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1.  Diabetic Retinopathy and Other Ocular Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2013;37(1):17-23.
To evaluate whether intensive treatment (INT) with the goal of achieving blood glucose levels as close to the nondiabetic range as safely possible reduced the risk of onset and progression of diabetic retinopathy (DR) in subjects with type 1 diabetes (T1D) compared with conventional therapy (CON).
The Diabetes Control and Complications Trial (DCCT) (1982–1993) was a multicenter, controlled clinical trial comparing INT with CON for onset and progression of DR. The Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994–present) is an observational follow-up of the DCCT cohort.
Of the 1,441 DCCT subjects, 726 had no DR (primary prevention cohort) and 715 had mild DR (secondary intervention cohort) at baseline. Subjects were followed for a mean of 6.5 years. INT median HbA1c was 7% compared with CON median of 9%. INT reduced the adjusted mean risk for the development of DR by 76% and slowed progression of DR by 54% compared with CON. Following DCCT, the HbA1c levels in the original INT and CON groups converged (year 8, INT 7.98%; CON 8.07%); nevertheless, the groups continued to have a durable effect of initial assigned therapy with significantly lower incidence of further DR progression in the INT group (hazard reduction 53–56%). Severe retinal outcomes and procedures to treat them were reduced by 50% in the original INT group.
INT delays the onset and slows the progression of DR. Furthermore, the early effects of metabolic control continue to accrue over many years despite subsequent comparable glycemic control (metabolic memory). These results emphasize the need for optimizing glycemic control as early as possible in patients with diabetes.
PMCID: PMC3867989  PMID: 24356593
2.  Green or Yellow Laser Treatment for Diabetic Macular Edema: Exploratory Assessment within the Diabetic Retinopathy Clinical Research Network 
Retina (Philadelphia, Pa.)  2013;33(10):2080-2088.
Explore differences in green compared with yellow focal/grid laser treatment on functional and anatomic endpoints in eyes with diabetic macular edema.
Data from two randomized clinical trials were evaluated for differences in visual acuity (VA) and optical coherence tomography (OCT) parameters, eyes were assigned to sham injection+prompt laser, ranibizumab+prompt laser, or prompt laser only; among subgroups of eyes treated exclusively and electively with either green or yellow laser.
In the sham injection+prompt laser group, the mean VA letter score change for eyes receiving green and yellow laser treatment, respectively, was +2.4±14 and +5.1±13 at the 52-week visit (P = 0.06), and +2.4±15 and +6.0±13 at the 104-week visit (P = 0.13), with no corresponding evidence of differences in OCT thickness. When comparing wavelength groups in the ranibizumab+prompt laser and prompt-laser only groups, meaningful differences in VA and OCT thickness were not detected at 1 or 2 years.
A trend towards improved vision outcome with yellow laser observed in one trial was not corroborated by anatomic outcomes or by the other trial. Without random assignment to different wavelengths controlling for bias and confounding, it is not possible to determine whether one wavelength is better than the other.
PMCID: PMC4126070  PMID: 23792486
diabetic macular edema; laser photocoagulation; laser wavelength
3.  The Reference Genome Sequence of Saccharomyces cerevisiae: Then and Now 
G3: Genes|Genomes|Genetics  2013;4(3):389-398.
The genome of the budding yeast Saccharomyces cerevisiae was the first completely sequenced from a eukaryote. It was released in 1996 as the work of a worldwide effort of hundreds of researchers. In the time since, the yeast genome has been intensively studied by geneticists, molecular biologists, and computational scientists all over the world. Maintenance and annotation of the genome sequence have long been provided by the Saccharomyces Genome Database, one of the original model organism databases. To deepen our understanding of the eukaryotic genome, the S. cerevisiae strain S288C reference genome sequence was updated recently in its first major update since 1996. The new version, called “S288C 2010,” was determined from a single yeast colony using modern sequencing technologies and serves as the anchor for further innovations in yeast genomic science.
PMCID: PMC3962479  PMID: 24374639
Saccharomyces cerevisiae; model organism; reference sequence; genome release; S288C
4.  Saccharomyces genome database provides new regulation data 
Nucleic Acids Research  2013;42(Database issue):D717-D725.
