Multivariate Models to Diagnose Early Referral-Warranted Retinopathy of Prematurity With Handheld Optical Coherence Tomography.

Purpose: The purpose of this study was to create multivariate models predicting early referral-warranted retinopathy of prematurity (ROP) using non-contact handheld spectral-domain optical coherence tomography (OCT) and demographic data. Methods: Between July 2015 and February 2018, infants ≤1500 grams birth weight or ≤30 weeks gestational age from 2 academic neonatal intensive care units were eligible for this study. Infants were excluded if they were too unstable to participate in ophthalmologic examination (2), had inadequate image quality (20), or received prior ROP treatment (2). Multivariate models were created using demographic variables and imaging findings to identify early referral-warranted ROP (referral-warranted ROP and/or pre-plus disease) by routine indirect ophthalmoscopy. Results: A total of 167 imaging sessions of 71 infants (45% male infants, gestational age 28.2+/-2.8 weeks, and birth weight 995.6+/-292.0 grams) were included. Twelve of 71 infants (17%) developed early referral-warranted ROP. The area under the receiver operating characteristic curve (AUC) was 0.94 for the generalized linear mixed model (sensitivity = 95.5% and specificity = 80.7%) and 0.83 for the machine learning model (sensitivity = 91.7% and specificity = 77.8%). The strongest variables in both models were birth weight, image-based Vitreous Opacity Ratio (an estimate of opacity density), vessel elevation, and hyporeflective vessels. A model using only birth weight and gestational age yielded an AUC of 0.68 (sensitivity = 77.3% and specificity = 63.4%), and a model using only imaging biomarkers yielded 0.88 (sensitivity = 81.8% and specificity = 84.8%). Conclusions: A generalized linear mixed model containing handheld OCT biomarkers can identify early referral-warranted ROP. Machine learning produced a less optimal model. Translational Relevance: With further validation, this work may lead to a better-tolerated ROP screening tool.

Vitreous opacities in infants born full-term and preterm by handheld swept-source optical coherence tomography.

PURPOSE: To compare vitreous opacity density in infants born at term and in infants born prematurely using an investigational handheld swept-source optical coherence tomography (SS-OCT). METHODS: Infants born at term underwent imaging once between 12 and 48 hours after birth; infants born prematurely were imaged at each routine retinopathy of prematurity (ROP) examination. Three masked, trained graders analyzed images. Semiautomated methods were used to quantify vitreous opacity density, which was correlated with ROP severity based on indirect ophthalmoscopy, other SS-OCT findings, and medical comorbidities. RESULTS: Between April 2018 and June 2019, 251 SS-OCT imaging sessions were performed on 78 infants (49% female; 36% preterm, with mean birth weight of 1018 ± 338 g and gestational age of 28.6 ± 3.2 weeks). All SS-OCT sessions produced images of adequate quality. Punctate vitreous opacities were present in 25 of 28 term infants (89%) and 41 of 50 premature infants (82%). Dice coefficient and F1 scores for intergrader agreement were 0.99 ± 0.03 and 0.77 ± 0.31, respectively. Vitreous opacity density was 0.118 ± 0.187 in prematurely born infants and 0.031 ± 0.118 in infants born at term (P = 0.009). In the former, vitreous opacity density was associated with ROP zone (P = 0.044) and stage (P = 0.031), intraventricular hemorrhage (P = 0.028), subchorionic hemorrhage (P = 0.026), and African American race (P = 0.023). In the latter, vitreous opacity density was associated with maternal diabetes (P = 0.049). CONCLUSIONS: Our investigational handheld SS-OCT achieved high-quality vitreoretinal images. In our study cohort, punctate vitreous opacities were a frequent finding in infants born at term and those born prematurely, with increased density in those born prematurely, particularly those with severe ROP.

Vitreous Findings by Handheld Spectral-Domain OCT Correlate with Retinopathy of Prematurity Severity.

PURPOSE: To evaluate the association between retinopathy of prematurity (ROP) and vitreous findings in premature infants detected by handheld spectral-domain (SD) OCT. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Consecutive sample of 92 premature infants requiring ROP screening at 2 academic neonatal intensive care units between July 2015 and March 2018. METHODS: Infants underwent handheld SD OCT at the time of routine ROP examinations. Two masked, trained graders analyzed right-eye vitreoretinal findings, including semiautomated quantification of punctate hyperreflective vitreous opacities within 5 foveal or parafoveal B-scans (vitreous opacity ratio). MAIN OUTCOME MEASURES: Excluding posttreatment data, vitreous findings were compared with clinical ROP diagnoses. RESULTS: Agreement between image graders for all vitreoretinal findings was 91% (κ = 0.86; 95% confidence interval, 0.82-0.90; P < 0.001). Among 92 infants undergoing 280 imaging sessions (52% male; mean gestational age, 28.3 ± 2.8 weeks; mean birthweight, 1014.5 ± 285.0 g), 36 of 92 (39%) demonstrated ROP. Punctate hyperreflective vitreous opacities were identified in 61 of 92 infants (66%). The presence of punctate hyperreflective vitreous opacities at least once was associated with a diagnosis of ROP (62% vs. 29% without opacities; P = 0.003), maximum ROP stage (P = 0.001), preplus or plus disease (24% vs. 5%; P = 0.005), and type 1 disease (14% vs. 2%; P = 0.03). Among 29 infants (45 imaging sessions) with right-eye punctate hyperreflective vitreous opacities, the vitreous opacity ratio from 2 graders (F1 score, 0.82 ± 0.36; Dice coefficient, 0.97 ± 0.04) correlated with ROP stage (P = 0.02). Tractional vitreous bands on imaging correlated with plus disease status (29% vs. 5% without bands; P = 0.05). CONCLUSIONS: Punctate hyperreflective vitreous opacities and tractional vitreous bands predict the presence and severity of ROP. Further studies should explore handheld OCT as a noninvasive ROP screening tool.

