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1.  Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-year Results from a Comparative Effectiveness Randomized Clinical Trial 
Ophthalmology  2016;123(6):1351-1359.
Provide 2-year efficacy, safety and treatment results comparing three anti-vascular endothelial growth factor (anti-VEGF) agents for center-involved diabetic macular edema (DME) utilizing a standardized follow-up and retreatment regimen.
Randomized clinical trial.
660 participants with DME causing visual acuity (VA) impairment.
Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed as frequently as monthly utilizing a protocol-specific follow-up and retreatment regimen. Focal/grid laser was added if DME persisted and was not improving at 6 months or later. Visits occurred every 4 weeks during year 1, and were extended up to every 4 months thereafter when VA and macular thickness were stable and injections were deferred.
Main Outcome Measures
Change in VA (efficacy), ocular/systemic adverse events (safety), retreatment frequency.
Median numbers of injections in year 2 were 5, 6, 6 and over 2 years were 15, 16, 15 in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P=0.08). Focal/grid laser was administered in 41%, 64%, and 52%, respectively (aflibercept-bevacizumab: P<0.001, aflibercept-ranibizumab: P=0.04, bevacizumab-ranibizumab: P=0.01). From baseline to 2 years, mean VA letter score improved by 12.8 with aflibercept, 10.0 with bevacizumab, and 12.3 with ranibizumab. Treatment group differences varied by baseline VA (interaction P=0.02). With worse baseline VA (20/50-20/320), mean improvement was 18.3, 13.3, and 16.1 letters, respectively (aflibercept-bevacizumab: P=0.02, aflibercept-ranibizumab: P=0.18, ranibizumab-bevacizumab: P=0.18). With baseline VA 20/32-20/40, mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P>0.10 for pairwise comparisons). Anti-Platelet Trialists’ Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P=0.047: aflibercept-bevacizumab: P=0.34, aflibercept-ranibizumab: P=0.047, ranibizumab-bevacizumab: P=0.20; global P=0.09 adjusted for potential confounders).
All 3 anti-VEGF groups had visual acuity improvement at 2 years with a decreased number of injections in year 2. VA outcomes were similar among treatment groups for eyes with baseline VA 20/32-20/40. Among eyes with worse baseline VA, aflibercept, on average, had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.
PMCID: PMC4877252  PMID: 26935357
2.  Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema 
To compare long-term vision and anatomic effects of ranibizumab with prompt or deferred laser vs laser or triamcinolone + laser with very deferred ranibizumab in diabetic macular edema (DME).
Randomized clinical trial.
Eight hundred and twenty-eight study eyes (588 [67%] completed the 5-year visit), at 52 sites, with visual acuity 20/32 to 20/320 and DME involving the central macula were randomly assigned to intravitreous ranibizumab (0.5 mg) with either (1) prompt or (2) deferred laser; (3) sham injection + prompt laser; or (4) intravitreous triamcinolone (4 mg) + rompt laser. The latter 2 groups could initiate ranibizumab as early as 74 weeks from baseline, for persistent DME with vision impairment. The main outcome measures were visual acuity, optical coherence central subfield thickness, and number of injections through 5 years.
At 5 years mean (± standard deviation) change in Early Treatment Diabetic Retinopathy Study visual acuity letter scores from baseline in the ranibizumab + eferred laser (N = 111), ranibizumab + rompt laser (N = 124), laser/very deferred ranibizumab (N = 198), and triamcinolone + laser/very deferred ranibizumab (N = 125) groups were 10 ± 13, 8 ± 13, 5 ± 14, and 7 ± 14, respectively. The dif-ference (95% confidence interval) in mean change be-tween ranibizumab + eferred laser and laser/very deferred ranibizumab and triamcinolone D laser/very deferred ranibizumab was 4.4 (1.2-7.6, P = .001) and 2.8 (−0.9 to 6.5, P = .067), respectively, at 5 years.
Recognizing limitations of follow-up available at 5 years, eyes receiving initial ranibizumab therapy for center-involving DME were likely have better long-term vision improvements than eyes managed with laser or triamcinolone + aser followed by very deferred ranibizumab for persistent thickening and vision impairment.
PMCID: PMC4811755  PMID: 26802783
3.  Persistent Macular Thickening After Ranibizumab Treatment for Diabetic Macular Edema With Vision Impairment 
JAMA ophthalmology  2016;134(3):278-285.
The prevalence of persistent diabetic macular edema (DME) after months of anti–vascular endothelial growth factor therapy and its effect on visual acuity are unknown.
To assess subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab.