The Saccharomyces Genome Database (SGD; is the community resource for genomic, gene and protein information about the budding yeast Saccharomyces cerevisiae, containing a variety of functional information about each yeast gene and gene product. We have recently added regulatory information to SGD and present it on a new tabbed section of the Locus Summary entitled ‘Regulation’. We are compiling transcriptional regulator–target gene relationships, which are curated from the literature at SGD or imported, with permission, from the YEASTRACT database. For nearly every S. cerevisiae gene, the Regulation page displays a table of annotations showing the regulators of that gene, and a graphical visualization of its regulatory network. For genes whose products act as transcription factors, the Regulation page also shows a table of their target genes, accompanied by a Gene Ontology enrichment analysis of the biological processes in which those genes participate. We additionally synthesize information from the literature for each transcription factor in a free-text Regulation Summary, and provide other information relevant to its regulatory function, such as DNA binding site motifs and protein domains. All of the regulation data are available for querying, analysis and download via YeastMine, the InterMine-based data warehouse system in use at SGD.
PMCID: PMC3965049  PMID: 24265222
5.  Evaluation of Visual Acuity Measurements after Autorefraction versus Manual Refraction in Eyes with and without Diabetic Macular Edema 
Archives of ophthalmology  2011;130(4):470-479.
To compare visual acuity (VA) scores after autorefraction versus research protocol manual refraction in eyes of patients with diabetes and a wide range of VA.
Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) VA Test© letter score (EVA) was measured after autorefraction (AR-EVA) and after Diabetic Retinopathy Clinical Research Network ( protocol manual refraction (MR-EVA). Testing order was randomized, study participants and VA examiners were masked to refraction source, and a second EVA utilizing an identical manual refraction (MR-EVAsupl) was performed to determine test-retest variability.
In 878 eyes of 456 study participants, median MR-EVA was 74 (Snellen equivalent approximately 20/32). Spherical equivalent was often similar for manual and autorefraction (median difference: 0.00, 5th and 95th percentiles −1.75 to +1.13 Diopters). However, on average, MR-EVA results were slightly better than AR-EVA results across the entire VA range. Furthermore, variability between AR-EVA and MR-EVA was substantially greater than the test-retest variability of MR-EVA (P<0.001). Variability of differences was highly dependent on autorefractor model.
Across a wide range of VA at multiple sites using a variety of autorefractors, VA measurements tend to be worse with autorefraction than manual refraction. Differences between individual autorefractor models were identified. However, even among autorefractor models comparing most favorably to manual refraction, VA variability between autorefraction and manual refraction is higher than the test-retest variability of manual refraction. The results suggest that with current instruments, autorefraction is not an acceptable substitute for manual refraction for most clinical trials with primary outcomes dependent on best-corrected VA.
PMCID: PMC3489033  PMID: 22159173
6.  Rationale for the Diabetic Retinopathy Clinical Research Network Treatment Protocol for Center-involved Diabetic Macular Edema 
Ophthalmology  2011;118(12):e5-e14.
Describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network ( randomized clinical trial.
Discussion of treatment protocol for DME.
Subjects with vision loss from DME involving the center of the macula.
The created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser in eyes with vision loss from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes, compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. In order to share their opinion on how ophthalmologists might emulate the study protocol, participating investigators developed guidelines based on the algorithm's underlying rationale.
Main Outcome Measures
Clinical guidelines based on a protocol.
The treatment protocol required real time feedback from a web-based data entry system for intravitreal injections, focal/grid laser, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month, or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed.
Duplication of the approach used in the randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published.
