poorer appointment adherence with longer travel distances, or having unpaid charges and greater social deprivation; they also attended fewer total appointments with faster behavioral progress. Comparatively, publicly-insured patients were not affected by travel distance and had higher consistent attendance with faster behavioral progress. Longer travel distance and difficulty paying service costs while living in greater social deprivation are barriers to care for commercially-insured patients. Targeted intervention may be needed for this specific subgroup to attend and stay engaged in treatment.

Participation, Pricing, and Enrollment in a Health Insurance "Public Option": Evidence From Washington State's Cascade Care Program.

Policy Points Policymakers considering introduction of a health insurance "public option" to lower health spending and reduce the number of uninsured can learn from Washington State, which offered the nation's first public option ("Cascade Care") through its state exchange in 2021. This article examines insurer participation, pricing, and enrollment in the Washington public option. The public option was the lowest-premium standard silver plan in 9 of the 19 counties in which it was offered. Cascade Care is available solely through private insurers. Voluntary participation of these insurers and uncertainty about the willingness of providers to participate may have hindered greater premium reductions and enrollment in the public option's first year. CONTEXT: State and federal policymakers considering introduction of a health insurance "public option" can learn from Washington State, which established the nation's first public option, with coverage beginning in January 2021. Public option plans were offered voluntarily by private insurers through the Washington Health Benefit Exchange and were subject to state-mandated plan design and payment requirements. METHODS: We used plan data from the Washington Health Benefit Exchange, linked to data from the US Census Bureau, the American Hospital Association, and InterStudy. We compared geographic availability and premiums of, and enrollment in, public option and non-public option plans, as well as characteristics of counties where the public option was available and counties where the public option was the lowest-premium plan. FINDINGS: At least one public option plan was available in 19 of 39 counties and was the lowest-premium option in 9 of the 19 counties where it was available. Five insurers offered public option plans, including one new entrant to the state and one new entrant to the Exchange. While public option availability was more common in counties where the Exchange was bigger and more competitive, public option plans had the lowest premium in smaller, less competitive counties. In the first year, 1% of enrollees selected the public option, in part due to automatic reenrollment of the majority of returning enrollees in their 2020 plan. CONCLUSIONS: Public option plans offered a low-premium choice in counties that otherwise had fewer affordable plans, but voluntary participation of insurers and providers and accompanying uncertainty about participation hindered widespread and substantial premium reductions. States should consider tying public option participation by insurers and providers to other state programs and using decision support tools to promote active enrollment. Federal policymakers can support state efforts while considering establishment of a national public option.

Diagnostic Dilemma of Hemoglobinopathies Using High Performance Liquid Chromatography Alone: A Case Report from a Resource-Constrained Setting.

Hemoglobinopathies are quite common in India, and multiple awareness and screening initiatives exist for detection of thalassemia in the population. One of the most common and successfully used method for thalassemia screening is the high performance liquid chromatography (HPLC) test. However, in spite of its excellent usefulness as a screening tool, there are situations where HPLC alone may not be able to make an accurate diagnosis. Here we highlight a fairly common situation where HPLC alone failed to confirm the diagnosis. A detailed family and transfusion history along with clinical examination and investigations, such as a complete hemogram, HPLC, along with molecular studies would have aided in diagnosis. Another cause of concern raised by this case is that the most common mutation in our population, such as IVS-I-5 (G>C), HBB: c.92+5G>C, was not represented in the HPLC, and thus, was missed during the preconception screening process, leading to a chain of events.

First Report of the 3'-Untranslated Region +1506 (A>C) [NM_000518.5: c.*32A>C] mutation on the ß-Globin Gene in the Indian Population.