We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness ≥250 μm on time domain optical coherence tomography) through the 24-week visit.
Four monthly intravitreous injections of ranibizumab and then as needed per protocol.
Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 μm and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (≥2 line) gain or loss of visual acuity among those eyes.
The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9%-66.9%), and 40.1% (99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline.
These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (≥2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists.
PMCID: PMC4786449  PMID: 26746868
4.  Ranibizumab Plus Prompt or Deferred Laser for Diabetic Macular Edema in Eyes with Vitrectomy Prior to Anti-Vascular Endothelial Growth Factor Therapy 
Retina (Philadelphia, Pa.)  2015;35(12):2516-2528.
The approach to managing diabetic macular edema (DME) in eyes with prior vitrectomy is based on limited evidence. Therefore, an exploratory post-hoc assessment of 3-year data from eyes with and without vitrectomy prior to randomization in a trial that evaluated ranibizumab+prompt or deferred laser for DME is presented.
Visual acuity (VA) and ocular coherence tomography (OCT) outcomes were compared between eyes with and without prior vitrectomy.
At baseline eyes with prior vitrectomy (n = 25) had longer duration of diabetes, worse VA, less thickened central subfield measurements on OCT, and were more apt to have worse diabetic retinopathy severity level or prior treatment for macular edema or cataract surgery than eyes without a history of vitrectomy (n = 335). Analyses adjusted for these baseline imbalances did not identify substantial differences between eyes with and without prior vitrectomy at each annual visit through 3 years for the favorable VA, OCT central subfield thickness or volume outcomes, although OCT improvement appeared slower in vitrectomy eyes during the first year.
This study provides little evidence that the beneficial clinical outcomes for patients with center-involved DME treated with anti-VEGF are affected in the long term by prior vitrectomy.
PMCID: PMC4658280  PMID: 26035510
Vitrectomy; diabetic macular edema; ranibizumab; anti-VEGF; OCT; visual acuity; macular thickness
5.  Repeated Intravitreous Ranibizumab Injections for Diabetic Macular Edema and the Risk of Sustained IOP Elevation or Ocular Hypotensive Treatment 
JAMA ophthalmology  2015;133(5):589-597.
For the management of retinal disease, use of intravitreous injections of anti-vascular endothelial growth factor has increased. Recent reports have suggested that this therapy may cause persistent intraocular pressure (IOP) elevation and potentially increase the risk of glaucoma in patients with retinal disease.
To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments in eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab.
Main Outcome Measure(s)
The cumulative probability of sustained IOP elevation, defined as an IOP of at least 22 mmHg and an increase of at least 6 mmHg from baseline at 2 consecutive visits, or initiation or augmentation of ocular hypotensive therapy, through 3 years of follow up.
Design, Setting, and Participants
An exploratory analysis was conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Of 486 participants (582 eyes) with center-involved diabetic macular edema and no pre-existing open-angle glaucoma, 260 eyes were randomly assigned to receive sham injection plus focal/grid laser; 322 to ranibizumab plus deferred or prompt focal/grid laser.
The mean baseline IOP in both treatment groups was 16±3 mmHg (range 5–24 mm Hg). The cumulative probability of sustained IOP elevation or initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5% in the ranibizumab plus prompt or deferred laser group versus 3.4% in the sham plus laser group (difference = 6.1%, 99% CI: −0.2% to 12.3%; hazard ratio = 2.9, 99% CI: 1.0 to 7.9, P = 0.01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years was similar in each group.
In eyes with center-involved diabetic macular edema and no prior open angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment. Clinicians should be aware of this risk and consider this information when following patients who have received intravitreous injections of anti-vascular endothelial growth factor for the treatment of diabetic macular edema.
PMCID: PMC4496789  PMID: 25719991
6.  Reproducibility of Spectral Domain Optical Coherence Tomography Retinal Thickness Measurements and Conversion to Equivalent Time Domain Metrics in Diabetic Macular Edema 
JAMA ophthalmology  2014;132(9):1113-1122.
Advances in retinal imaging have led to the development of optical coherence tomography (OCT) instruments that incorporate spectral domain (SD) technology. Understanding measurement variability and relationships between retinal thickness measurements obtained on different machines is critical for proper use in clinical trials and clinical settings.
Evaluate reproducibility of retinal thickness measurements from OCT images obtained by time domain (TD) (Zeiss Stratus) and SD (Zeiss Cirrus and Heidelberg Spectralis) instruments and formulate equations to convert retinal thickness measurements from SD-OCT to equivalent values on TD-OCT.