PMCID: PMC3253487  PMID: 22136692
8.  Antiangiogenic Therapy for Ischemic Retinopathies 
Neovascularization is a common pathological process in various retinal vascular disorders including diabetic retinopathy (DR), age-related macular degeneration (AMD) and retinal vein occlusion (RVO). The development of neovascular vessels may lead to complications such as vitreous hemorrhage, fibrovascular tissue formation, and traction retinal detachments. Ultimately, irreversible vision loss may result. Various proangiogenic factors are involved in these complex processes. Different antiangiogenic drugs have been formulated in an attempt treat these vascular disorders. One factor that plays a major role in the development of retinal neovascularization is vascular endothelial growth factor (VEGF). Anti-VEGF agents are currently FDA approved for the treatment of AMD and RVO. They are also extensively used as an off-label treatment for diabetic macular edema (DME), proliferative DR, and neovascular glaucoma. However, at this time, the long-term safety of chronic VEGF inhibition has not been extensively evaluated. A large and rapidly expanding body of research on angiogenesis is being conducted at multiple centers across the globe to determine the exact contributions and interactions among a variety of angiogenic factors in an effort to determine the therapeutic potential of antiangiogenic agent in the treatment of a variety of retinal diseases.
In retinal vascular disorders (e.g., age-related macular degeneration), VEGF plays a major role in the development of retinal neovascularization. Anti-VEGF agents are effective, but their long-term safety must be monitored.
PMCID: PMC3367538  PMID: 22675660
9.  Protection From Retinopathy and Other Complications in Patients With Type 1 Diabetes of Extreme Duration 
Diabetes Care  2011;34(4):968-974.
To assess complication prevalence and identify protective factors in patients with diabetes duration of ≥50 years. Characterization of a complication-free subgroup in this cohort would suggest that some individuals are protected from diabetes complications and allow identification of endogenous protective factors.
Cross-sectional, observational study of 351 U.S. residents who have survived with type 1 diabetes for ≥50 years (Medalists). Retinopathy, nephropathy, neuropathy, and cardiovascular disease were assessed in relation to HbA1c, lipids, and advanced glycation end products (AGEs). Retrospective chart review provided longitudinal ophthalmic data for a subgroup.
A high proportion of Medalists remain free from proliferative diabetic retinopathy (PDR) (42.6%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%). Current and longitudinal (the past 15 years) glycemic control were unrelated to complications. Subjects with high plasma carboxyethyl-lysine and pentosidine were 7.2-fold more likely to have any complication. Of Medalists without PDR, 96% with no retinopathy progression over the first 17 years of follow-up did not experience retinopathy worsening thereafter.
The Medalist population is likely enriched for protective factors against complications. These factors might prove useful to the general population with diabetes if they can be used to induce protection against long-term complications. Specific AGE combinations were strongly associated with complications, indicating a link between AGE formation or processing with development of diabetic vasculopathy.
PMCID: PMC3064059  PMID: 21447665
10.  Visual Acuity Testing Using Autorefraction or Pinhole Occluder as Compared with a Manual Protocol Refraction in Individuals with Diabetes 
Ophthalmology  2010;118(3):537-542.
To compare visual acuity (VA) scores obtained after autorefraction or using a pinhole occluder to scores obtained after refraction according to a standard clinical research protocol.
Prospective, comparative case series
One hundred and ten study participants (209 eyes) with diabetes mellitus and a broad range of diabetic retinopathy severity and visual acuity (VA).
VA was measured after autorefraction by a Topcon KR-8000 autorefractor as well as after a Diabetic Retinopathy Clinical Research Network ( protocol manual refraction. The order of testing was randomized and examiners were masked to the source of each refraction. A second VA measurement, utilizing an identical manual refraction, was made in a subset of eyes (N = 144, 69%) in order to establish test-retest variability for comparison purposes. All eyes underwent VA testing using a pinhole occluder.
Main Outcome Measures
Best corrected VA as measured by the Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Test© (E-ETDRS).
In all eyes, the median E-ETDRS VA letter score (EVA) obtained after manual refraction (MR-EVA) was 69 (Snellen equivalent 20/40), ranging from 4 to 93 (20/800 to 20/16). The median MR-EVA was slightly better than the median EVA obtained after autorefraction (AR-EVA), with a median difference (AR-EVA – MR-EVA) of −1 letter (25th, 75th percentiles: −4, 2 letters). The absolute difference between AR-EVA and MR-EVA was similar to the test-retest variability of MR-EVA alone. In contrast, MR-EVA was better than EVA obtained using a pinhole occluder (PH-EVA), (median PH-EVA – MR-EVA: −4 letters [−9, 0]), and had significantly less test-retest variability (P<0.001). Generally, the spherical equivalent of autorefraction was slightly more hyperopic (or less myopic) than the spherical equivalent of manual refraction (median difference: +0.25 Diopters [0, +0.63 Diopters]).
