Early Single-Examination Optical Coherence Tomography Biomarkers for Treatment-Requiring Retinopathy of Prematurity.

Purpose: Optical coherence tomography (OCT) is an emerging adjunct imaging modality to evaluate retinopathy of prematurity (ROP). From an 11-year research database, we identify early OCT biomarkers that predict treatment-requiring ROP (TR-ROP). Methods: For preterm infants with acceptable OCT images at 32 ± 1 weeks postmenstrual age (PMA), we extracted the following measures: total retina, inner retinal layer (IRL), and outer retinal layer (ORL) thicknesses at the fovea and the parafovea, inner nuclear layer (INL) and choroidal thickness, parafovea/fovea (P/F) ratio, and presence of macular edema. Using univariable and multivariable logistic regression models, we evaluated the association between retinal and choroidal OCT measurements at 32 ± 1 weeks PMA and development of TR-ROP. Results: Of 277 eyes (145 infants) with usable OCT images, 67 eyes had TR-ROP. Lower P/F ratio (P < 0.0001), thicker foveal IRL (P = 0.0001), and thinner choroid (P = 0.03) were associated with TR-ROP in univariable analysis, but lost significance of association when adjusted for gestational age and race. Absence of macular edema was associated with TR-ROP when adjusted for gestational age and race (P = 0.01). In 185 eyes without macular edema, P/F ratio was associated with TR-ROP in both univariable analysis (P < 0.0001) and multivariable analysis (P = 0.02) with adjustment for gestational age and race. Conclusions: Presence of macular edema at 32 ± 1 weeks PMA in infants with lower gestational age may be protective against TR-ROP. In infants without macular edema, P/F ratio may be an early OCT biomarker for development of TR-ROP. Incorporation of early OCT biomarkers may be useful in prediction of TR-ROP.

Longitudinal Choroidal Development in Preterm Infants.

Purpose: To characterize changes in subfoveal choroidal thickness in preterm infants from 30 to 60 weeks' postmenstrual age (PMA). Design: The prospective, observational Study of Eye Imaging in Preterm infantS (BabySTEPS) enrolled infants eligible for retinopathy of prematurity screening per the American Association of Pediatrics guidelines. Subjects: Infants imaged with an investigational, handheld OCT at ≥ 4 distinct imaging sessions between 30 to 60 weeks' PMA as part of BabySTEPS. Methods: Average choroidal thickness across the central subfoveal 1 mm in each eye at each time point was measured using custom segmentation software, and errors were manually corrected by a trained grader. We prospectively collected birth history data. A segmented mixed model was used to analyze the change in choroidal thickness as a function of PMA, birth weight, and gestational age (GA). Main Outcome Measures: Characterization of normative subfoveal choroidal thickness values and choroidal growth rate between 30 to 60 weeks' PMA. Results: We included 592 imaging sessions of 79 preterm infants (152 eyes). Mean (± standard deviation) GA was 27.5 ± 2.5 weeks. Mean choroidal thickness was 141.4 ± 34.5 µm at 30 weeks, 272.2 ± 83.9 µm at 38 weeks, and 306.2 ± 77.4 µm between 56 and 60 weeks. Between 30 and 60 weeks' PMA, choroidal growth followed a biphasic model, with a linear growth rate of 14.8 µm per week (95% confidence interval [CI], 13.6-16.0) from 30 until 38.4 weeks, then cessation of growth, with a growth rate of 0.3 µm per week (95% CI, -1.1 to 1.6) from 38.4 to 60 weeks. Infants with extremely low birth weight (ELBW; < 1000 g) and extremely preterm (GA < 28 weeks) infants had significantly slower initial growth rates compared with very low and low birth weight and very preterm and preterm infants (ELBW 13.0 vs. 21.0 µm per week; P < 0.0001 and extremely preterm 13.2 vs. 18.0 µm per week; P = 0.003). Conclusions: Preterm infant choroidal thickness experiences rapid linear growth from 30 to 38 weeks' PMA, at which time growth nearly stops. These foundational measurements and identification of the impact of extremes of low birth weight and prematurity on choroidal development will be essential as researchers begin to understand the role of choroidal development in ocular and retinal health in human infants. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