The 3'-untranslated region (3'-UTR) is well known to be associated with the post-transcriptional regulation, because of the presence of important sequences that influence the fate of mRNA, and thus, in protein synthesis. The present study describes a point mutation on the ß-globin 3'-UTR, +1506 (A>C) (HBB: c.*32A>C) in an Indian family during prenatal diagnosis (PND) screening of an at-risk couple. The members of the family heterozygous for this mutation presented with a typical ß-thalassemia (ß-thal) phenotype. The haplotype analysis of the ß-globin gene cluster was determined for this mutation and observed to be linked with haplotype [- + - + + + +]. Common α-globin gene deletions, triplication, and the Xmnl polymorphism, were also looked for and found to be absent in the family. The identified HBB: c.*32A>C mutation is located in the first adenylate uridylate (AU) motif of the four AU motifs situated in the 3'-UTR region of the ß-globin gene. Bioinformatics analysis revealed binding of two miRNAs, hsa-miR-451a and hsa-miR-3914, at the mutation position, possibly influencing the mRNA stability by recruiting RNA binding proteins. This is the third publication reporting the 3'-UTR +1506 (A>C) mutation worldwide and the first report of the existence of this mutation in the Indian population, emphasizing the high heterogeneity of this population.

Changes in Liver Stiffness, Measured by Magnetic Resonance Elastography, Associated With Hepatic Decompensation in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Single measurements of liver stiffness (LS) by magnetic resonance elastography (MRE) have been associated with outcomes of patients with primary sclerosing cholangitis (PSC), but the significance of changes in LS over time are unclear. We investigated associations between changes in LS measurement and progression of PSC. METHODS: We performed a retrospective review of 204 patients with patients who underwent 2 MREs at a single center between January 1, 2007 and December 31, 2018. We collected laboratory data and information on revised Mayo PSC risk and model for end-stage liver disease scores, the PSC risk estimate tool, and levels of aspartate transferase at the time of each MRE. The ΔLS/time was determined by the change in LS between the second MRE compared to the first MRE divided by the time between examinations. The primary endpoint was development of hepatic decompensation (ascites, variceal hemorrhage or hepatic encephalopathy). RESULTS: The median LS measurement was 2.72 kPa (interquartile range, 2.32-3.44 kPa) and the overall change in LS was 0.05 kPa/y. However, ΔLS/y was 10-fold higher in patients anticipated to have cirrhosis (0.31 kPa/y) compared to patients with no fibrosis (0.03 kPa/y). The median LS increased over time in patients who ultimately developed hepatic decompensation (0.60 kPa/y; interquartile range, 0.21-1.26 kPa/y) vs but remained static in patients who did not (reduction of 0.04/y; interquartile range, reductions of 0.26 to 0.17 kPa/y) (P < .001). The ΔLS/y value associated with the highest risk of hepatic decompensation was Δ0.34 kPa/y (hazard ratio [HR], 13.29; 95% CI, 0.23-33.78). After we adjusted for baseline LS and other risk factors, including serum level of alkaline phosphatase and the Mayo PSC risk score, ΔLS/y continued to be associated with hepatic decompensation. The optimal single LS cut-off associated with the hepatic decompensation was 4.32 kPa (HR, 60.41; 95% CI, 17.85-204.47). A combination of both cut-off values was associated with risk of hepatic decompensation (concordance score, 0.93; 95% CI, 0.88-0.98) CONCLUSIONS: A single LS measurement and changes in LS over time are independently associated with hepatic decompensation in patients with PSC. However, changes in LS occur slowly in patients without advanced fibrosis or hepatic decompensation.

Understanding Geographic Variation in Systemic Overuse Among the Privately Insured.

BACKGROUND: Medical care overuse is a significant source of patient harm and wasteful spending. Understanding the drivers of overuse is essential to the design of effective interventions. OBJECTIVE: We tested the association between structural factors of the health care delivery system and regional differences systemic overuse. RESEARCH DESIGN: We conducted a retrospective analysis of deidentified claims for 18- to 64-year-old adults from the IBM MarketScan Commercial Claims and Encounters Database. We calculated a semiannual Johns Hopkins Overuse Index for each of the 375 Metropolitan Statistical Areas in the United States, from January 2011 to June 2015. We fit an ordinary least squares regression to model the Johns Hopkins Overuse Index as a function of regional characteristics of the health care system, adjusted for confounders and time. RESULTS: The supply of regional health care resources was associated with systemic overuse in commercially insured beneficiaries. Regional characteristics associated with systemic overuse included number of physicians per 1000 residents (P=0.001) and higher Medicare malpractice geographic price cost index (P<0.001). Regions with a higher density of primary care physicians (P=0.008) and a higher proportion of hospital-based providers (P=0.016) had less systemic overuse. Differences in hospital and insurer market power were inversely associated with systemic overuse. CONCLUSIONS: Systemic overuse is associated with observable, structural characteristics of the regional health care system. These findings suggest that interventions that aim to improve care efficiency via reductions in overuse should focus on the structural drivers of this phenomenon, rather than on the eradication of individual overused procedures.