Given the substantial time and effort required for training and certification of study protocol refractionists, and the similarity between AR-EVA and MR-EVA, further evaluation of autorefraction, but not pinhole occluder testing, as an alternative to the current clinical research gold standard of ETDRS protocol manual refraction in study participants with diabetic retinopathy is warranted.
PMCID: PMC3057328  PMID: 20947171
11.  Comparison of Film and Digital Fundus Photographs in Eyes of Individuals with Diabetes Mellitus 
This study was a comparison of the performance of film and digital fundus photographs in grading diabetic retinopathy.
To compare grading of diabetic retinopathy (DR) and diabetic macular edema (DME) from stereoscopic film versus stereoscopic digital photographs obtained from a subset of Diabetic Retinopathy Clinical Research Network ( participants.
In this photographic media comparison study, digital and film images were obtained at a single study visit from some of the subjects enrolled in active clinical study protocols. Digital camera systems and digital and film photographers were certified to obtain images according to standard procedures. Images were graded for DR severity and DME in a masked fashion by Fundus Photograph Reading Center (Madison, WI) graders. Agreement between gradings was assessed by calculating the percentage of agreement and κ statistics.
Images obtained with both film and digital media were submitted for 155 eyes of 96 study participants. On a nine-step Early Treatment Diabetic Retinopathy study DR severity scale, grading agreed exactly in 74%, and was within one step of agreement in 93%, with a weighted κ statistic of 0.82 (95% confidence interval [CI], 0.71–0.92). On a nine-step DME severity scale and three-step clinically significant macular edema (CSME) scale, grading agreed exactly in 39% and 88%, respectively, and within one step in 70% and 92% (weighted κ statistic, 0.44 [95% Cl, 0.34–0.54] and 0.72 [95% Cl, 0.55–0.90], respectively).
Among clinical sites participating in the, agreement between film and digital images was substantial to almost perfect for DR severity level and moderate to substantial for DME and CSME severity levels, respectively. Replacement of film fundus images with digital images for DR severity level should not adversely affect clinical trial quality. ( numbers, NCT00367133, NCT00369486, NCT00444600, NCT00445003, NCT00709319.)
PMCID: PMC3176025  PMID: 21571677
12.  modMine: flexible access to modENCODE data 
Nucleic Acids Research  2011;40(Database issue):D1082-D1088.
In an effort to comprehensively characterize the functional elements within the genomes of the important model organisms Drosophila melanogaster and Caenorhabditis elegans, the NHGRI model organism Encyclopaedia of DNA Elements (modENCODE) consortium has generated an enormous library of genomic data along with detailed, structured information on all aspects of the experiments. The modMine database ( described here has been built by the modENCODE Data Coordination Center to allow the broader research community to (i) search for and download data sets of interest among the thousands generated by modENCODE; (ii) access the data in an integrated form together with non-modENCODE data sets; and (iii) facilitate fine-grained analysis of the above data. The sophisticated search features are possible because of the collection of extensive experimental metadata by the consortium. Interfaces are provided to allow both biologists and bioinformaticians to exploit these rich modENCODE data sets now available via modMine.