MACULAR NEUROVASCULAR ABNORMALITIES IN A CHILD WITH INCONTINENTIA PIGMENTI ON HANDHELD OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To report macular neurovascular abnormalities in a child with incontinentia pigmenti using handheld optical coherence tomography (OCT) and OCT angiography (OCT-A). METHODS: An eye of a child with incontinentia pigmenti enrolled in BabySTEPS was imaged using an investigational noncontact, handheld swept-source OCT device during examination under anesthesia. Custom MATLAB scripts were used to generate depth-resolved vascular slabs, B-scans with flow overlay, and retinal thickness maps. RESULTS: Depth-resolved OCT and OCT-A imaging demonstrated focal areas of decreased capillary flow that corresponded to areas of both inner retinal and outer retinal thinning on retinal thickness maps. Atypical diving of superficial retinal vessels occurred as they traversed from thin retina to normal-thickness retina. CONCLUSION: Depth-resolved OCT and OCT-A identified retinal vascular abnormalities that were not evident on fundus photography or fluorescein angiography. This case depicted concurrent, localized abnormalities in retinal thickness and microvasculature in an eye with incontinentia pigmenti.

Biphasic change in retinal nerve fibre layer thickness from 30 to 60 weeks postmenstrual age in preterm infants.

BACKGROUND/AIMS: The optic nerve development during the critical postnatal weeks of preterm infants is unclear. We aimed to investigate the change of retinal nerve fibre layer (RNFL) in preterm infants. METHODS: We used an investigational handheld optical coherence tomography (OCT) system to serially image awake preterm infants between 30 and 60 weeks postmenstrual age (PMA) at the bedside. We assessed RNFL thickness in the papillomacular bundle and nasal macular ganglion cell layer+inner plexiform layer (GCL+IPL) thickness. We applied a segmented mixed model to analyse the change in the thickness of RNFL and GCL+IPL as a function of PMA. RESULTS: From 631 OCT imaging sessions of 101 infants (201 eyes), RNFL thickness followed a biphasic model between 30 and 60 weeks, with an estimated transition at 37.8 weeks PMA (95% CI: 37.0 to 38.6). RNFL thickness increased at 1.8 µm/week (95% CI: 1.6 to 2.1) before 37.8 weeks and decreased at -0.3 µm/week (95% CI: -0.5 to -0.2) afterwards. GCL+IPL thickness followed a similar biphasic model, in which the thickness increased at 2.9 µm/week (95% CI: 2.5 to 3.2) before 39.5 weeks PMA (95% CI: 38.8 to 40.1) and then decreased at -0.8 µm/week (95% CI: -0.9 to -0.6). CONCLUSION: We demonstrate the feasibility of monitoring RNFL and GCL+IPL thickness from OCT during the postnatal weeks of preterm infants. Thicknesses follow a biphasic model with a transition age at 37.8 and 39.5 weeks PMA, respectively. These findings may shed light on optic nerve development in preterm infants and assist future study designs.

Integrated Visualization Highlighting Retinal Changes in Retinopathy of Prematurity From 3-Dimensional Optical Coherence Tomography Data.

Importance: Early diagnosis of plus disease is critical in the management of retinopathy of prematurity (ROP). However, there is substantial interexpert disagreement in the diagnosis of plus disease based on vascular changes alone. Information derived from optical coherence tomography (OCT) may help characterize the severity of vascular and structural abnormalities in ROP. Objective: To describe integrated visualization of 3-dimensional (3-D) data from investigational swept-source OCT optimized to delineate retinal vascular and microanatomical features in eyes with and without ROP. Design, Setting, and Participants: This cross-sectional, observational report of OCT was captured in the prospective Study of Eye Imaging in Preterm Infants (BabySTEPS) designed in July 2016 at the Duke Health Intensive Care Nursery. Between December 2018 and August 2019, 2 preterm infants born at 24 and 30 weeks' gestation were enrolled, underwent ROP screening, and were imaged at those screening visits. Data at 36 weeks' postmenstrual age were analyzed via this visualization developed between September 2020 and May 2021. Main Outcomes and Measures: Superimposed en face retinal vascular shadow view (RVSV) montages and thickness maps were used along with OCT B-scans to evaluate retinal vasculature and cross-section in eyes with and without ROP. Results: In the right eyes of 2 infants, 3-D data were integrated and visualized from investigational bedside OCT imaging at the posterior pole. In the infant who developed type 1 ROP, RVSV-OCT confirmed presence of dilated and tortuous posterior pole vessels, shunting, and incomplete perifoveal vascular development, resulting in a temporal notch of avascular retina in zone 1. The thickness map revealed irregular pockets of thickening and thinning, and integrated visualization outlined the demarcation between thicker vascularized retina and thinner avascular fovea and presence of extraretinal neovascularization overlying elevated vessels in the superior arcades. In the infant without ROP (stage 0), RVSV-OCT revealed no abnormal vascular findings at the posterior pole. The integrated visualization showed a dome-shaped retinal thickening at the fovea, which was confirmed as macular edema. Conclusions and Relevance: In 2 preterm infants in BabySTEPS, 3-D visualization of OCT findings during the ongoing ROP disease process demonstrated supplemental information about the retinal vasculature and microanatomy that can be useful to clinicians. These additional details provided by OCT could be integrated into future ROP screening methods with artificial intelligence-based analytics.