Biosimilar Uptake in Medicare Part B Varied Across Hospital Outpatient Departments and Physician Practices: The Case of Filgrastim.

OBJECTIVES: To examine the uptake of filgrastim-sndz (Zarxio), the first biosimilar to launch in the United States, in the Medicare Part B fee-for-service program from its launch in September 2015 to December 2017 and compare characteristics of patients and facilities that used filgrastim-sndz or originator filgrastim (Neupogen). METHODS: The 20% sample of Medicare Part B fee-for-service administrative claims data was used to extract information on claims for any filgrastim product between January 1, 2015 and December 31, 2017. RESULTS: The utilization of filgrastim-sndz in Medicare Part B increased sharply between January and August 2016, surpassing filgrastim by November 2017, contributing to a 30% decrease in overall spending on this drug since 2015. Uptake was faster and larger in physician practices compared with hospital outpatient departments. About 77% of patients receiving filgrastim-sndz were new users. Utilization patterns indicated that product selection occurred at the facility level, rather than being at the discretion of the prescribing physician or driven by patient characteristics. CONCLUSION: Uptake of biosimilar filgrastim in the Medicare Part B program occurred despite multiple challenges to the adoption of biosimilars in the US market, suggesting that substantial potential savings could be generated by improving biosimilar uptake. Our findings indicated that physician practices and hospital outpatient departments have distinctive biosimilar uptake patterns. Thus policy makers aiming to contain Medicare Part B spending might consider focusing on incentivizing biosimilar uptake among hospital outpatient departments.

Concentration of Physician Services Across Insurers and Effects on Quality: Early Evidence From Medicare Advantage.

BACKGROUND: A growing proportion of Medicare beneficiaries is covered by private insurers through Medicare Advantage, yet little is known about how these plans are structured in terms of relationships with physicians and implications for quality of care. OBJECTIVE: The objective of this study was to assess whether greater physician concentration of services across insurers was associated with higher quality in Medicare Advantage (MA), overall and particularly among MA insurers serving a high proportion of vulnerable enrollees. RESEARCH DESIGN: A retrospective cohort design with regression analysis. DATA SOURCES: The primary dataset was 2014 MA encounter records submitted by insurers to the Centers for Medicare and Medicaid Services, covering 600,329 physicians across 119 insurers. These data were merged with Centers for Medicare and Medicaid Services data on MA contract quality rating as well as physician characteristics in the Medicare Data on Provider Practice and Specialty file. MEASURES: Two measures were generated to capture the concentration of physician services across insurers: the percentage of a physician's Medicare services which was through MA (MA penetration); and the percentage of a physician's MA services with a specific insurer (insurer share of MA services). RESULTS: Greater MA penetration and insurer share of MA services were each associated with higher MA plan quality. The relationship between insurer share and quality was stronger in contracts with a relatively high percentage of disabled enrollees. CONCLUSION: Greater physician concentration of services across MA insurers was associated with a higher quality of care overall and especially among vulnerable enrollees.

Financial Eligibility Criteria and Medication Coverage for Independent Charity Patient Assistance Programs.

