Hepatocellular Carcinoma Diagnosis and Management in 2021: A National Veterans Affairs Quality Improvement Project.

BACKGROUND & AIMS: The coronavirus disease-2019 pandemic profoundly disrupted preventative health care services including cancer screening. As the largest provider of cirrhosis care in the United States, the Department of Veterans Affairs (VA) National Gastroenterology and Hepatology Program aimed to assess factors associated with hepatocellular carcinoma (HCC) stage at diagnosis, treatment, and survival. METHODS: Veterans with a new diagnosis of HCC in 2021 were identified from electronic health records (N = 2306). Structured medical record extraction was performed by expert reviewers in a 10% random subsample of Veterans with new HCC diagnoses. Factors associated with stage at diagnosis, receipt of treatment, and survival were assessed using multivariable models. RESULTS: Among 199 patients with confirmed HCC, the average age was 71 years and most (72%) had underlying cirrhosis. More than half (54%) were at an early stage (T1 or T2) at diagnosis. Less-advanced liver disease, number of imaging tests adequate for HCC screening, HCC diagnosis in the VA, and receipt of VA primary care were associated significantly with early stage diagnosis. HCC-directed treatments were administered to 145 (73%) patients after a median of 37 days (interquartile range, 19-54 d) from diagnosis, including 70 (35%) patients who received potentially curative treatments. Factors associated with potentially curative (vs no) treatments included HCC screening, early stage at diagnosis, and better performance status. Having fewer comorbidities and better performance status were associated significantly with noncurative (vs no) treatment. Early stage diagnosis, diagnosis in the VA system, and receipt of curative treatment were associated significantly with survival. CONCLUSIONS: These results highlight the importance of HCC screening and engagement in care for HCC diagnosis, treatment, and survival while demonstrating the feasibility of developing a national quality improvement agenda for HCC screening, diagnosis, and treatment.

The Impact of Social Determinants of Health on Eye Care Utilization in a National Sample of People with Diabetes.

PURPOSE: To evaluate the association of social determinants of health (SDoH) with eye care utilization among people with diabetes mellitus using the 2013-2017 National Health Interview Survey (NHIS). DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Participants ≥ 18 years of age with self-reported diabetes. METHODS: The SDoH in the following domains were used: (1) economic stability; (2) neighborhood, physical environment, and social cohesion; (3) community and social context; (4) food environment; (5) education; and (6) health care system. An aggregate SDoH score was calculated and divided into quartiles, with Q4 representing those with the highest adverse SDoH burden. Survey-weighted multivariable logistic regression models evaluated the association of SDoH quartile with eye care utilization in the preceding 12 months. A linear trend test was conducted. Domain-specific mean SDoH scores were calculated, and the performance of domain-specific models was compared using area under the curve (AUC). MAIN OUTCOME MEASURE: Eye care utilization in the preceding 12 months. RESULTS: Of 20 807 adults with diabetes, 43% had not used eye care. Greater adverse SDoH burden was associated with decrements in odds of eye care utilization (P < 0.001 for trend). Participants in the highest quartile of adverse SDoH burden (Q4) had a 58% lower odds (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.37-0.47) of eye care utilization than those in Q1. The domain-specific model using economic stability had the highest performing AUC (0.63; 95% CI, 0.62-0.64). CONCLUSIONS: Among a national sample of people with diabetes, adverse SDoH were associated with decreased eye care utilization. Evaluating and intervening upon the effects of adverse SDoH may be a means by which to improve eye care utilization and prevent vision loss. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Characterization of the furin cleavage motif for HIV-1 trimeric envelope glycoprotein by intact LC-MS analysis.