The ingenol-based protein kinase C agonist GSK445A is a potent inducer of HIV and SIV RNA transcription.

Activation of the NF-κB signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption in vitro. However, significant toxicity risks and the lack of evidence supporting their activity in vivo have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV/simian immunodeficiency virus (SIV) transcription and virus production in vitro and demonstrate pharmacological activity in nonhuman primates (NHP). CD4+ T cells from people living with HIV and from SIV+ rhesus macaques (RM) on antiretroviral therapy (ART) exposed in vitro to 25 nM of GSK445A produced cell-associated viral transcripts as well as viral particles at levels similar to those induced by PMA/Ionomycin, indicating that GSK445A can potently reverse HIV/SIV latency. Importantly, these concentrations of GSK445A did not impair the proliferation or survival of HIV-specific CD8+ T cells, but instead, increased their numbers and enhanced IFN-γ production in response to HIV peptides. In vivo, GSK445A tolerability was established in SIV-naïve RM at 15 µg/kg although tolerability was reduced in SIV-infected RM on ART. Increases in plasma viremia following GSK445A administration were suggestive of increased SIV transcription in vivo. Collectively, these results indicate that GSK445A is a potent HIV/SIV LRA in vitro and has a tolerable safety profile amenable for further evaluation in vivo in NHP models of HIV cure/remission.

Depth-Resolved Visualization of Perifoveal Retinal Vasculature in Preterm Infants Using Handheld Optical Coherence Tomography Angiography.

Purpose: To establish methods to visualize depth-resolved perifoveal retinal vasculature in preterm infants using handheld optical coherence tomography angiography (OCT-A). Methods: In this exploratory study, eyes of preterm infants were imaged using an investigational noncontact, handheld swept-source OCT-A device as part of the prospective BabySTEPS infant retinal imaging study. We selected high-quality OCT-A volumes at two developmental stages for analysis. Customized MATLAB scripts were used to segment retinal layers, test offset parameters, and generate depth-resolved OCT-A slabs. The superficial (SCP), intermediate (ICP), and deep (DCP) capillary plexuses were visualized and qualitatively assessed by three image graders. Results: Six eyes from six preterm infants were included in this analysis. A three-layered perifoveal retinal vasculature was successfully visualized in all three eyes (three infants) in the 40 weeks postmenstrual age (PMA) group (one of three eyes with treated type 1 retinopathy of prematurity [ROP]). No obvious ICP or DCP was found in good-quality scans of the three eyes (three infants) in the 35 weeks PMA group (three of three eyes developed type 1 ROP). Conclusions: Custom segmentation parameters are useful to visualize perifoveal retinal vasculature in preterm infants. At term age, a three-layered capillary structure is visible in most eyes, while prior to detectable flow within the ICP and DCP, the perifoveal vasculature may be better visualized in two layers. Translational Relevance: Development of segmentation parameters for depth-resolved OCT-A of perifoveal retinal vasculature in preterm infants facilitates the study of human retinal vascular development and vascular pathologies of ROP.

Evaluating the association of clinical factors and optical coherence tomography retinal imaging with axial length and axial length growth among preterm infants.

PURPOSE: To study the association of clinical factors and optical coherence tomography (OCT) retinal imaging with axial length (AL) and AL growth in preterm infants METHODS: Among a subgroup of infants from the prospective BabySTEPS study who were screened for retinopathy of prematurity (ROP) and had both AL measured and OCT imaging performed, we analyzed data collected prior to 42 weeks postmenstrual age (PMA) and prior to ROP treatment. Using linear mixed effects models, we evaluated associations between AL and AL growth with gestational age (GA), birthweight, PMA, sex, race, multiparity, maximum ROP stage, and OCT features. RESULTS: We included 66 infants (132 eyes), mean GA = 27.6 weeks (SD = 2.3; range: 23.0-34.4) and mean birthweight = 961 g (SD = 269, range: 490-1580). In the final predictive model, longer AL was associated with earlier GA, higher birthweight, later PMA, non-White race, and thicker subfoveal choroid (all p values ≤ 0.01). AL increased linearly up to 42 weeks PMA. There was no difference in AL growth rate by GA, sex, race, multiparity, maximum ROP severity, central foveal thickness, or subfoveal choroidal thickness (all p values > 0.05); but AL growth rate was slower in infants with lower birthweight (p = 0.01). CONCLUSIONS: Among preterm infants, those with earlier GA, higher birthweight, later PMA, non-White race, and thicker subfoveal choroid had the longest AL. AL increased linearly up to 42 weeks PMA and lower birthweight was associated with slower AL growth. These findings may improve the accuracy of measurements taken on preterm infants using imaging techniques affected by AL (e.g., measuring lateral dimensions on OCT). TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02887157 , date of registration: August 25, 2016.