Measuring and compensating for ocular longitudinal chromatic aberration.

It is well known that the eye's optics and media introduce monochromatic and chromatic aberration unique to each individual. Once monochromatic aberrations are removed with adaptive optics (AO), longitudinal chromatic aberrations (LCA) define the fidelity for multi-wavelength, high-resolution vision testing and retinal imaging. AO vision simulation systems and AO scanning laser ophthalmoscopes (AOSLOs) typically use the average population LCA to compensate for focus offsets between different wavelengths precluding fine, individualized control. The eye's LCA has been characterized extensively using either subjective (visual perception) or objective (imaging) methods. Classically, these have faced inconsistencies due to extraneous factors related to depth of focus, monochromatic aberration, and wavelength-dependent light interactions with retinal tissue. Here, we introduce a filter-based Badal LCA compensator that offers the flexibility to tune LCA for each individual eye and demonstrate its feasibility for vision testing and imaging using multiple wavelengths simultaneously. Incorporating the LCA compensator in an AOSLO allowed the first objective measurements of LCA based on confocal, multi-wavelength foveal cone images and its comparison to measures obtained subjectively. The objective LCA thus obtained was consistent with subjective estimates in the same individuals and hence resolves the prior discrepancies between them. Overall, the described approach will benefit applications in retinal imaging and vision testing where the focus of multiple wavelengths needs to be controlled independently and simultaneously.

Foveal Crowding Resolved.

Crowding is the substantial interference of neighboring items on target identification. Crowding with letter stimuli has been studied primarily in the visual periphery, with conflicting results for foveal stimuli. While a cortical locus for peripheral crowding is well established (with a large spatial extent up to half of the target eccentricity), disentangling the contributing factors in the fovea is more challenging due to optical limitations. Here, we used adaptive optics (AO) to overcome ocular aberrations and employed high-resolution stimuli to precisely characterize foveal lateral interactions with high-contrast letters flanked by letters. Crowding was present, with a maximal edge-to-edge interference zone of 0.75-1.3 minutes at typical unflanked performance levels. In agreement with earlier foveal contour interaction studies, performance was non-monotonic, revealing a recovery effect with proximal flankers. Modeling revealed that the deleterious effects of flankers can be described by a single function across stimulus sizes when the degradation is expressed as a reduction in sensitivity (expressed in Z-score units). The recovery, however, did not follow this pattern, likely reflecting a separate mechanism. Additional analysis reconciles multiple results from the literature, including the observed scale invariance of center-to-center spacing, as well as the size independence of edge-to-edge spacing.

Circuitry to explain how the relative number of L and M cones shapes color experience.

The wavelength of light that appears unique yellow is surprisingly consistent across people even though the ratio of middle (M) to long (L) wavelength sensitive cones is strikingly variable. This observation has been explained by normalization to the mean spectral distribution of our shared environment. Our purpose was to reconcile the nearly perfect alignment of everyone's unique yellow through a normalization process with the striking variability in unique green, which varies by as much as 60 nm between individuals. The spectral location of unique green was measured in a group of volunteers whose cone ratios were estimated with a technique that combined genetics and flicker photometric electroretinograms. In contrast to unique yellow, unique green was highly dependent upon relative cone numerosity. We hypothesized that the difference in neural architecture of the blue-yellow and red-green opponent systems in the presence of a normalization process creates the surprising dependence of unique green on cone ratio. We then compared the predictions of different theories of color vision processing that incorporate L and M cone ratio and a normalization process. The results of this analysis reveal that-contrary to prevailing notions--postretinal contributions may not be required to explain the phenomena of unique hues.

Reduction of mouse atherosclerosis by urokinase inhibition or with a limited-spectrum matrix metalloproteinase inhibitor.

AIMS: Elevated activity of urokinase plasminogen activator (uPA) and MMPs in human arteries is associated with accelerated atherosclerosis, aneurysms, and plaque rupture. We used Apoe-null mice with macrophage-specific uPA overexpression (SR-uPA mice; a well-characterized model of protease-accelerated atherosclerosis) to investigate whether systemic inhibition of proteolytic activity of uPA or a subset of MMPs can reduce protease-induced atherosclerosis and aortic dilation. METHODS AND RESULTS: SR-uPA mice were fed a high-fat diet for 10 weeks and treated either with an antibody inhibiting mouse uPA (mU1) or a control antibody. mU1-treated mice were also compared with PBS-treated non-uPA-overexpressing Apoe-null mice. Other SR-uPA mice were treated with one of three doses of a limited-spectrum synthetic MMP inhibitor (XL784) or vehicle. mU1 reduced aortic root intimal lesion area (20%; P = 0.05) and aortic root circumference (12%; P = 0.01). All XL784 doses reduced aortic root intimal lesion area (22-29%) and oil-red-O-positive lesion area (36-42%; P < 0.05 for all doses and both end points), with trends towards reduced aortic root circumference (6-10%). Neither mU1 nor XL784 significantly altered percent aortic surface lesion coverage. Several lines of evidence identified MMP-13 as a mediator of uPA-induced aortic MMP activity. CONCLUSIONS: Pharmacological inhibition of either uPA or selected MMPs decreased atherosclerosis in SR-uPA mice. uPA inhibition decreased aortic dilation. Differential effects of both agents on aortic root vs. distal aortic atherosclerosis suggest prevention of atherosclerosis progression vs. initiation. Systemic inhibition of uPA or a subset of MMPs shows promise for treating atherosclerosis.