Importance: Although independent charity patient assistance programs improve patient access to costly prescription drugs, recent federal investigations have raised questions about their potential to increase pharmaceutical spending and to violate the federal Anti-Kickback Statute. Little is known about the design of the programs, patient eligibility, or drug coverage. Objective: To examine the eligibility criteria of the independent charity patient assistance programs and the drugs covered by them. Design, Setting, and Participants: Descriptive cross-sectional study of the 6 largest independent charities offering patient assistance programs for patients including, but not limited to, Medicare beneficiaries in 2018. These charities offered 274 different disease-specific patient assistance programs. Drugs were identified for subgroup analysis that had any use reported on the Medicare Part D spending dashboard and any off-patent brand-name drugs that incurred more than $10 000 in Medicare spending per beneficiary in 2016. Exposures: Support by independent charity patient assistance programs. Main Outcomes and Measures: The primary outcomes were the characteristics of patient assistance programs, including assistance type, insurance coverage (vs uninsured), and income eligibility. The secondary outcomes were the cost of the drugs covered by the patient assistance programs and the coverage of expensive off-patent brand-name drugs vs substitutable generic drugs. Results: Among the 6 independent charity foundations included in the analysis, their total revenue in 2017 ranged from $24 million to $532 million, and expenditures on patient assistance programs ranged from $24 million to $353 million, representing on average, 86% of their revenue. Of the 274 patient assistance programs offered by these organizations, 168 (61%) provided only co-payment assistance, and the most common therapeutic area covered was cancer or cancer treatment-related symptoms (113 patient assistance programs; 41%). A total of 267 programs (97%) required insurance coverage as an eligibility criterion (ie, excluded uninsured patients). The most common income eligibility limit was 500% of the federal poverty level. The median annual cost of the drugs per beneficiary covered by the programs was $1157 (interquartile range, $247-$5609) compared with $367 (interquartile range, $100-$1500) for the noncovered drugs. Off-patent brand-name drugs (cost: >$10 000) were covered by a mean of 3.1 (SD, 2.0) patient assistance programs, whereas their generic equivalents were covered by a mean of 1.2 (SD, 1.0) patient assistance programs. Conclusions and Relevance: In 2018, among 274 patient assistance programs operated by the 6 independent charity foundations, the majority did not provide coverage for uninsured patients. Medications that were covered by the patient assistance programs were generally more expensive than those that were not covered.

Performance in the Medicare Shared Savings Program by Accountable Care Organizations Disproportionately Serving Dual and Disabled Populations.

BACKGROUND: The growth of accountable care organizations (ACOs) and other alternative payment models has prompted concern about whether these models will disadvantage providers who serve vulnerable populations, particularly those living in poverty or with a disability. OBJECTIVE: To examine performance by ACOs in the top quintile of their proportion of beneficiaries dually enrolled in Medicare and Medicaid (high-dual) and the top quintile of disabled beneficiaries (high-disabled). RESEARCH DESIGN: This is a retrospective cohort study. SUBJECTS: The 333 ACOs in the Medicare Shared Savings Program in 2014, followed through 2016. MEASURES: Quality scores, savings per beneficiary, whether or not the ACO shared savings, and amount of shared savings. RESULTS: High-dual and high-disabled ACOs had slightly lower quality and similar or higher baseline spending than other ACOs, but achieved greater savings per beneficiary than other ACOs ($212 vs. $51 for high-dual ACOs, P=0.04; $241 vs. $44 for high-disabled ACOs, P=0.012). Further, these ACOs were equally or more likely to earn shared savings; just over 30% of high-dual ACOs earned shared savings compared with 25% of non-high-dual ACOs (P=0.35) and 38% of high-disabled ACOs earned shared savings compared with 23% of non-high-disabled ACOs (P=0.013). In longitudinal analyses, we found a decrease in the differences in quality between high-social risk and other ACOs over time. Savings remained higher for high-dual and high-disabled ACOs relative to other ACOs over 2014-2016 though the gap narrowed over time. CONCLUSIONS: High-dual and high-disabled ACOs had similar or higher spending than other ACOs at baseline, but achieved greater savings and were equally or more likely to earn shared savings, suggesting that alternative payment models can have positive financial outcomes for providers who serve vulnerable populations.

How does expansion of public health insurance affect risk pools and premiums in the market for private health insurance? Evidence from Medicaid and the Affordable Care Act Marketplaces.

Private insurance market risk pools are likely to be directly affected by expansions of public insurance, in turn affecting premiums. We investigate the effects of Medicaid expansion on private health insurance markets using data on the plans offered through the health insurance "Marketplaces" (also known as Exchanges) established by the Affordable Care Act. We employ geographic matching to compare premiums for private plans in neighboring counties that straddle expansion and nonexpansion states and find that premiums of Marketplace plans are 11% lower in Medicaid expansion states, controlling for demographic and health characteristics as well as measures of health care access. These results are consistent with evidence on the composition of the private insurance risk pool in expansion versus nonexpansion states and associated differences in expected health spending.