Foveal Differentiation and Inner Retinal Displacement Are Arrested in Extremely Premature Infants.

Purpose: Children with a history of prematurity often have poorly developed foveae but when during development foveal differences arise. We hypothesize that the course of foveal development is altered from the time of preterm birth. Methods: Eyes of 102 preterm infants undergoing retinopathy of prematurity screening examinations in the STudy of Eye imaging in Premature infantS (BabySTEPS) (NCT02887157) were serially imaged between 30 and 42 weeks postmenstrual age (PMA) using handheld optical coherence tomography systems. Total retinal thickness, inner retinal layer (IRL) thickness, and outer retinal layer (ORL) thickness were measured at the foveal center and parafovea. Foveal put depth, IRL thickness, and ORL thickness were compared between infants born at different gestational ages using mixed effects models. Results: Foveal pit depth and IRL thickness were inversely related to gestational age; on average, the most premature infants had the thickest IRL and shallowest pits at all PMAs. Differences were evident by 30 weeks PMA and persisted through 42 weeks PMA. The foveal pits of the most premature infants did not progressively deepen, and the IRLs did not continue to thin with increasing chronological age. Conclusions: Foveation in extremely preterm infants is arrested from the earliest observed ages and fails to progress through term equivalent age. The developmental displacement of the IRL from the foveal center into the parafovea does not occur normally after preterm birth. These observations suggest that foveal hypoplasia seen in children with history of prematurity is due to disturbances in foveal development that manifest within weeks of birth.

Local Anatomic Precursors to New-Onset Geographic Atrophy in Age-Related Macular Degeneration as Defined on OCT.

PURPOSE: In macula-wide analyses, spectral-domain (SD) optical coherence tomography (OCT) features including drusen volume, hyperreflective foci, and OCT-reflective drusen substructures independently predict geographic atrophy (GA) onset secondary to age-related macular degeneration (AMD). We sought to identify SD OCT features in the location of new GA before its onset. DESIGN: Retrospective study. PARTICIPANTS: Age-Related Eye Disease Study 2 Ancillary SD OCT Study participants. METHODS: We analyzed longitudinally captured SD OCT images and color photographs from 488 eyes of 488 participants with intermediate AMD at baseline. Sixty-two eyes with sufficient image quality demonstrated new-onset GA on color photographs during study years 2 through 7. The area of new-onset GA and one size-matched control region in the same eye were segmented separately, and corresponding spatial volumes on registered SD OCT images at the GA incident year and at 2, 3, and 4 years previously were defined. Differences in SD OCT features between paired precursor regions were evaluated through matched-pairs analyses. MAIN OUTCOME MEASURES: Localized SD OCT features 2 years before GA onset. RESULTS: Compared with paired control regions, GA precursor regions at 2, 3, and 4 years before (n = 54, 33, and 25, respectively) showed greater drusen volume (P = 0.01, P = 0.003, and P = 0.003, respectively). At 2 and 3 years before GA onset, they were associated with the presence of hypertransmission (P < 0.001 and P = 0.03, respectively), hyperreflective foci (P < 0.001 and P = 0.045, respectively), OCT-reflective drusen substructures (P = 0.004 and P = 0.03, respectively), and loss or disruption of the photoreceptor zone, ellipsoid zone, and retinal pigment epithelium (RPE, P < 0.001 and P = 0.005-0.045, respectively). At 4 years before GA onset, precursor regions were associated with photoreceptor zone thinning (P = 0.007) and interdigitation zone loss (P = 0.045). CONCLUSIONS: Evolution to GA is heralded by early local photoreceptor changes and drusen accumulation, detectable 4 years before GA onset. These precede other anatomic heralds such as RPE changes and drusen substructure emergence detectable 1 to 2 years before GA. This study thus identified earlier end points for GA as potential therapeutic targets in clinical trials.

Macular OCT Characteristics at 36 Weeks' Postmenstrual Age in Infants Examined for Retinopathy of Prematurity.