Cross-sectional observational study. Each study eye underwent two replicate Stratus scans followed by two replicate Cirrus or Spectralis (real time image registration utilized) scans centered on the fovea.
Private and institutional practices
Diabetic persons with at least one eye with central-involved diabetic macular edema (DME), defined as Stratus central subfield thickness (CST)≥250μm. An additional normative cohort, individuals with diabetes but without DME, was enrolled.
Main Outcome Measure(s)
OCT CST and macular volume
The Bland-Altman coefficient of repeatability for relative change in CST (the degree of change that could be expected from measurement variability) was lower on Spectralis compared with Stratus and Cirrus scans (7%, 12–15%, and 14%, respectively). For each cohort, the initial Stratus CST was within 10% of the replicate Stratus measurement 92% of the time; the conversion equations predicted a Stratus CST within 10% of the observed thickness 86% and 89% of the time for Stratus/Cirrus and Stratus/Spectralis groups, respectively. The Bland-Altman limits of agreement for relative change in CST between machines (the degree of change that could be expected from measurement variability, combined within and between instrument variability) were 21% for Cirrus and 19% for Spectralis, comparing predicted versus actual Stratus measurement.
Conclusions and Relevance
Reproducibility appears better on Spectralis than Cirrus and Stratus. Conversion equations to transform Cirrus or Spectralis measurements to Stratus-equivalent values, within 10% of the observed Stratus thickness values, appear feasible. CST changes beyond 10% when using the same machine or 20% when switching machines, after conversion to Stratus equivalents, are likely due to a change in retinal thickness and not measurement error.
PMCID: PMC4366946  PMID: 25058482
7.  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
8.  Exploratory Analysis of Effect of Intravitreal Ranibizumab or Triamcinolone on Worsening of Diabetic Retinopathy in a Randomized Clinical Trial 
JAMA ophthalmology  2013;131(8):1033-1040.
The standard care for proliferative diabetic retinopathy (PDR) usually is panretinal photocoagulation (PRP), an inherently destructive treatment which can cause iatrogenic vision loss. Therefore, evaluating effects of therapies for diabetic macular edema (DME) on development or worsening of PDR might lead to new therapies for PDR.
To evaluate effects of intravitreal ranibizumab or triamcinolone acetonide, administered to treat DME, on worsening of diabetic retinopathy.
Exploratory analysis was performed on worsening of retinopathy, defined as one or more of the following: (1) worsening from no PDR to PDR, (2) worsening of 2 or more severity levels on reading center assessment of fundus photographs in eyes without PDR at baseline, (3) having PRP, (4) vitreous hemorrhage, or (5) vitrectomy for treatment of PDR.
Community- and university-based ophthalmology practices.
Subjects with central-involved diabetic macular edema causing visual acuity impairment.
Eyes were assigned randomly to sham+prompt focal/grid laser, 0.5-mg intravitreal ranibizumab+prompt or deferred (≥24 weeks) laser, or 4-mg intravitreal triamcinolone+prompt laser.
Main Outcome Measure
3-year cumulative probabilities for retinopathy worsening.
For eyes without PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening (P value comparison with sham+prompt laser) were 23% using sham+prompt laser, 18% with ranibizumab+prompt laser (P = 0.25), 7% with ranibizumab+deferred laser (P = 0.001), and 37% with triamcinolone+prompt laser (P = 0.10). For eyes with PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening were 40%, 21% (P = 0.05), 18% (P = 0.02), and 12% (P<0.001), respectively.
Conclusions and Relevance
Intravitreal ranibizumab appears to be associated with a reduced risk of diabetic retinopathy worsening in eyes with or without PDR. Intravitreal triamcinolone also appears to be associated with a reduced risk of PDR worsening. These findings suggest that use of these drugs to prevent worsening of diabetic retinopathy may be feasible. Given the exploratory nature of these analyses, the risk of endophthalmitis following intravitreal injections, and that intravitreal triamcinolone can cause cataract or glaucoma, use of these treatments to reduce the rates of worsening of retinopathy, with or without PDR, does not seem warranted at this time.
PMCID: PMC4162127  PMID: 23807371
9.  Comparison of Time- and Spectral-Domain Optical Coherence Tomography in Management of Diabetic Macular Edema 
Some clinical trials that proved the benefits of anti-VEGF therapy for diabetic macular edema (DME) based retreatment decisions on visual acuity and time-domain ocular coherence tomography (TD-OCT) central subfield thickness changes since the last treatment. This study assessed the impact of TD-OCT followed by spectral domain (SD)-OCT on as needed treatment decision-making in the management of DME with anti-VEGF medications.