Moving Toward High-Value Health Care: Integrating Delivery System Reform into 2020 Policy Proposals.

Issue: Delivery system reform has been a focus of regulatory and legislative policy to date, but it is unclear how policymakers will integrate reforms into their plans for 2020 and beyond. Goal: To present and evaluate options for integrating delivery system reform into upcoming legislative proposals. Methods: Literature review. Findings and Conclusions: Policymakers should integrate delivery system reform into their 2020 plans to continue driving value in the health care system. Several options exist for promoting delivery system reform either through a state-based block grant approach or federal public plan approach. We identify three main principles that are critical for success of reform efforts: information sharing and infrastructure, flexibility to innovate, and alignment and stability of efforts.

Elements of Program Design in Medicare's Value-based and Alternative Payment Models: a Narrative Review.

Increasing emphasis on value in health care has spurred the development of value-based and alternative payment models. Inherent in these models are choices around program scope (broad vs. narrow); selecting absolute or relative performance targets; rewarding improvement, achievement, or both; and offering penalties, rewards, or both. We examined and classified current Medicare payment models-the Hospital Readmissions Reduction Program (HRRP), Hospital Value-Based Purchasing Program (HVBP), Hospital-Acquired Conditions Reduction Program (HACRP), Medicare Advantage Quality Star Rating program, Physician Value-Based Payment Modifier (VM) and its successor, the Merit-Based Incentive Payment System (MIPS), and the Medicare Shared Savings Program (MSSP) on these elements of program design and reviewed the literature to place findings in context. We found that current Medicare payment models vary significantly across each parameter of program design examined. For example, in terms of scope, the HRRP focuses exclusively on risk-standardized excess readmissions and the HACRP on patient safety. In contrast, HVBP includes 21 measures in five domains, including both quality and cost measures. Choices regarding penalties versus bonuses are similarly variable: HRRP and HACRP are penalty-only; HVBP, VM, and MIPS are penalty-or-bonus; and the MSSP and MA quality star rating programs are largely bonus-only. Each choice has distinct pros and cons that impact program efficacy. Unfortunately, there are scant data to inform which program design choice is best. While no one approach is clearly superior to another, the variability contained within these programs provides an important opportunity for Medicare and others to learn from these undertakings and to use that knowledge to inform future policymaking.

Using Behavioral Economics to Design Physician Incentives That Deliver High-Value Care.

Behavioral economics provides insights about the development of effective incentives for physicians to deliver high-value care. It suggests that the structure and delivery of incentives can shape behavior, as can thoughtful design of the decision-making environment. This article discusses several principles of behavioral economics, including inertia, loss aversion, choice overload, and relative social ranking. Whereas these principles have been applied to motivate personal health decisions, retirement planning, and savings behavior, they have been largely ignored in the design of physician incentive programs. Applying these principles to physician incentives can improve their effectiveness through better alignment with performance goals. Anecdotal examples of successful incentive programs that apply behavioral economics principles are provided, even as the authors recognize that its application to the design of physician incentives is largely untested, and many outstanding questions exist. Application and rigorous evaluation of infrastructure changes and incentives are needed to design payment systems that incentivize high-quality, cost-conscious care.

Effectiveness of Prenatal Screening for Hemoglobinopathies in a Developing Country.

The thalassemias are among the most common monogenic diseases worldwide, a national health burden in India. There are estimated 7500-12,000 babies born with ß-thalassemia major (ß-TM) every year in this country. Couples who are at-risk of having children with hemoglobin (Hb) disorders desired to have the option of avoiding the birth of an affected child by prenatal diagnosis (PND). Thus, the prenatal women are a highly important target group for carrier screening and preventing the birth of thalassemic children in the country. The present study was conducted among 20,883 pregnant women, irrespective of gravida and duration of pregnancy, from the prenatal clinic of Nilratan Sarkar (NRS) Medical College & Hospital, Kolkata, West Bengal, India, from February 2009 to November 2012. Thalassemia carrier status was assessed by high performance liquid chromatography (HPLC) along with red blood cell (RBC) indices. Husbands of all thalassemia carrier women were advised and persuaded to undergo screening for hemoglobinopathies. The couples were counseled to undergo PND if both of them were detected to be thalassemia carriers. The data were statistically analyzed to evaluate the efficacy of this procedure.