PURPOSE: To report our ability to capture,-grade reliably, and analyze bedside macular OCT images from preterm infants and relate OCT findings to biological factors and retinopathy of prematurity (ROP) status at a single time window in the Study of Eye Imaging in Preterm Infants (BabySTEPS). DESIGN: Prospective, observational study. PARTICIPANTS: Preterm infants eligible for ROP screening with parental consent for research and a 36 ± 1 weeks' postmenstrual age (PMA) visit. METHODS: We imaged both eyes of preterm infants with an investigational noncontact, handheld swept-source (SS) OCT at the time of clinical ROP examinations. Macular OCT features and layer thicknesses for untreated eyes of infants at 36 ± 1 weeks' PMA were compared with demographic data and clinical ROP examination performed by experts. Statistical analyses accounted for the use of both eyes of infants. MAIN OUTCOME MEASURES: Macular OCT features and layer thicknesses, gender, race or ethnicity, gestational age, birth weight, ROP stage, and plus disease. RESULTS: We captured macular OCT from 169 eyes (1 eye excluded because of prior ROP treatment) at 36 ± 1 weeks' PMA. The quality of OCT volumes was excellent in 33 eyes (19%), acceptable in 112 eyes (67%), poor in 24 eyes (14%), and unusable in 0 eyes (0%). Macular edema was present in 60% of eyes and was bilateral in 82% of infants with edema. At the fovea, retinal and inner nuclear layer thickness increased with edema severity: 183 ± 36 µm and 51 ± 27 µm in mild (16% of eyes), 308 ± 57 µm and 163 ± 53 µm in moderate (25%), and 460 ± 76 µm and 280 ± 83 µm in severe edema (12%), respectively. With an increase in ROP stage from 0 to 2, the mean ± standard deviation retinal thickness at the fovea increased from 227± 124 µm to 297 ± 99 µm (P < 0.001). The choroid was thinner, 155 ± 72 µm, with preplus or plus disease versus without, 236 ± 79 µm (P = 0.04), whereas retinal thickness did not vary. CONCLUSIONS: We demonstrated the reliability of methods and the prevalence of OCT findings in preterm infants enrolled in BabySTEPS at a single time point of 36 ± 1 weeks' PMA. Variations in layer thicknesses in infants at this time point may reflect abnormalities resulting from delay in foveal development that may be impacted by macular edema, ROP, or both.

Birth Weight Is a Significant Predictor of Retinal Nerve Fiber Layer Thickness at 36 Weeks Postmenstrual Age in Preterm Infants.

PURPOSE: To assess retinal nerve fiber layer (RNFL) thickness in preterm infants. DESIGN: Prospective observational study. METHODS: We imaged 83 awake infants (159 eyes) at 36 ± 1 weeks postmenstrual age (defined as the time elapsed between the first day of the last maternal menstrual period and the time at imaging) using a handheld optical coherence tomography (OCT) system at the bedside. Blinded graders semi-automatically segmented RNFL in the papillomacular bundle (-15 to +15° relative to the fovea-optic nerve axis). We correlated RNFL thickness and 7 characteristics of interest (sex, race, ethnicity, gestational age, birth weight, stage of retinopathy at prematurity, and presence of pre-plus or plus disease) via univariable and multivariable regressions. RESULTS: RNFL was 3.4 µm thicker in the right eyes than in the left eyes (P < .001). Among 7 characteristics, birth weight was the only independent predictor of RNFL thickness (P < .001). A 250-g increase in birth weight was associated with 5.2 µm (95% confidence interval: 3.3-7.0) increase in RNFL thickness. Compared with very preterm infants, extremely preterm infants had thinner RNFL (58.0 ± 10.7 µm vs 63.4 ± 10.7 µm, P = .03), but the statistical significance disappeared after adjustment for birth weight (P = .25). RNFL thickness was 11.2 µm thinner in extremely low birth weight infants than in very low birth weight infants (55.5 ± 8.3 µm vs. 66.7 ± 10.2 µm; P < .001). The difference remained statistically significant after adjustment for gestational age. CONCLUSION: Birth weight is a significant independent predictor of RNFL thickness near birth, implying that the retinal ganglion cells reserve is affected by intrauterine processes that affect birth weight.

Localized Optical Coherence Tomography Precursors of Macular Atrophy and Fibrotic Scar in the Comparison of Age-Related Macular Degeneration Treatments Trials.