Patients previously treated for DME with anti-VEGF medications in the Retina Division of the Wilmer Eye Institute, following an institutional review board–approved informed consent process, underwent clinical examination, TD-, and SD-OCT imaging. Their retina specialists recorded whether additional anti-VEGF therapy was recommended and their level of certainty in the decision after performing a clinical examination and reviewing a TD-OCT, and then again after reviewing a SD-OCT.
Data were collected for 129 treatment decision pairs involving 67 eyes from 46 subjects. Nonconcordant decisions occurred in 9 (7%) treatment decision pairs. In 7 of these (5%, 95% confidence interval [CI]: 2%–11%), the addition of SD-OCT changed the retina specialist's decision from not recommending to recommending retreatment. The addition of SD-OCT increased the certainty of the retina specialist in 36% (95% CI: 27%–45%) of all treatment decision pairs.
Spectral-domain OCT does not appear to change the ultimate treatment decision or increase the level of certainty of the retina specialist relative to TD-OCT in most cases of DME under anti-VEGF management in clinical practice. The few nonconcordant decisions appear to trend toward recommending more anti-VEGF therapy following SD-OCT.
Spectral-domain optical coherence tomography (SD-OCT) does not appear to change the ultimate treatment decision or increase the level of certainty of the retina specialist relative to time-domain OCT in most cases of diabetic macular edema under anti-VEGF management in clinical practice.
PMCID: PMC3945899  PMID: 24526445
optical coherence tomography; macular edema; diabetic retinopathy
11.  Observational study of subclinical diabetic macular edema 
Eye  2012;26(6):833-840.
To determine the rate of progression of eyes with subclinical diabetic macular edema (DME) to clinically apparent DME or DME necessitating treatment during a 2-year period.
In all, 43 eyes from 39 study participants with subclinical DME, defined as absence of foveal center edema as determined with slit lamp biomicroscopy but a center point thickness (CPT) between 225 and 299 μm on time domain (Stratus, Carl Zeiss Meditec) optical coherence tomography (OCT) scan, were enrolled from 891 eyes of 582 subjects screened. Eyes were evaluated annually for up to 2 years for the primary outcome, which was an increase in OCT CPT of at least 50 μm from baseline and a CPT of at least 300 μm, or treatment for DME (performed at the discretion of the investigator).
The cumulative probability of meeting an increase in OCT CPT of at least 50 μm from baseline and a CPT of at least 300 μm, or treatment for DME was 27% (95% confidence interval (CI): 14%, 38%) by 1 year and 38% (95% CI: 23%, 50%) by 2 years.
Although subclinical DME may be uncommon, this study suggests that between approximately one-quarter and one-half of eyes with subclinical DME will progress to more definite thickening or be judged to need treatment for DME within 2 years after its identification.
PMCID: PMC3376297  PMID: 22441027
diabetic macular edema; optical coherence tomography; subclinical diabetic macular edema
12.  Retinal Thickness in People with Diabetes and Minimal or No Diabetic Retinopathy: Heidelberg Spectralis Optical Coherence Tomography 
To evaluate macular thickness in people with diabetes but minimal or no retinopathy using Heidelberg Spectralis optical coherence tomography (OCT).
In a multicenter, cross-sectional study of mean retinal thickness, on Spectralis OCT in the nine standard OCT subfields, spanning a zone with 6-mm diameter, center point, and total retinal volume were evaluated. Central subfield (CSF) thickness was evaluated for association with demographic and clinical factors. Stratus OCT scans also were performed on each participant.
The analysis included 122 eyes (122 participants) with diabetes and no (n = 103) or minimal diabetic retinopathy (n = 19) and no macular retinal thickening on clinical exam. Average CSF thickness was 270 ± 24 μm. Central subfield thickness was significantly greater in males relative to females (mean 278 ± 23 μm vs. 262 ± 22 μm, P < 0.001). After adjusting for gender, no additional factors were found to be significantly associated with CSF thickness (P > 0.10). Mean Stratus OCT CSF thickness was 199 ± 24 μm.
Mean CSF thickness is approximately 70 μm thicker when measured with Heidelberg Spectralis OCT as compared with Stratus OCT among individuals with diabetes in the absence of retinopathy or with minimal nonproliferative retinopathy and a normal macular architecture. CSF thickness values ≥320 μm for males and 305 μm for females (∼2 SDs above the average for this normative cohort) are proposed as gender-specific thickness levels to have reasonable certainty that diabetic macular edema involving the CSF is present using Spectralis measurements.