PMCID: PMC3245176  PMID: 22080565
13.  The modENCODE Data Coordination Center: lessons in harvesting comprehensive experimental details 
The model organism Encyclopedia of DNA Elements (modENCODE) project is a National Human Genome Research Institute (NHGRI) initiative designed to characterize the genomes of Drosophila melanogaster and Caenorhabditis elegans. A Data Coordination Center (DCC) was created to collect, store and catalog modENCODE data. An effective DCC must gather, organize and provide all primary, interpreted and analyzed data, and ensure the community is supplied with the knowledge of the experimental conditions, protocols and verification checks used to generate each primary data set. We present here the design principles of the modENCODE DCC, and describe the ramifications of collecting thorough and deep metadata for describing experiments, including the use of a wiki for capturing protocol and reagent information, and the BIR-TAB specification for linking biological samples to experimental results. modENCODE data can be found at
Database URL:
PMCID: PMC3170170  PMID: 21856757
14.  Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project 
Gerstein, Mark B. | Lu, Zhi John | Van Nostrand, Eric L. | Cheng, Chao | Arshinoff, Bradley I. | Liu, Tao | Yip, Kevin Y. | Robilotto, Rebecca | Rechtsteiner, Andreas | Ikegami, Kohta | Alves, Pedro | Chateigner, Aurelien | Perry, Marc | Morris, Mitzi | Auerbach, Raymond K. | Feng, Xin | Leng, Jing | Vielle, Anne | Niu, Wei | Rhrissorrakrai, Kahn | Agarwal, Ashish | Alexander, Roger P. | Barber, Galt | Brdlik, Cathleen M. | Brennan, Jennifer | Brouillet, Jeremy Jean | Carr, Adrian | Cheung, Ming-Sin | Clawson, Hiram | Contrino, Sergio | Dannenberg, Luke O. | Dernburg, Abby F. | Desai, Arshad | Dick, Lindsay | Dosé, Andréa C. | Du, Jiang | Egelhofer, Thea | Ercan, Sevinc | Euskirchen, Ghia | Ewing, Brent | Feingold, Elise A. | Gassmann, Reto | Good, Peter J. | Green, Phil | Gullier, Francois | Gutwein, Michelle | Guyer, Mark S. | Habegger, Lukas | Han, Ting | Henikoff, Jorja G. | Henz, Stefan R. | Hinrichs, Angie | Holster, Heather | Hyman, Tony | Iniguez, A. Leo | Janette, Judith | Jensen, Morten | Kato, Masaomi | Kent, W. James | Kephart, Ellen | Khivansara, Vishal | Khurana, Ekta | Kim, John K. | Kolasinska-Zwierz, Paulina | Lai, Eric C. | Latorre, Isabel | Leahey, Amber | Lewis, Suzanna | Lloyd, Paul | Lochovsky, Lucas | Lowdon, Rebecca F. | Lubling, Yaniv | Lyne, Rachel | MacCoss, Michael | Mackowiak, Sebastian D. | Mangone, Marco | McKay, Sheldon | Mecenas, Desirea | Merrihew, Gennifer | Miller, David M. | Muroyama, Andrew | Murray, John I. | Ooi, Siew-Loon | Pham, Hoang | Phippen, Taryn | Preston, Elicia A. | Rajewsky, Nikolaus | Rätsch, Gunnar | Rosenbaum, Heidi | Rozowsky, Joel | Rutherford, Kim | Ruzanov, Peter | Sarov, Mihail | Sasidharan, Rajkumar | Sboner, Andrea | Scheid, Paul | Segal, Eran | Shin, Hyunjin | Shou, Chong | Slack, Frank J. | Slightam, Cindie | Smith, Richard | Spencer, William C. | Stinson, E. O. | Taing, Scott | Takasaki, Teruaki | Vafeados, Dionne | Voronina, Ksenia | Wang, Guilin | Washington, Nicole L. | Whittle, Christina M. | Wu, Beijing | Yan, Koon-Kiu | Zeller, Georg | Zha, Zheng | Zhong, Mei | Zhou, Xingliang | Ahringer, Julie | Strome, Susan | Gunsalus, Kristin C. | Micklem, Gos | Liu, X. Shirley | Reinke, Valerie | Kim, Stuart K. | Hillier, LaDeana W. | Henikoff, Steven | Piano, Fabio | Snyder, Michael | Stein, Lincoln | Lieb, Jason D. | Waterston, Robert H.
Science (New York, N.Y.)  2010;330(6012):1775-1787.
We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor–binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor–binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
PMCID: PMC3142569  PMID: 21177976
15.  Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema 
Ophthalmology  2010;117(6):1064-1077.e35.
Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
Multicenter, randomized clinical trial.
A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.
Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (≥24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
Main Outcome Measures
Best-corrected visual acuity and safety at 1 year.
