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In this work we introduce CUTS (Contrastive and Unsupervised Training for Segmentation), the first fully unsupervised deep learning framework for medical image segmentation to better utilize the vast majority of imaging data that is not labeled or annotated. Segmenting medical images is a critical task for facilitating both patient diagnoses and quantitative research. A major limiting factor is the lack of labeled data, as obtaining expert annotations for each new set of imaging data or task can be expensive, labor intensive, and inconsistent across annotators. Thus, we utilize self-supervision from pixels and their local neighborhoods in the images themselves. Our unsupervised approach optimizes a training objective that leverages concepts from contrastive learning and autoencoding. In contrast to prior work, our framework segments medical images with a novel two-stage approach without relying on any labeled data at any stage. The first stage involves the creation of a "pixel-centered patch" that embeds every pixel along with its surrounding patch, using a vector representation in a high-dimensional latent embedding space. The second stage utilizes diffusion condensation, a multi-scale topological data analysis approach, to dynamically coarse-grain these embedding vectors at all levels of granularity. The final outcome is a series of coarse-to-fine segmentations that highlight image structures at various scales. We show successful multi-scale segmentation on natural images, retinal fundus images, and brain MRI images. Our framework delineates structures and patterns at different scales which may carry distinct information relevant to clinical interpretation. As we tackle the problem of segmenting medical images at multiple meaningful granularities without relying on any label, we demonstrate the possibility to circumvent tedious and repetitive manual annotations in future practice., Comment: Updated Table 1. Rerun supervised and STEGO after unified codebase. Correct bug in multi-class dice and hausdorff

Purpose To investigate the underlying reason for the previously observed impact of baseline lesion size, number, and circularity on geographic atrophy (GA) growth rate. Design Retrospective analysis of a multicenter, prospective, randomized controlled trial. Participants Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. Methods We manually delineated atrophic lesions on color fundus photographs of 318 eyes with GA followed up over at least 2 visits (mean follow-up duration, 5.1 ± 3.0 years). We calculated GA area growth rate for each eye based on the first and last visit. GA perimeter-adjusted growth rate was defined as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye. Main Outcome Measures GA area growth rate, growth rate of the square root of GA area, and GA perimeter-adjusted growth rate. Results GA area growth rate was correlated strongly with mean GA perimeter (r2 = 0.66). GA area growth rate was associated with baseline GA area (r2 = 0.39; P Conclusions The growth rate of GA area is associated strongly with lesion perimeter. This relationship explains the previously observed influences of baseline GA size, lesion number, and circularity on GA growth rate. GA perimeter-adjusted growth rate is uncorrelated with the 3 morphologic factors and may serve as a surrogate outcome measure to monitor GA progression in future studies.

To examine the association between geographic atrophy (GA) disease characteristics and mortality risk. We manually delineated color fundus photographs of 209 Age-Related Eye Disease Study (AREDS) participants with GA secondary to age-related macular degeneration to identify total area of atrophy, GA effective radius growth rate, disease laterality, and the presence of foveal center involvement. Associations between GA characteristics and mortality were assessed with Cox proportional hazards models adjusted for health status indicators. During a median follow-up of 6.8 years, 48 (23.0%) participants with GA died. In adjusted models, accounting for age, sex, and health status, participants with total GA area in the highest quartile had a significantly increased risk of all-cause mortality compared to those with total GA area in the lowest quartile (hazard ratio [HR], 3.42; 95% confidence interval [CI], 1.32–8.86; P = 0.011). GA effective radius growth rate, bilateral disease, and the presence of foveal center involvement were not significantly associated with mortality. In a multivariable model, including health status indicators and all GA characteristics, total area of atrophy in the highest quartile remained significantly associated with mortality (HR, 4.65; 95% CI, 1.29–16.70; P = 0.019). More extensive GA, as indicated by a greater total area of atrophy, was associated with an increased risk of all-cause mortality in our cohort. The extent of GA may reflect the extent of underlying disease processes that contribute to greater mortality risk, further suggesting that GA may be part of a systemic rather than purely ocular disease process.