Generating a soluble and native-like trimeric envelope glycoprotein (Env) with high efficacy as an immunogen has been a major focus for developing an effective vaccine against HIV-1. The Env immunogen is a heavily glycosylated protein composed of 3 identical surface gp120 and gp41 subunits that form into a trimer of heterodimers (3 × 28 N-glycan sites). During Env immunogen production, endogenous furin works to cleave a hexa-arginine motif connecting the gp120 and gp41 subunits, which is needed to ensure proper protein folding and a native-like conformation of Env. Verification of the overall identity and proteolytic cleavage of Env is therefore important for HIV-1 vaccine development and product quality. Herein, we report the first work using LC-MS to (1) achieve fast and accurate intact mass measurement of Env after deglycosylation and (2) confidently identify the furin cleavage sites.

Time to disease recurrence in noninfectious uveitis following long-acting injectable fluocinolone acetonide implant.

PURPOSE: To determine the time to disease recurrence with long-acting injectable fluocinolone acetonide implant (FAi) for noninfectious intermediate, posterior, and panuveitis. METHODS: This was a retrospective study of patients with at least 12 months of follow-up who had completed a 2-year prospective, investigational new drug study with 0.18-mg FAi. Time to uveitis recurrence or cystoid macular edema (CME) occurrence was recorded. RESULTS: Twelve eyes from 12 participants (mean age 43 years, range 25-64 years) were included. Patients were followed for a mean of 34.2 months (range, 12.0-56.9 months) after completion of the prospective trial. Five eyes (42%) did not have a documented uveitis recurrence or CME occurrence. Five eyes (42%) had a uveitis recurrence with the mean time to recurrence 36.1 months (range, 22.8-61.1 months) after FAi implantation. Two eyes (16%) had CME alone, the mean time to occurrence 36.9 months (range 36.1-42.1 months). On Kaplan-Meier analysis, the estimated probability of remaining recurrence-free 36 months after FAi implantation was 0.67 (95% confidence interval, 0.34-0.86). CONCLUSIONS: Data of study participants after completing a clinical trial suggest that the injectable FAi for noninfectious uveitis can provide control for 3 years on average. These long-term data support the use of FAi to control noninfectious uveitis.

Characterization of AEBSF-antibody modifications for a protease inhibitor supplementation strategy.

Application of a protease inhibitor, 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), during the cell culture process was demonstrated to effectively reduce proteolytic activity at a specific amino acid site during the production of an HIV-1 broadly neutralizing antibody (bNAb). However, the addition of AEBSF could potentially introduce some modifications to the bNAb protein. Experimental design from sample preparation to LC-MS characterization was performed using middle-up and bottom-up approaches to identify AEBSF-modified species for the bNAb using an AEBSF supplementation in the cell culture media. Modified species along with the unmodified control sample were also subjected to binding activity assessment. The results showed that two amino acids (Tyr177 and Lys250) were susceptible to AEBSF modification in the bNAb test articles but at a negligible level and not in the CDR regions, which therefore did not reduce the in vitro binding activity of the bNAb.

Hydrolysis-Kinetic Study of AEBSF, a Protease Inhibitor Used during Cell-Culture Processing of the HIV-1 Broadly Neutralizing Antibody CAP256-VRC25.26.

One approach to mitigate product clipping during HIV mAb CAP256-VRC26.25 cell-culture development is the addition of the protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) to the cell-culture media. AEBSF can undergo hydrolysis to form an inactive compound, 4-(2-aminoethyl) benzenesulfonic acid. Using mass-spectrometry detection, a kinetic profile of AEBSF hydrolysis was generated for conditions simulating those of cell culture at pH 7.0 and 37 °C. It was found that increasing the pH or the temperature could accelerate AEBSF hydrolysis. The kinetic-study results in this report provide an analytical characterization and guidance when optimizing an AEBSF-addition strategy for product-clipping control during cell-culture development and offer an alternative approach for AEBSF-related clearance studies post protein production.

Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis.