The 1-year mean change (±standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9±11, P<0.001) and ranibizumab + deferred laser group (+9±12, P<0.001) but not in the triamcinolone + prompt laser group (+4±13, P=0.31) compared with the sham + prompt laser group (+3±13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.
PMCID: PMC2937272  PMID: 20427088
16.  Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema 
Ophthalmology  2010;117(5):946-953.
To identify factors associated with the visual acuity outcome following focal/grid photocoagulation for diabetic macular edema (DME) among eyes randomized to the focal/grid photocoagulation treatment group within the Diabetic Retinopathy Clinical Research Network ( trial comparing triamcinolone with focal/grid laser.
Multicenter, randomized clinical trial.
Three hundred thirty eyes with DME assigned to the focal/grid photocoagulation group, visual acuity 20/40 to 20/320 and optical coherence tomography (OCT) central subfield thickness ≥250 microns.
Eyes were treated with a protocol-defined photocoagulation technique, which was repeated at 4-month intervals for persistent or recurrent edema. Separate logistic regression models were used to evaluate the associations of demographic, clinical, OCT, and fundus photographic variables with visual acuity improvement or worsening of 10 or more letters from baseline to 2 years. The association of the initial visual acuity outcome after treatment with the subsequent visual acuity course also was evaluated.
Main Outcome Measures
Visual acuity measured with the electronic Early Treatment Diabetic Retinopathy Study method.
Worse baseline visual acuity was the only factor found to be associated with more frequent visual acuity improvement (P<0.001), and both greater baseline OCT-measured retinal volume (P=0.001) and better baseline visual acuity (P=0.009) were found to be associated with more frequent visual acuity worsening. Visual acuity outcomes were similar in eyes with and without prior macular or panretinal photocoagulation. The initial visual acuity outcome at 4 months was not generally predictive of the subsequent course. Many eyes that worsened 10 or more letters from baseline to 4 months subsequently improved, and many eyes that initially improved, subsequently worsened.
At this time, focal/grid photocoagulation remains the standard management for DME and these results do not alter this paradigm.
PMCID: PMC2864322  PMID: 20122739
17.  Preliminary Assessment of Celecoxib and Microdiode Pulse Laser Treatment of Diabetic Macular Edema 
Retina (Philadelphia, Pa.)  2010;30(3):459-467.
Inflammation may play an important role in the pathogenesis of diabetic macular edema, a major cause of vision loss in persons with diabetes. The purpose of this study was to evaluate combined antiinflammatory therapy and laser approaches for treating patients with diabetic macular edema.
In this prospective, factorial, randomized, multicenter trial, we compared cyclo-oxygenase-2 inhibitor (celecoxib) with placebo and diode grid laser with standard Early Treatment Diabetic Retinopathy Study focal laser treatment in 86 participants with diabetic macular edema. The primary outcome is change in visual acuity of ≥15 letters from baseline, and the secondary outcomes include a 50% reduction in the retinal thickening of diabetic macular edema measured by optical coherence tomography and a 50% reduction in leakage severity on fluorescein angiography.
Visual acuity and retinal thickening data from >2 years of follow-up did not show evidence of differences between the medical and laser treatments. However, participants assigned to the celecoxib group were more likely to have a reduction in fluorescein leakage when compared with the placebo group (odds ratio = 3.6; P < 0.01).
This short-term study did not find large visual function benefits of treatment with celecoxib or diode laser compared with those of standard laser treatment. A suggestive effect of celecoxib in reducing fluorescein leakage was observed.
PMCID: PMC3025102  PMID: 20038863
diabetic macular edema; celecoxib; diode grid laser photocoagulation; ETDRS type focal photocoagulation; optical coherence tomography
18.  Effects of Dilation on Electronic-ETDRS Visual Acuity (EVA) in Diabetic Patients 
To evaluate the effect of pupillary dilation on electronic-ETDRS visual acuity (EVA) in diabetic subjects and to assess post-dilation EVA as a surrogate for pre-dilation visual acuity (VA).
Methods and Design refraction and EVA were measured pre- and post-dilation in diabetic subjects by independent, masked examiners.