Financial incentives for home-based health monitoring: a randomized controlled trial.

BACKGROUND: Home wireless device monitoring could play an important role in improving the health of patients with poorly controlled chronic diseases, but daily engagement rates among these patients may be low. OBJECTIVE: To test the effectiveness of two different magnitudes of financial incentives for improving adherence to remote-monitoring regimens among patients with poorly controlled diabetes. DESIGN: Randomized, controlled trial. (Clinicaltrials.gov Identifier: NCT01282957). PARTICIPANTS: Seventy-five patients with a hemoglobin A1c greater than or equal to 7.5% recruited from a Primary Care Medical Home practice at the University of Pennsylvania Health System. INTERVENTIONS: Twelve weeks of daily home-monitoring of blood glucose, blood pressure, and weight (control group; n = 28); a lottery incentive with expected daily value of $2.80 (n = 26) for daily monitoring; and a lottery incentive with expected daily value of $1.40 (n = 21) for daily monitoring. MAIN MEASURES: Daily use of three home-monitoring devices during the three-month intervention (primary outcome) and during the three-month follow-up period and change in A1c over the intervention period (secondary outcomes). KEY RESULTS: Incentive arm participants used devices on a higher proportion of days relative to control (81% low incentive vs. 58%, P = 0.007; 77% high incentive vs. 58%, P = 0.02) during the three-month intervention period. There was no difference in adherence between the two incentive arms (P = 0.58). When incentives were removed, adherence in the high incentive arm declined while remaining relatively high in the low incentive arm. In month 6, the low incentive arm had an adherence rate of 62% compared to 35% in the high incentive arm (P = 0.015) and 27% in the control group (P = 0.002). CONCLUSIONS: A daily lottery incentive worth $1.40 per day improved monitoring rates relative to control and had significantly better efficacy once incentives were removed than a higher incentive.

Role of N-ε- carboxy methyl lysine, advanced glycation end products and reactive oxygen species for the development of nonproliferative and proliferative retinopathy in type 2 diabetes mellitus.

PURPOSE: The aim of the present study was to evaluate the collective role of N-epsilon-carboxy methyl lysine (N(ε)-CML), advanced glycation end-products (AGEs), and reactive oxygen species (ROS) for the development of retinopathy among type 2 diabetic subjects. METHODS: Seventy type 2 diabetic subjects with nonproliferative diabetic retinopathy (NPDR), 105 subjects with proliferative diabetic retinopathy (PDR), and 102 patients with diabetes but without retinopathy (DNR) were enrolled in this study. In addition, 95 normal individuals without diabetes were enrolled as healthy controls in this study. Serum and vitreous N(ε)-CML and AGEs were measured by enzyme-linked immunosorbent assay. The peripheral blood mononuclear cell (PBMC) ROS level was measured by flow cytometric analysis. Serum and PBMC total thiols were measured by spectrophotometry. RESULTS: Serum AGEs and N(ε)-CML levels were significantly elevated in subjects with PDR (p<0.0001) and NPDR (p=0.0297 and p<0.0001, respectively) compared to DNR subjects. Further vitreous AGEs and N(ε)-CML levels were found to be significantly high among PDR subjects compared to the control group (p<0.0001). PBMC ROS production was found to be strikingly high among NPDR (p<0.0001) and PDR (p<0.0001) subjects as compared to the DNR group. Serum and PBMC total thiol levels were remarkably decreased in NPDR (p<0.0001 and p=0.0043, respectively) and PDR (p=0.0108 and p=0.0332 respectively) subjects than those were considered as DNR. CONCLUSIONS: Our findings suggest that N(ε)-CML and ROS are the key modulators for the development of nonproliferative retinopathy among poorly controlled type 2 diabetic subjects. Furthermore, AGEs under persistent oxidative stress and the deprived antioxidant state might instigate the pathogenic process of retinopathy from the nonproliferative to the proliferative state.