BACKGROUND AND AIMS: Hyperinsulinemia and insulin resistance are hallmark features of nonalcoholic fatty liver disease and steatohepatitis (NASH). It remains unclear whether and how insulin contributes to the development of fibrosis in NASH. In this study, we explored insulin signaling in the regulation of hepatic stellate cell (HSC) activation and the progression of NASH-fibrosis. METHODS: Phosphorylation of Akt and p70S6K were examined in primary HSC and in a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet for 24 weeks. HSC activation was analyzed for the changes in cell morphology, intracellular lipid droplets, expression of α-SMA and cell proliferation. The serum markers and histology for NASH-fibrosis were also characterized in animals. RESULTS: Insulin enhanced the expression of smooth muscle actin-α in quiescent but not in activated HSC in culture. Insulin-mediated activation of the PI3K/Akt-p70S6K pathway was involved in the regulation of profibrogenic effects of insulin. Although insulin did not stimulate HSC proliferation directly, the insulin-PI3K/Akt-p70S6K pathway was necessary for serum-enhanced cell proliferation during initial HSC activation. In a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet, hyperinsulinemia is associated with the activation of p70S6K and enhanced fibrosis. CONCLUSION: The insulin-PI3K/Akt-p70S6K pathway plays an important role in the early activation of HSC. The profibrogenic effect of insulin is dependent on the activation stage of HSC. Dysregulation of the insulin pathway likely correlates with the development of fibrosis in NASH, suggesting a potentially novel antifibrotic target of inhibiting insulin signaling in HSC.

Kidney injury molecule-1 (KIM-1) mediates renal epithelial cell repair via ERK MAPK signaling pathway.

The expression of kidney injury molecule-1 (KIM-1), a very promising sensitive and specific urinary biomarker for acute renal injury, is markedly upregulated in injured and regenerating renal proximal tubular epithelial cells following ischemic or toxic insults, suggesting a possible role for this molecule in renal repair process. In the present study, we report that expression of KIM-1 facilitates renal tubular epithelial cell repair by promoting cell migration and proliferation. KIM-1 expression also enhances ERK MAPK activation, and the modulatory effect of KIM-1 on cellular repair process is likely mediated via ERK MAPK signaling pathway.

A Treat-to-Target Concept to Guide the Medical Management of Hepatorenal Syndrome.

BACKGROUND: The principle of treating-to-target has been successfully applied to many diseases with significant improvement in patient care and as a useful guidance for healthcare providers. Appreciation of the central role for arterial vasodilatation in the pathogenesis of hepatorenal syndrome (HRS) has led to routine use of vasoconstrictors in combination with albumin in patients with HRS. An appropriate target to guide such therapy, however, has not yet been established. AIMS: The purpose of the current study was to identify a suitable target that can predict clinical outcome and guide the medical management of type 1 HRS, a condition associated with very poor prognosis. METHODS: A total of 85 patients with type 1 HRS who received a combination therapy of vasoconstrictors and albumin were enrolled. A potential therapeutic target was identified by univariate and multivariate logistic regression analyses. The treat-to-target concept to guide the management of HRS was then tested via a retrospective cohort study. RESULTS: A change in mean arterial pressure (MAP) during treatment was identified as a sole independent predictor for patient survival. Compared with mild or no increase in MAP, achievement in a marked increase in MAP of more than 10 mmHg in these patients was associated with better overall survival and transplant-free survival. Increased MAP to higher than 15 mmHg did not result in further improvement in clinical outcome. CONCLUSIONS: A treat-to-target concept by the use of a specific goal of MAP is feasible and may potentially guide the medical management of type 1 HRS.

Targeting an early and substantial increase in mean arterial pressure is critical in the management of type 1 hepatorenal syndrome: a combined retrospective and pilot study.