PURPOSE: To identify precursors of macular atrophy (MA) and of fibrotic scar (FS) in eyes treated with anti-vascular endothelial growth factor through pixel-mapping analysis of baseline optical coherence tomography (OCT). METHODS: Design: Cross-sectional analysis. SETTING: Multicenter clinical trial. PATIENT POPULATION: 68 eyes from the Comparison of Age-Related Macular Degeneration Treatments Trials. INTERVENTION: Treatment with anti-vascular endothelial growth factor agents. MAIN OUTCOME MEASURE: The percentage of MA or FS pixels with each OCT feature at baseline, and the odds ratio for baseline pixels with an OCT feature to develop MA or FS. RESULTS: Retinal pigment epithelium atrophy and photoreceptor loss on OCT were highly predictive of MA at that location at years 2 and 5 (P < .0001), but accounted for only 22.5% of the ensuing atrophy at year 2 and less at year 5. Among pixels of MA at year 2, 78% were preceded by thick drusen, 54% by subretinal macular neovascularization (MNV), and 22.5% by no detectable OCT features. MNV, subretinal hyperreflective material, pigment epithelial detachment, intraretinal fluid, and sub-retinal pigment epithelium fluid were predictive of FS at that location (P values <.05). More than 75% of the pixels of FS at years 2 and 5 were preceded by pixels of baseline MNV. CONCLUSIONS: Most pixels of FS were preceded by components of neovascularization. Although one-quarter of MA was accounted for by pre-existing evidence of atrophy on OCT alone, the development of MA in areas of thick drusen, areas with and without subretinal MNV lesion, and areas without detectable OCT precursors argues that the development of MA is multifactorial and may follow, in part, a non-neovascular pathway.

Repeatability and Reproducibility of Axial and Lateral Measurements on Handheld Optical Coherence Tomography Systems Compared with Tabletop System.

Purpose: To compare the repeatability and reproducibility of axial and lateral retinal measurements using handheld optical coherence tomography (OCT) systems and a tabletop OCT system. Methods: Graders measured central foveal thickness (CFT), optic nerve-to-fovea distance (OFD), and retinal nerve fiber layer (RNFL) thickness on OCT scans of the right eye of 10 healthy adults. Three OCT systems were used: handheld Leica Envisu, investigational handheld swept-source OCT (UC3), and Heidelberg Spectralis tabletop system. All eyes were imaged five times with each OCT system by each of two imagers. A components of variance analysis provided estimates of repeatability (variation due to random error) and reproducibility (variation due to imager, grader, and random error) expressed as standard deviation and (coefficient of variation %). Results: Repeatability of CFT (µm) for Envisu, UC3, and Spectralis was 5.9 (2.6%), 6.9 (2.9%), and 4.7 (2.1%), and the reproducibility was 6.1 (2.7%), 7.3 (3.1%), and 4.7 (2.1%), respectively. The repeatability of OFD (mm) was 0.13 (2.9%), 0.10 (2.3%), and 0.07 (1.6%), and the reproducibility was 0.13 (3.0%), 0.10 (2.3%), and 0.07 (1.6%,) respectively. The repeatability for RNFL thickness (µm) for Envisu, UC3, and Spectralis was 4.3 (7.8%), 2.7 (5.4%), and 2.9 (4.9%), and the reproducibility was 4.5 (8.3%), 2.9 (5.8%), and 2.9 (4.9%), respectively. Conclusions: All three OCT systems had good repeatability and reproducibility with coefficients of variation of less than 3.5% for CFT and OFD measurements, and less than 8.5% for RNFL thickness. Translational Relevance: Our findings inform the repeatability and reproducibility of retinal axial and lateral measurements on handheld OCT and are useful for both clinical research and patient care.

Auto-Processed Retinal Vessel Shadow View Images From Bedside Optical Coherence Tomography to Evaluate Plus Disease in Retinopathy of Prematurity.

Purpose: To describe the creation of en face retinal vessel shadow view (RVSV) optical coherence tomography (OCT) images and assess the feasibility of using these for evaluating vascular disease in preterm infants at risk for retinopathy of prematurity (ROP). Methods: In this exploratory study, we selected images from eyes with a range of ROP vascular disease, prospectively acquired from preterm infants using an investigational, noncontact, handheld, bedside swept-source OCT. We autosegmented OCT volumes using custom infant-specific software, extracted RVSV-OCT images from volumetric data bracketed around the retinal pigment epithelium, and automontaged the resulting RVSV-OCT images. Three masked ophthalmologists graded the RVSV-OCT montages as plus, pre-plus, or neither and ranked them by relative vascular disease severity. Results: We selected images from 17 imaging sessions (7 plus, 4 pre-plus, 6 neither on clinical examination). On review, 15/17 (88%) RVSV-OCT montages were gradable for plus, pre-plus, or neither and all 17 montages were rankable for relative severity. Intergrader agreement for plus, pre-plus, or neither grading was good (κ, 0.67; 95% confidence interval, 0.42-0.86) and for relative severity ranking was excellent (intraclass correlation coefficient, 0.98; 95% confidence interval, 0.96-0.99). Conclusions: Our novel automatic processing method can create RVSV-OCT montages optimized for retinal vessel visualization for ROP screening. Although our data support the feasibility of using RVSV-OCT montages for ranking relative vascular disease severity, there is room for improved OCT image capture and processing methods in preterm infants screened for ROP. Translational Relevance: Creation and grading of RVSV-OCT images could eventually be integrated into an alternative method for ROP screening.