In 129 eyes of 66 subjects, median [25th, 75th percentiles] pre-dilation EVA score was 69 [54, 86] (Snellen-equivalent 20/40-1 [20/80-1, 20/20+1]). Pre-dilation VA was ≥20/20, 20/25-20/40, 20/50-20/80, and <20/80 in 29%, 19%, 26%, and 26% of eyes, respectively. Median EVA change post-dilation was -3 letters [-7, 0]. EVA change was ≥15 letters (≥ 3 ETDRS lines) in 9% of eyes and ≥10 letters (≥ 2 ETDRS lines) in 19% of eyes. Extent of change (range +12 to -25 letters) was associated with baseline VA. No relationship was identified between EVA change and gender, race, lens status, refractive error, DR severity, or primary cause of vision loss.
In an optimized clinical trial setting, there is a decline in best-corrected EVA after dilation in diabetic subjects. The large range and magnitude of VA change preclude using post-dilation EVA as a surrogate for undilated VA.
PMCID: PMC2762194  PMID: 18936147
19.  Comparison of Time-Domain OCT and Fundus Photographic Assessments of Retinal Thickening in Eyes with Diabetic Macular Edema 
To explore the correlation between optical coherence tomography (OCT) and stereoscopic fundus photographs (FP) for the assessment of retinal thickening (RT) in diabetic macular edema (DME) within a clinical trial.
OCT, FP, and best corrected visual acuity (VA) measurements were obtained in both eyes of 263 participants in a trial comparing two photocoagulation techniques for DME. Correlation coefficients (r) were calculated comparing RT measured by OCT, RT estimated from FP, and VA. Principal variables were central subfield retinal thickness (CSRT) obtained from the OCT fast macular map and DME severity assessed by a reading center using a seven-step photographic scale combining the area of thickened retina within 1 disc diameter of the foveal center and thickening at the center.
Medians (quartiles) for retinal thickness within the center subfield by OCT at baseline increased from 236 (214, 264) μm in the lowest level of the photographic scale to 517 (455, 598) μm in the highest level (r = 0.67). However, CSRT interquartile ranges were broad and overlapping between FP scale levels, and there were many outliers. Correlations between either modality and VA were weaker (r = 0.57 for CSRT, and r = 0.47 for the FP scale). OCT appeared to be more reproducible and more sensitive to change in RT between baseline and 1 year than was FP.
There was a moderate correlation between OCT and FP assessments of RT in patients with DME and slightly less correlation of either measure with VA. OCT and FP provide complementary information but neither is a reliable surrogate for VA.
PMCID: PMC2408888  PMID: 18316700
20.  Retinal expression, regulation, and functional bioactivity of prostacyclin-stimulating factor 
Journal of Clinical Investigation  2000;106(4):541-550.
Prostacyclin-stimulating factor (PSF) acts on vascular endothelial cells to stimulate the synthesis of the vasodilatory molecule prostacyclin (PGI2). We have examined the expression, regulation, and hemodynamic bioactivity of PSF both in whole retina and in cultured cells derived from this tissue. PSF was expressed in all retinal cell types examined in vitro, but immunohistochemical analysis revealed PSF mainly associated with retinal vessels. PSF expression was constitutive in retinal pericytes (RPCs) but could be modulated in bovine retinal capillary endothelial cells (RECs) by cell confluency, hypoxia, serum starvation, high glucose concentrations, or inversely by soluble factors present in early vs. late retinopathy, such as TGF-β, VEGF, or bFGF. In addition, RPC-conditioned media dramatically increased REC PGI2 production, a response inhibited by blocking PSF with a specific antisense oligodeoxynucleotide (ODN). In vivo, PGI2 increased retinal blood flow (RBF) in control and diabetic animals. Furthermore, the early drop in RBF during the initial weeks after inducing diabetes in rats, as well as the later increase in RBF, both correlated with levels of retinal PSF. RBF also responded to treatment with RPC-conditioned media, and this effect could be partially blocked using the antisense PSF ODN. We conclude that PSF expressed by ocular cells can induce PGI2, retinal vascular dilation, and increased retinal blood flow, and that alterations in retinal PSF expression may explain the biphasic changes in RBF observed in diabetes.
PMCID: PMC380244  PMID: 10953029

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