BACKGROUND: Appreciation of the central role for arterial vasodilatation in the pathogenesis of hepatorenal syndrome (HRS) has led to routine use of vasoconstrictors in combination with albumin as a medical therapy for HRS. Various vasoconstrictors have been explored but the optimal approach for such therapies has not yet been established. AIMS: The purpose of this study was to examine the role of targeting an early and substantial increase in mean arterial pressure (MAP) in the management of type 1 HRS, a condition associated with very poor prognosis. METHODS: A total of 59 patients with type 1 HRS who received a combination therapy of vasoconstrictors and albumin were enrolled into a retrospective cohort study. Subjects having a substantial increase of more than 10 mmHg in MAP by day 3 after initiation of therapy were categorized as MAP responders and the rest as MAP non-responders. In addition, five patients were enrolled into a prospective pilot study in which a titration protocol of vasoconstrictors was followed to achieve early goal-directed therapy (EGDT). RESULTS: MAP responders achieved significantly higher incidence of treatment success or total response, less requirement of dialysis and more incidence of liver transplantation. More importantly, this response is associated with better short-term and long-term overall survival as well as transplant-free survival. The effectiveness of such an approach was further confirmed in the pilot study which followed an EGDT protocol. CONCLUSIONS: Using an early and substantial increase in MAP as a therapeutic target is associated with favorable clinical outcomes in the management of type 1 HRS.

Downbeat nystagmus secondary to familial hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis is a rare autosomal recessive disorder characterized by severe inflammation induced by defective natural killer cell function, which triggers a state of highly stimulated but ineffective immune response. This disorder can affect multiple organ systems, and neurologic manifestations include irritability, seizures, impaired consciousness, meningismus, and cranial nerve palsies. We describe a unique case of hemophagocytic lymphohistiocytosis in which downbeat nystagmus developed due to cerebellar swelling with compression of the cervicomedullary junction.

Social Risk Groups in Patients With Diabetes With Differing Eye Care Utilization and Vision Outcomes.

Purpose: To evaluate whether latent class analysis on social determinants of health (SDoH) data can identify social risk groups that differ by adverse SDoH and vision outcomes in patients with diabetes. Methods: This was a prospective cohort study of adults ≥18 years with diabetes who completed a SDoH survey. Latent class analysis was used to cluster patients into social risk groups. The association of social risk group and severity of diabetic retinopathy, history of lapses in diabetic retinopathy care, and visual acuity was evaluated. Results: A total of 1006 participants were included. The three social risk groups differed by sociodemographic characteristics. The average age was 65, 60, and 54 in Groups 1, 2, and 3 respectively. Most (51%) patients in group 1 were non-Hispanic White, 66% in group 2 were non-Hispanic Black, and 80% in group 3 were Hispanic. Group 1 had the lowest burden of adverse SDoH per person (average 3.6), group 2 had 8.2, and group 3 had 10.5. In general, group 1 lacked diabetic retinopathy knowledge, group 2 had financial insecurity and difficulties with transportation, and group 3 had financial insecurity and did not have health insurance. Social risk group was associated with a history of lapses in diabetic retinopathy care, and presenting with worse vision. Conclusions and Translational Relevance: We identified distinct social risk groups among patients seeking care for diabetic retinopathy that differed by social needs, eye care utilization, and vision. Identifying these groups and their specific needs can help guide interventions to effectively address adverse SDoH and improve eye care utilization and vision outcomes among patients with diabetes.

Association of Neighborhood Socioeconomic Disadvantage with Proliferative Diabetic Retinopathy.