Central subfield (CSF) thickness is approximately 70 μm greater on Spectralis than on Stratus OCT among individuals with diabetes and minimal or no retinopathy. Proposed sex-specific CSF minimums for trials of center involved diabetic macular edema using Spectralis, are 320 μm for males and 305 μm for females.
PMCID: PMC3522439  PMID: 23132803
13.  Association of Fluorescein Angiographic Features with Visual Acuity and with Optical Coherence Tomographic and Stereoscopic Color Fundus Photographic Features of Diabetic Macular Edema in a Randomized Clinical Trial 
Retina (Philadelphia, Pa.)  2010;30(10):1627-1637.
Fluorescein angiography (FA) has been performed as part of the management of diabetic macular edema (DME) for many years. Its current role relative to the role of optical coherence tomography (OCT) is not well defined.
To evaluate the associations of FA features with visual acuity, and with OCT, and fundus photographic characteristics in eyes with DME.
In a clinical trial, conducted by the Diabetic Retinopathy Clinical Research Network to compare two methods of laser photocoagulation to treat DME, FA (film and digital), color photographs, OCT, and visual acuity measurements were obtained at baseline and at 1 year. Grading of morphologic features was performed at a reading center. Reproducibility of FAs was assessed and the correlations of FA features with visual acuity, OCT, and color photograph features were computed.
From 79 clinical sites, data of 323 study eyes and 203 fellow non-study eyes were analyzed. Fluorescein leakage area at baseline was associated with reduced visual acuity, increased OCT measures of retinal thickness and volume, and color photographic measurements of retinal thickening (r = 0.33 – 0.58). No important associations were found with changes from baseline to 12 months in these parameters or with any of the other variables analyzed.
Fluorescein leakage is associated with visual acuity and some OCT and color photographic variables. We did not identify any unique FA variables that had a stronger association with visual acuity than OCT measures of retinal thickness. These data may be useful to investigators planning future DME clinical trials.
PMCID: PMC3489031  PMID: 20706173
Fluorescein angiography; diabetic macular edema; optical coherence tomography; fluorescein angiographic leakage; visual acuity; cystoid macular edema; digital fundus photography
14.  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
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.  Effect of Focal/Grid Photocoagulation on Visual Acuity and Retinal Thickening in Eyes with Non-Center Involved Clinically Significant Diabetic Macular Edema 
Retina (Philadelphia, Pa.)  2009;29(5):613-617.
To report visual acuity and anatomic changes from baseline to 12 months after modified ETDRS style (focal/grid) photocoagulation in eyes with non-center involved (non-CI) clinically significant macular edema (CSME).
Visual acuity, optical coherence tomography, fluorescein angiography, and fundus photography data were analyzed from eyes with non-CI CSME treated with modified ETDRS style (focal/grid) photocoagulation in a Diabetic Retinopathy Clinical Research Network trial.
Among the 22 eyes (of 22 patients) with 12 month follow-up, median visual acuity letter score remained within one letter of baseline over 12 months. The median central subfield retinal thickness decreased by 10μm, median total macular volume decreased by 0.2mm3, and median fluorescein leakage area within the grid decreased by 0.7 disc areas.
We are unaware of any other systematic evaluation of eyes with non-CI CSME since the ETDRS. Focal/grid laser in these non-CI eyes was associated with relatively stable visual acuity and retinal thickness measurements, and decreased fluorescein leakage area at 1 year. One year visual acuity results are consistent with those published by the ETDRS, despite the intervening significant differences in the management of diabetes. Although this was a small study without a concurrent control group, the ETDRS recommendation to consider focal/grid laser in eyes with non-CI CSME still seems appropriate.
PMCID: PMC2735881  PMID: 19373126
Diabetic macular edema; focal/grid laser photocoagulation
17.  Diabetic Macular Edema: What is Focal and What is Diffuse? 
American journal of ophthalmology  2008;146(5):649-655.e6.
To review the available information on classification of diabetic macular edema (DME) as focal or diffuse.
Interpretive essay.
Literature review and interpretation.
The terms focal and diffuse diabetic macular edema are frequently used without clear definitions. Published definitions often use different examination modalities and are often inconsistent. Evaluating published information on prevalence of focal and diffuse DME, response of focal and diffuse DME to treatments, and importance of focal and diffuse DME in assessing prognosis is hindered because the terms are inconsistently employed. A newer vocabulary may be more constructive, one that describes discrete components of the concepts such as extent and location of macular thickening, involvement of the center of the macula, quantity and pattern of lipid exudates, source of fluorescein leakage, and regional variation in macular thickening, and that distinguishes these terms from the use of the term focal when describing one type of photocoagulation technique. Developing methods for assessing component variables that can be used in clinical practice and establishing reproducibility of the methods will be important tasks.