Subclinical Retinal versus Brain Findings in Infants with Hypoxic Ischemic Encephalopathy.

PURPOSE: To detect retinal features and abnormalities on optical coherence tomography (OCT) without pupil dilation and relate these to brain injury in infants with a clinical diagnosis of hypoxic ischemic encephalopathy (HIE). METHODS: Under an institutional review board-approved protocol, we imaged eight infants without pharmacologic mydriasis, using handheld, non-contact spectral-domain (Leica Microsystems, IL) or investigational swept-source OCT at the bedside in an intensive care nursery, after birth (depending on primary clinical care team permission based on health status) and weekly until discharge. The newborn infant with HIE is neurologically unstable; therefore, pharmacologic mydriasis and stimulation with visible light for retinal examination are usually avoided. We analyzed images for retinal pathologies, central foveal thickness, and retinal nerve fiber layer (RNFL) thickness at the papillomacular bundle and compared them to historical controls and published normative data, HIE clinical assessment, and abnormalities on brain magnetic resonance imaging (MRI). RESULTS: On OCT, three of eight infants had bilateral multiple small macular and perimacular cystoid spaces; two of these three infants also had pronounced retinal ganglion cell layer thinning and severe brain injury on MRI and the third had bilateral paracentral acute middle maculopathy and mild brain injury on MRI. Other findings in HIE infant eyes included abnormally thin fovea and thin RNFL and markers of retinal immaturity such as the absence of sub-foveal photoreceptor development and sub-foveal fluid. CONCLUSIONS: Bedside handheld OCT imaging within the first 2 weeks of life revealed retinal injury in infants with HIE-related brain injury. Future studies may determine the relationship between acute/subacute retinal abnormalities and brain injury severity and neurodevelopmental outcomes in HIE.

Understanding the variability of handheld spectral-domain optical coherence tomography measurements in supine infants.

PURPOSE: Central foveal thickness (CFT) measurements from optical coherence tomography (OCT) scans provide a precise measure of severity of pathologic changes in the fovea, progress of disease and response to treatment. Although these measures are additionally valuable to assess foveal development in infants, their reproducibility is not known. The goal of this retrospective study is to evaluate the variation and reproducibility of CFT measurements using handheld spectral-domain OCT (hh-SDOCT) in supine infants compared to conventional adult tabletop imaging. METHODS: Imaging sessions with multiple macular, volume scans in one eye were selected for analysis from two participant groups: Group 1, 25 imaging sessions from 21 preterm infants without macular edema imaged supine in the nursery using hh-SDOCT (Leica/Bioptigen Envisu C2300, RTP, NC); Group 2, 25 imaging sessions from 25 adults imaged using tabletop Bioptigen SDOCT. For each imaging session, three macular OCT volumes with acceptable image quality were selected for analysis. CFTs were measured using a customized script for automatic segmentation. An expert grader and a typical grader corrected the segmentation lines for the central foveal frame. Coefficient of variations (CV) and intraclass correlation coefficients (ICC) were calculated for graders and systems and compared to the previous literature on OCT reproducibility. RESULTS: CFT measurements were repeatable and reproducible for both handheld and tabletop SDOCT systems. For handheld, grader ICC (CI) and mean CV were 0.94 (0.90-0.97) and 3.8 (typical) and 0.98 (0.96-0.99) and 2.9 (expert), and for tabletop were 0.91(0.83-0.96) and 2.1 (typical) and 0.92 (0.86-0.96) and 1.9 (expert). Intergrader reproducibility of handheld and tabletop SDOCT systems were ICC(CI) 0.97 (0.95-0.98) and 0.93 (0.89-0.96) respectively, and both are comparable to previously reported reproducibility of tabletop systems. CONCLUSION: Handheld SDOCT is a reproducible instrument to measure foveal thicknesses in supine infants. It can be used in clinical research to evaluate foveal changes during retinal development and pathological conditions.