OBJECTIVE OR PURPOSE: To evaluate the association between neighborhood socioeconomic deprivation, distance from ophthalmology clinics, and diagnosis of proliferative diabetic retinopathy (PDR). DESIGN: Retrospective cohort study. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Adult patients (≥18 years) with diabetes mellitus at Johns Hopkins Hospital and University of Wisconsin-Madison. METHODS, INTERVENTION, OR TESTING: Patient addresses were geocoded and the block group was linked to the 2021 national Area Deprivation Index (ADI). ADI was divided into quartiles, with higher quartiles indicating greater socioeconomic disadvantage. The distance between patient's residence and ophthalmology clinics was calculated. Multivariable logistic regression models were used to analyze the association between ADI quartile, distance from clinic, and PDR, adjusted for demographics and insurance status. The interaction between ADI and distance was tested. MAIN OUTCOME MEASURES: Diagnosis of PDR. RESULTS: 73,618 patients were included. A significant interaction was observed between ADI quartile and distance from ophthalmology clinics (P < .001). Among patients residing within 8 miles of clinics, those in higher ADI quartiles had increased odds of PDR compared to those in ADI Q1 (Q2: OR 1.36, 95% CI 1.12-1.65; Q3: OR 1.79, 95% CI 1.46-2.19; Q4: OR 2.60, 95% CI 2.09-3.25; P<.001 for trend). Conversely, for patients living more than 8 miles from clinics, the odds of PDR were similar across ADI quartiles (Q1: OR 0.85, 95% CI 0.73-0.98; Q2: OR 1.02, 95% CI 0.87-1.12; Q3: OR 1.08, 95% CI 0.90-1.30). However, patients in all ADI quartiles more than 8 miles had greater odds of PDR compared to those in the same ADI quartile within 8 miles (OR 3.15, 95% CI 2.61-3.80, OR 1.97, 95% CI 1.71-2.27, OR 1.79, 95% CI 1.51-2.12, and OR 1.31, 95% CI 1.07-1.61 in ADI Q1 to Q4 respectively). CONCLUSIONS: Patients living in neighborhoods with greater socioeconomic disadvantage and further from ophthalmology clinics have greater odds of PDR. These findings suggest the potential utility of targeted interventions in socioeconomically deprived and distant areas to reduce PDR-related blindness.

Improving the Identification of Diabetic Retinopathy and Related Conditions in the Electronic Health Record Using Natural Language Processing Methods.

Purpose: To compare the performance of 3 phenotyping methods in identifying diabetic retinopathy (DR) and related clinical conditions. Design: Three phenotyping methods were used to identify clinical conditions including unspecified DR, nonproliferative DR (NPDR) (mild, moderate, severe), consolidated NPDR (unspecified DR or any NPDR), proliferative DR, diabetic macular edema (DME), vitreous hemorrhage, retinal detachment (RD) (tractional RD or combined tractional and rhegmatogenous RD), and neovascular glaucoma (NVG). The first method used only International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes (ICD-10 Lookup System). The next 2 methods used a Bidirectional Encoder Representations from Transformers with a dense Multilayer Perceptron output layer natural language processing (NLP) framework. The NLP framework was applied either to free-text of provider notes (Text-Only NLP System) or both free-text and ICD-10 diagnosis codes (Text-and-International Classification of Diseases [ICD] NLP System). Subjects: Adults ≥18 years with diabetes mellitus seen at the Wilmer Eye Institute. Methods: We compared the performance of the 3 phenotyping methods in identifying the DR related conditions with gold standard chart review. We also compared the estimated disease prevalence using each method. Main Outcome Measures: Performance of each method was reported as the macro F1 score. The agreement between the methods was calculated using the kappa statistic. Prevalence estimates were also calculated for each method. Results: A total of 91 097 patients and 692 486 office visits were included in the study. Compared with the gold standard, the Text-and-ICD NLP System had the highest F1 score for most clinical conditions (range 0.39-0.64). The agreement between the ICD-10 Lookup System and Text-Only NLP System varied (kappa of 0.21-0.81). The prevalence of DR and related conditions ranged from 1.1% for NVG to 17.9% for DME (using the Text-and-ICD NLP System). Conclusions: The prevalence of DR and related conditions varied significantly depending on the methodology of identifying cases. The best performing phenotyping method was the Text-and-ICD NLP System that used information in both diagnosis codes as well as free-text notes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Automated identification of fleck lesions in Stargardt disease using deep learning enhances lesion detection sensitivity and enables morphometric analysis of flecks.