Little evidence exists that characteristics of DME described by the terms focal and diffuse help to explain variation in visual acuity or response to treatment. It is unresolved whether a concept of focal and diffuse DME will prove clinically useful despite frequent usage of the terms when describing management of DME. Further studies to address the issues are needed.
PMCID: PMC2785449  PMID: 18774122
18.  Optical Coherence Tomography Measurements and Analysis Methods in Optical Coherence Tomography Studies of Diabetic Macular Edema 
Ophthalmology  2008;115(8):1366-1371.e1.
To evaluate optical coherence tomography (OCT) measurements and methods of analysis of OCT data in studies of diabetic macular edema (DME).
Associations of pairs of OCT variables and results of three analysis methods using data from two studies of DME.
Two hundred sixty-three subjects from a study of modified Early Treatment of Diabetic Retinopathy Study (mETDRS) versus modified macular grid (MMG) photocoagulation for DME and 96 subjects from a study of diurnal variation of DME.
Correlations were calculated for pairs of OCT variables at baseline and for changes in the variables over time. Distribution of OCT measurement changes, predictive factors for OCT measurement changes, and treatment group outcomes were compared when three measures of change in macular thickness were analyzed: absolute change in retinal thickness, relative change in retinal thickness, and relative change in retinal thickening.
Main Outcome Measures
Concordance of results using different OCT variables and analysis methods.
Center point thickness correlated highly with central subfield mean thickness (CSMT) at baseline (0.98–0.99). The distributions of changes in CSMT were approximately normally distributed for absolute change in retinal thickness and relative change in retinal thickness, but not for relative change in retinal thickening. The macular thinning in the mETDRS group was significantly greater than in the MMG group when absolute change in retinal thickness was used, but not when relative change in thickness and relative change in thickening were used. Relative change in macular thickening provides unstable data in eyes with mild degrees of baseline thickening, unlike the situation with absolute or relative change in retinal thickness.
Central subfield mean thickness is the preferred OCT measurement for the central macula because of its higher reproducibility and correlation with other measurements of the central macula. Total macular volume may be preferred when the central macula is less important. Absolute change in retinal thickness is the preferred analysis method in studies involving eyes with mild macular thickening. Relative change in thickening may be preferable when retinal thickening is more severe.
PMCID: PMC2748270  PMID: 18675696
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.  Agreement Between Clinician and Reading Center Gradings of Diabetic Retinopathy Severity Level at Baseline in a Phase 2 Study of Intravitreal Bevacizumab for Diabetic Macular Edema 
Retina (Philadelphia, Pa.)  2008;28(1):36-40.
Summary Statement
Comparison of clinician and reading center assessments of diabetic retinopathy severity demonstrated moderate agreement on a 4-step scale that pooled a majority of cases in a single broad step of the scale.
To evaluate agreement in diabetic retinopathy severity classification by retina specialists performing ophthalmoscopy versus Reading Center (RC) grading of 7-field stereoscopic fundus photographs in a phase 2 clinical trial of intravitreal bevacizumab for center-involved diabetic macular edema.
Clinicians’ grading scale used 4 levels: microaneurysms only, mild/moderate non-proliferative diabetic retinopathy (NPDR), severe NPDR, and proliferative diabetic retinopathy (PDR) or prior panretinal photocoagulation (PRP) or both. The Reading Center scale used 8 levels: microaneurysms only, mild NPDR, moderate NPDR, moderately severe NPDR, severe NPDR, mild PDR, moderate PDR, and high-risk PDR. Percent agreement and kappa statistic were defined by collapsing RC categories to match those used by clinicians.
There was agreement in 89/118 eyes (75%) with kappa=0.55 (95% confidence interval: [0.41, 0.68]). In 6 eyes, disagreements were of potential substantial clinical importance: 5 eyes with subtle retinal neovascularization and 1 with a small preretinal hemorrhage identified only in photographs.
Clinician grading of retinopathy severity had moderate agreement with Reading Center grading and might be useful for placing eyes into broad baseline categories.