To assess retinal nerve fiber layer (RNFL) thickness in preterm infants.Prospective observational study.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.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.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.

BackgroundThe macular central 1 mm diameter zone is crucial to patients’ visual acuity, but the long-term natural history of central sparing in eyes with geographic atrophy (GA) is unknown.MethodsWe manually segmented GA in 210 eyes with GA involving central 1 mm diameter zone (mean follow-up=3.8 years) in the Age-Related Eye Disease Study. We measured the residual area in central 1 mm diameter zone and calculated central residual effective radius (CRER) as square root of (residual area/π). A linear mixed-effects model was used to model residual size over time. We added a horizontal translation factor to each data set to account for different durations of GA involving the central zone.ResultsThe decline rate of central residual area was associated with baseline residual area (p=0.008), but a transformation from central residual area to CRER eliminated this relationship (p=0.51). After the introduction of horizontal translation factors to each data set, CRER declined linearly over approximately 13 years (r2=0.80). The growth rate of total GA effective radius was 0.14 mm/year (95% CI 0.12 to 0.15), 3.7-fold higher than the decline rate of CRER (0.038 mm/year, 95% CI 0.034 to 0.042). The decline rate of CRER was 53.3% higher in eyes with than without advanced age-related macular degeneration in the fellow eyes at any visit (p=0.007).ConclusionsCRER in eyes with GA declined linearly over approximately 13 years and may serve as an anatomic endpoint in future clinical trials aiming to preserve the central zone.

Topic Determining the natural history of unifocal versus multifocal geographic atrophy (GA) secondary to nonexudative age-related macular degeneration. Clinical Relevance The association between GA focality (i.e., unifocal vs. multifocal lesions) and enlargement rate is inconsistent in the literature. Some studies report a comparable growth rate between unifocal and multifocal GA, whereas others suggest the growth rate varies widely between the 2 groups. Methods We searched 5 literature databases up to May 3, 2019, for studies that classified treatment-naive GA patients based on lesion focality. We performed a random effects meta-analysis to determine the growth rates of GA. To account for different entry times among cohorts, we introduced a horizontal translation factor to the dataset of each cohort. Heterogeneity and study quality were assessed using the I2 statistic and Quality in Prognosis Studies tool, respectively. Publication bias was evaluated by funnel plots and the Egger test. Results We included 12 studies with 3489 eyes from 3001 patients. After the introduction of translation factors, the effective radius of unifocal and multifocal GA enlarged linearly over approximately 7 years. The effective radius growth rate of multifocal GA (0.199±0.012 mm/year) was 46.3% higher than the growth rate of unifocal GA (0.136±0.008 mm/year; P 2 and 3 ). This difference disappeared after we accounted for different baseline total perimeters between unifocal and multifocal groups. The measured GA growth rate was consistent across studies using color fundus photography, fundus autofluorescence, or OCT (P = 0.35–0.99). Conclusions The effective radius of GA enlarges linearly and steadily over time in both unifocal and multifocal GA. The lesion focality is a significant prognostic factor for the GA effective radius growth rate. We propose that the growth rate of GA area is directly proportional to the total lesion perimeter (a measure of the number of retinal pigment epithelium cells exposed at the lesion border). Additional studies are needed to understand the cellular mechanisms underlying this relationship.