PURPOSE: To classify fleck lesions and assess artificial intelligence (AI) in identifying flecks in Stargardt disease (STGD). METHODS: A retrospective study of 170 eyes from 85 consecutive patients with confirmed STGD. Fundus autofluorescence images were extracted, and flecks were manually outlined. A deep learning model was trained, and a hold-out testing subset was used to compare with manually identified flecks and for graders to assess. Flecks were clustered using K-means clustering. RESULTS: Of the 85 subjects, 45 were female, and the median age was 37 years (IQR 25-59). A subset of subjects (n=41) had clearly identifiable fleck lesions, and an AI was successfully trained to identify these lesions (average Dice score of 0.53, n=18). The AI segmentation had smaller (0.018 compared with 0.034 mm2, p<0.001) but more numerous flecks (75.5 per retina compared with 40.0, p<0.001), but the total size of flecks was not different. The AI model had higher sensitivity to detect flecks but resulted in more false positives. There were two clusters of flecks based on morphology: broadly, one cluster of small round flecks and another of large amorphous flecks. The per cent frequency of small round flecks negatively correlated with subject age (r=-0.31, p<0.005). CONCLUSIONS: AI-based detection of flecks shows greater sensitivity than human graders but with a higher false-positive rate. With further optimisation to address current shortcomings, this approach could be used to prescreen subjects for clinical research. The feasibility and utility of quantifying fleck morphology in conjunction with AI-based segmentation as a biomarker of progression require further study.

Neighborhood-Level Social Determinants of Health and Presenting Characteristics for Rhegmatogenous Retinal Detachments.

Importance: Functional outcomes after repair of rhegmatogenous retinal detachments (RRDs) are highly dependent on baseline visual acuity and foveal status. Adverse social determinants of health (SDOH) can present barriers to timely presentation for repair and limit vision outcomes. Objective: To evaluate the association between neighborhood-level SDOH with baseline severity (visual acuity and fovea status) of RRD. Design, Setting, and Participants: This was a retrospective cohort study that included adult patients 18 years and older who underwent primary repair of uncomplicated RRD at the Wilmer Eye Institute from January 2008 to December 2018. Study data were analyzed from December 2023 to April 2024. Exposures: The census block group of patient home addresses were matched to multiple neighborhood-level SDOH including the Area Deprivation Index (ADI), per capita income, percentage of renters, percentage of rent burden, percentage of people using a food assistance program, percentage of uninsured individuals, mode of transportation to work, distance to the nearest transit stop, total road density, National Walkability Index, Index of Medical Underservice score, and aggregate cost of medical care. Main Outcomes and Measures: Odds of presenting with vision worse than 20/40 or fovea-involving RRD using multivariable logistic regression adjusting for age, sex, race and ethnicity, and insurance. Results: A total of 700 patients (mean [SD] age, 57.9 [12.4] years; 432 male [61.7%]) were included. Every decile increase in ADI, indicating more socioeconomic disadvantage, was associated with an increased odds of presenting with worse visual acuity and fovea-involving RRD (odds ratio [OR], 1.14; 95% CI, 1.04-1.24; P = .004 and OR, 1.13; 95% CI, 1.04-1.22; P = .005, respectively). Each $1000 increase in per capita income was associated with lower odds of presenting with worse vision (OR, 0.99; 95% CI, 0.98-0.99; P = .001). Every 1% increase in percentage of workers who drove to work was associated with an increased odds of presenting with worse vision and fovea-involving RRD (OR, 1.02; 95% CI, 1.01-1.03; P = .005 and OR, 1.01; 95% CI, 1.00-1.03; P = .04, respectively). Conclusions and Relevance: Results of this cohort study suggest that patients with a residence in neighborhoods with more socioeconomic deprivation or a higher percentage of workers who drove to work were more likely to present with more severe RRD even after accounting for multiple individual-level characteristics. These findings support consideration of public policy changes to address the barriers faced by patients residing in certain neighborhoods who seek prompt surgical intervention for RRD to reduce health disparities in RRD outcomes.

Variations in Electronic Health Record-Based Definitions of Diabetic Retinopathy Cohorts: A Literature Review and Quantitative Analysis.