PMCID: PMC2377181  PMID: 18185135
Diabetic retinopathy level; Diabetic retinopathy severity; fundus photograph grading; non-proliferative diabetic retinopathy; ophthalmoscopic grading; proliferative diabetic retinopathy
21.  Visible light and risk of age-related macular degeneration. 
Sunlight exposure has been suggested as a cause of AMD. To examine this, we collected detailed histories of ocular sun exposure in 838 watermen who work on the Chesapeake Bay. The presence and severity of AMD was assessed in stereo macular photographs. Macular changes were classified into four grades of increasing severity ranging from the presence of 5 or more drusen (AMD-1) to extensive geographic atrophy or disciform scars (AMD-4). Previously, we found no association between AMD and ocular exposure to either UV-B (290 to 320 nm) or two bands of UV-A (320 to 340 nm and 340 to 400 nm). We have undertaken further analysis to determine whether ocular exposure to violet light (400 to 450 nm), blue light (400 to 500 nm), or all visible light (400 to 700 nm) was associated with AMD. Ocular exposure was estimated using model computations of ambient irradiance and estimates of the ratio of ocular to ambient exposure. Compared to age-matched controls, established cases (AMD-4), but not milder cases, had significantly higher exposure to both blue and visible light over the preceding 20 years (Wilcoxon sign rank test, P = 0.027). There was no difference in exposure at younger ages. These data suggest that high levels of exposure to blue and visible light late in life may be important in causing AMD.
PMCID: PMC1298584  PMID: 2095019
22.  Tracking excited–state charge and spin dynamics in iron coordination complexes 
Nature  2014;509(7500):345-348.
Crucial to many light-driven processes in transition metal complexes is the absorption and dissipation of energy by 3d electrons1–4. But a detailed understanding of such non-equilibrium excited-state dynamics and their interplay with structural changes is challenging: a multitude of excited states and possible transitions result in phenomena too complex to unravel when faced with the indirect sensitivity of optical spectroscopy to spin dynamics5 and the flux limitations of ultrafast X-ray sources6,7. Such a situation exists for archetypal polypyridyl iron complexes, such as [Fe(2,2′-bipyridine)3]2+, where the excited-state charge and spin dynamics involved in the transition from a low- to a high-spin state (spin crossover) have long been a source of interest and controversy6–15. Here we demonstrate that femtosecond resolution X-ray fluorescence spectroscopy, with its sensitivity to spin state, can elucidate the spin crossover dynamics of [Fe(2,2′-bipyridine)3]2+ on photoinduced metal-to-ligand charge transfer excitation. We are able to track the charge and spin dynamics, and establish the critical role of intermediate spin states in the crossover mechanism. We anticipate that these capabilities will make our method a valuable tool for mapping in unprecedented detail the fundamental electronic excited-state dynamics that underpin many useful light-triggered molecular phenomena involving 3d transition metal complexes.
PMCID: PMC5668134  PMID: 24805234
23.  Brain derived neurotrophic factor and serotonin transporter binding as markers of clinical response to fluoxetine therapy in children with autism 
Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has shown favorable effects in some children with autism. There are no previous studies evaluating the connection between clinical outcome and markers of clinical response to fluoxetine treatment. We examined serum brain derived neurotrophic factor (BDNF) concentrations and serotonin transporter (SERT) binding in the medial frontal cortex and midbrain, measured by single photon emission computed tomography (SPECT) scanning, in a group of 13 autistic children and adolescents (12 males, one female; age 5-16 years), who were treated for six months with fluoxetine at a dose range of 10–40 mg/day. Clinical response was evaluated by the Autism Treatment Evaluation Checklist (ATEC). Serum concentrations of BDNF and SERT binding were measured at baseline and two months after termination of fluoxetine treatment.
At baseline, before starting fluoxetine treatment, the serum concentration of BDNF had a bimodal distribution in the autism group with either a low concentration (n = 8, mean 1497 pg/mL) or a high concentration (n = 5, mean 14062 pg/mL) with respect to controls (n = 15, mean 9652 pg/mL), and SERT binding was uniformly low in the autistic subjects in medial frontal cortex and midbrain. Fluoxetine treatment led to positive effects in several aspects of communication, socialization and cognitive awareness, with 6 out 13 subjects being particularly good responders. These six also had a significant decrease in BDNF (p = 0.03) and minimal change in SERT binding after therapy. The other 7 subjects showed a trend towards an increase in BDNF and SERT binding.
Our results indicate that fluoxetine may improve core autistic symptoms, and that this clinical response is linked to a decrease in serum BDNF.