Handheld Optical Coherence Tomography Normative Inner Retinal Layer Measurements for Children <5 Years of Age.

PURPOSE: Measurements of the ganglion cell complex (GCC), comprising the retinal nerve fiber (RNFL), ganglion cell, and inner plexiform layers, can be correlated with vision loss caused by optic nerve disease. Handheld optical coherence tomography (HH-OCT) can be used with sedation in children who are not amenable to traditional imaging. We report GCC and RNFL measurements in normal children using HH-OCT. DESIGN: Prospective observational study of normal children ≤5 years of age. METHODS: Healthy, full-term children ≤5 years of age undergoing sedation or anesthesia were enrolled. Exclusion criteria included prematurity and pre-existing neurologic, genetic, metabolic, or intraocular pathology. Demographic data, axial length (Master-Vu Sonomed Escalon, Lake Success, New York, USA), and HH-OCT macular and optic nerve volume scans at 0° (Bioptigen, Inc., Morrisville, North Carolina, USA) were obtained. Retinal segmentation was completed with DOCTRAP software, creating average volume thickness maps. RESULTS: Sixty-seven children (67 eyes, 31 males ranging in age from 3.4-70.9 months) were enrolled. Average axial length was 21.2 ± 1.0 mm with mean spherical equivalent +1.49 ± 1.34 diopters (range -2.25 to 4.25). Average GCC volume for the total retina was 0.28 ± 0.04 mm3. Forty-seven of these eyes had RNFL analysis. Average RNFL thickness of the papillomacular bundle was 38.2 ± 9.5 µm. There was no correlation between GCC volume, RNFL thickness, patient age, or axial length. CONCLUSION: Average GCC volume and RNFL thickness was stable from 6 months to 5 years of age. This study provides normative data for GCC and RNFL obtained by HH-OCT in healthy eyes of young children, to serve in evaluating those with optic neuropathies.

Distribution of OCT Features within Areas of Macular Atrophy or Scar after 2 Years of Anti-VEGF Treatment for Neovascular AMD in CATT.

PURPOSE: Macular atrophy and scar increase in prevalence during treatment for neovascular age-related macular degeneration and are associated with poor visual acuity. We sought to identify the distribution of spectral-domain OCT (SD-OCT)-determined features and subretinal lesion thicknesses at sites of macular scar or atrophy after 2 years of treatment in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). DESIGN: Cross-sectional analysis. PARTICIPANTS: CATT participants with SD-OCT, color photographic (CP) and fluorescein angiogram (FA; CP/FA) images at year 2. METHODS: Sixty-eight study eyes at year 2 in CATT were selected based on image quality and CP/FA-determined predominant presence of the following: geographic atrophy (GA, n = 25), non-GA (NGA, n = 44), fibrotic scar (FS, n = 26), or non-FS (NFS, n = 7). The CP/FA components were delineated by CP/FA readers; SD-OCT morphologic features and thicknesses were delineated by OCT readers. Using custom software and graphic user interfaces, images were registered, overlaying features and components per pixel; differences were analyzed across groups. MAIN OUTCOME MEASURES: OCT features, CP/FA components, and retinal and subretinal lesion thicknesses at each pixel of regional overlays. RESULTS: SD-OCT assessment of registered areas of pathology revealed the following: (1) retinal pigment epithelium atrophy (with or without residual lesion material) covered 75% of pixels designated as GA, 22% of NGA, 24% of NFS, and 46% of FS (P < 0.001). (2) Photoreceptor layer thinning covered 85% of GA, 42% of NGA, 33% of NFS, and 59% of FS (P < 0.001). (3) Subretinal lesion features covered 31% of GA, 42% of NGA, 85% of NFS, and 92% of FS (P < 0.001). Mean thickness of the subretinal lesion complex (measured in microns ± standard deviation) differed among GA (48±25 µm), NGA (61±35 µm), NFS (83±17 µm), and FS (151±74 µm) (P < 0.001). In eyes with GA, the thickness was greater in areas with residual lesion (51.4±27 µm) than in those without (27.2±9 µm). CONCLUSIONS: Retinal pigment epithelium atrophy and photoreceptor layer thinning are common not only in areas of macular atrophy but also in areas of FS. Photoreceptor loss extends beyond the areas of clinically apparent atrophy and FS. Subretinal lesion components were common in areas of scar, but they were also present in nearly one-third or more of areas of macular atrophy.

Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor.

We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide- N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human pharmacokinetics and lower efficacious doses relative to 1.