Purpose: Use of the electronic health record (EHR) has motivated the need for data standardization. A gap in knowledge exists regarding variations in existing terminologies for defining diabetic retinopathy (DR) cohorts. This study aimed to review the literature and analyze variations regarding codified definitions of DR. Design: Literature review and quantitative analysis. Subjects: Published manuscripts. Methods: Four graders reviewed PubMed and Google Scholar for peer-reviewed studies. Studies were included if they used codified definitions of DR (e.g., billing codes). Data elements such as author names, publication year, purpose, data set type, and DR definitions were manually extracted. Each study was reviewed by ≥ 2 authors to validate inclusion eligibility. Quantitative analyses of the codified definitions were then performed to characterize the variation between DR cohort definitions. Main Outcome Measures: Number of studies included and numeric counts of billing codes used to define codified cohorts. Results: In total, 43 studies met the inclusion criteria. Half of the included studies used datasets based on structured EHR data (i.e., data registries, institutional EHR review), and half used claims data. All but 1 of the studies used billing codes such as the International Classification of Diseases 9th or 10th edition (ICD-9 or ICD-10), either alone or in addition to another terminology for defining disease. Of the 27 included studies that used ICD-9 and the 20 studies that used ICD-10 codes, the most common codes used pertained to the full spectrum of DR severity. Diabetic retinopathy complications (e.g., vitreous hemorrhage) were also used to define some DR cohorts. Conclusions: Substantial variations exist among codified definitions for DR cohorts within retrospective studies. Variable definitions may limit generalizability and reproducibility of retrospective studies. More work is needed to standardize disease cohorts. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Similar Risk of Kidney Failure among Patients with Blinding Diseases Who Receive Ranibizumab, Aflibercept, and Bevacizumab: An Observational Health Data Sciences and Informatics Network Study.

PURPOSE: To characterize the incidence of kidney failure associated with intravitreal anti-VEGF exposure; and compare the risk of kidney failure in patients treated with ranibizumab, aflibercept, or bevacizumab. DESIGN: Retrospective cohort study across 12 databases in the Observational Health Data Sciences and Informatics (OHDSI) network. SUBJECTS: Subjects aged ≥ 18 years with ≥ 3 monthly intravitreal anti-VEGF medications for a blinding disease (diabetic retinopathy, diabetic macular edema, exudative age-related macular degeneration, or retinal vein occlusion). METHODS: The standardized incidence proportions and rates of kidney failure while on treatment with anti-VEGF were calculated. For each comparison (e.g., aflibercept versus ranibizumab), patients from each group were matched 1:1 using propensity scores. Cox proportional hazards models were used to estimate the risk of kidney failure while on treatment. A random effects meta-analysis was performed to combine each database's hazard ratio (HR) estimate into a single network-wide estimate. MAIN OUTCOME MEASURES: Incidence of kidney failure while on anti-VEGF treatment, and time from cohort entry to kidney failure. RESULTS: Of the 6.1 million patients with blinding diseases, 37 189 who received ranibizumab, 39 447 aflibercept, and 163 611 bevacizumab were included; the total treatment exposure time was 161 724 person-years. The average standardized incidence proportion of kidney failure was 678 per 100 000 persons (range, 0-2389), and incidence rate 742 per 100 000 person-years (range, 0-2661). The meta-analysis HR of kidney failure comparing aflibercept with ranibizumab was 1.01 (95% confidence interval [CI], 0.70-1.47; P = 0.45), ranibizumab with bevacizumab 0.95 (95% CI, 0.68-1.32; P = 0.62), and aflibercept with bevacizumab 0.95 (95% CI, 0.65-1.39; P = 0.60). CONCLUSIONS: There was no substantially different relative risk of kidney failure between those who received ranibizumab, bevacizumab, or aflibercept. Practicing ophthalmologists and nephrologists should be aware of the risk of kidney failure among patients receiving intravitreal anti-VEGF medications and that there is little empirical evidence to preferentially choose among the specific intravitreal anti-VEGF agents. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.