PMCID: PMC5650230
Autism; Brain derived neurotrophic factor; Clinical outcome; Fluoxetine; Serotonin transporter; Single photon emission computed tomography
24.  Performance of the ATLAS track reconstruction algorithms in dense environments in LHC Run 2 
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With the increase in energy of the Large Hadron Collider to a centre-of-mass energy of 13 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {TeV}$$\end{document}TeV for Run 2, events with dense environments, such as in the cores of high-energy jets, became a focus for new physics searches as well as measurements of the Standard Model. These environments are characterized by charged-particle separations of the order of the tracking detectors sensor granularity. Basic track quantities are compared between 3.2 fb\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{-1}$$\end{document}-1 of data collected by the ATLAS experiment and simulation of proton–proton collisions producing high-transverse-momentum jets at a centre-of-mass energy of 13 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {TeV}$$\end{document}TeV. The impact of charged-particle separations and multiplicities on the track reconstruction performance is discussed. The track reconstruction efficiency in the cores of jets with transverse momenta between 200 and 1600 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {GeV}$$\end{document}GeV is quantified using a novel, data-driven, method. The method uses the energy loss, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text { d}}{} \textit{E}/d\textit{x}$$\end{document}dE/dx, to identify pixel clusters originating from two charged particles. Of the charged particles creating these clusters, the measured fraction that fail to be reconstructed is \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$0.061 \pm 0.006\ {\text {(stat.)}} \pm 0.014\ {\text {(syst.)}}$$\end{document}0.061±0.006(stat.)±0.014(syst.) and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$0.093 \pm 0.017\ {\text {(stat.)}}\pm 0.021\ {\text {(syst.)}}$$\end{document}0.093±0.017(stat.)±0.021(syst.) for jet transverse momenta of 200–400 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {GeV}$$\end{document}GeV and 1400–1600 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {GeV}$$\end{document}GeV, respectively.
PMCID: PMC5638380
25.  Clinical Experience with Telavancin for the Treatment of Patients with Bone and Joint Infections: Preliminary Results from the Telavancin Observational Use Registry (TOUR™) 
Open Forum Infectious Diseases  2017;4(Suppl 1):S90.
Telavancin (TLV) is a lipoglycopeptide antibacterial active against a wide range of Gram-positive pathogens, including methicillin-sensitive and -resistant Staphylococcus aureus (MSSA and MRSA). Bone and joint infections represent a complex set of diseases requiring prolonged antimicrobial therapy and are commonly caused by Gram-positive pathogens, including S. aureus.
The Telavancin Observational Use Registry (TOUR™) is a multicenter chart review study designed to characterize infection types, pathogens, and outcomes of patients treated with TLV in clinical practice. Data from TOUR were used to characterize a subset of bone and joint patients. Clinical data including patient demographics, pathogens, outcomes, and adverse events (AEs) were analyzed. Clinical outcomes were determined by investigators’ assessment.
As of March 31, 2017, data for more than 1000 patients were collected from 46 sites. Of these, 286 patients were treated for bone and joint infections. Among these 286 patients, median age was 57 years (range 18−92 years) and 27% (n = 76) were aged ≥65 years, 66% (n = 189) were male, and 84% (n = 241) were White. The median body mass index was 30.0 kg/m2 (range 19.2−62.7 kg/m2). MRSA was the most commonly isolated pathogen at baseline (38%; n = 108). The median TLV daily dose and duration of treatment were 750 mg (range 300−1500 mg) or 8.3 mg/kg (range 3.7−16.9 mg/kg) and 26.5 days (range 1−119 days), respectively. Telavancin was used as second-line therapy in 71% (n = 202) of patients, and the majority of patients (66%; n = 189) were treated as outpatients. Overall, 71% (n = 203) of patients were cured or improved to step-down therapy, 9% (n = 25) failed treatment, 10% (n = 30) had an indeterminate clinical outcome at end of therapy (EOT), and 10% (n = 28) had missing or undocumented outcomes. Among the patients who had outcome assessment (n = 258) at EOT, 79% were cured or improved to step-down therapy and 10% failed therapy. AEs were reported in 45 patients; six reported a serious AE, and 32 had AEs leading to TLV discontinuation.
In a real-world setting, once-daily TLV produced a positive clinical response in >70% of patients with difficult-to-treat bone and joint infections and may represent an alternative treatment option.
C. Sims, Theravance Biopharma US, Inc.: Investigator and Speaker’s Bureau, Research grant, Research support and Speaker honorarium. A. Bressler, Theravance Biopharma US, Inc.: Investigator, Scientific Advisor, Shareholder and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. M. Lacy, Theravance Biopharma US, Inc.: Employee, Salary. A. Osmukhina, Theravance Biopharma US, Inc.: Employee and Shareholder, RSU, Stock Options and Salary. B. Castaneda-Ruiz, Theravance Biopharma US, Inc.: Employee and Shareholder, Salary
PMCID: PMC5632217

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