Prior studies of vision-related quality of life (VRQoL) have examined advanced age-related macular degeneration (AMD) as a single group or focused on neovascular AMD (nAMD), even though advanced AMD can refer to either central geographic atrophy (GA) or nAMD. We compared the natural progression of VRQoL in central GA versus nAMD. We included Age-Related Eye Disease Study (AREDS) participants with central GA (n = 206) or nAMD (n = 198) who completed the National Eye Institute Visual Function Questionnaire (NEI-VFQ) between 1997 and 2005. The rate of change of VRQoL was calculated as the slopes of linear models fit to longitudinal individual-level NEI-VFQ scores. Multivariable regressions identified factors associated with experiencing a decline in VRQoL during the study period and cross-sectional VRQoL score. There was a minor decline in VRQoL prior to the development of nAMD but a significantly steeper decline after progression to nAMD (0.49 ± 2.91 vs. 3.30 ± 5.58 NEI-VFQ units/year; p < 0.001). The rates of VRQoL decline were similar before and after the development of central GA (1.99 ± 4.97 vs. 1.68 ± 4.65 NEI-VFQ units/year; p = 0.66). Prior to the development of advanced AMD, the rate of VRQoL decline was greater for participants destined to develop central GA versus nAMD (p = 0.007), while postprogression to advanced disease, the rate was greater in nAMD compared with central GA (p = 0.012). Female gender (odds ratio [OR] 2.61, 95% confidence interval [CI] 1.38-5.06; p = 0.003) and higher baseline VRQoL score (OR 1.03, 95% CI 1.01–1.06; p = 0.006) were independently associated with experiencing a longitudinal decline in VRQoL. The natural progression of VRQoL differed in central GA versus nAMD, both before and after the development of advanced disease, suggesting that future studies should consider separating these phenotypes. Females and those with a higher baseline VRQoL were more likely to experience a longitudinal decline in VRQoL following progression to advanced AMD.

Topic Systematic review and meta-analysis of the natural history of autosomal recessive Stargardt disease (STGD1). Clinical Relevance Controversy exists regarding the progression pattern of atrophic lesions secondary to STGD1, and the reported growth rates vary widely among studies. Methods We searched in 6 literature databases up through March 15, 2019, to identify studies that monitored atrophy progression by fundus autofluorescence in untreated eyes with STGD1 for 6 months or more. We analyzed both study- and individual-level data from the included studies using 3 models: the area linear model (ALM), radius linear model (RLM), and area exponential model (AEM), in which the area, radius, and natural log–transformed area changes linearly with time, respectively. A horizontal translation factor was added to each dataset to correct for different participants’ entry times into the studies. The best model was determined by the predicted age of lesion onset and dependence of growth rates on baseline lesion sizes. The risk of bias was assessed using the Newcastle-Ottawa scale. Results Of 3158 articles screened, 7 studies (564 eyes) met our inclusion criteria. Cumulative study- and individual-level datasets fit along a straight line in the RLM after introducing horizontal translation factors to correct for different entry times (r2 = 0.99 and r2 = 0.93, respectively). The growth rate of effective lesion radius was 0.104 mm/year (95% confidence interval, 0.086–0.123 mm/year). The age of atrophy onset predicted by the RLM (22.7±5.0 years) was comparable to the reported age at onset of symptoms (22.1±3.1 years); in contrast, the predictions by the ALM and AEM deviated from this number by more than 5 years. Based on the individual-level data, the effective radius growth rate was independent of the baseline lesion size (r = 0.06); in comparison, the growth rates of area and natural log-transformed area were significantly dependent on the baseline lesion size (r = 0.47 and r = –0.33, respectively). Conclusions The progression of STGD1 lesions followed the RLM in both study- and individual-level data. The effective radius growth rate of atrophic lesions could serve as a reliable outcome measure to monitor STGD1 progression.

Topic Systematic review and meta-analysis of how fellow eye status predicts the progression rate of geographic atrophy (GA). Clinical Relevance The status of age-related macular degeneration (AMD) in the fellow eye has been used as an indicator of the GA progression rates in primary eyes, but the reported growth rates vary widely in prior clinical studies. Methods We searched MEDLINE, EMBASE, Cochrane Library, Clinicaltrials.gov , and PubMed up to September 12, 2018, for studies that classified treatment-naive GA patients based on different AMD manifestations in the fellow eyes and that monitored GA progression in the primary eyes. Three fellow eye statuses were analyzed: (1) no GA or choroidal neovascularization (CNV) in the fellow eye, (2) GA in the fellow eye, and (3) CNV in the fellow eye. To account for the patients’ different entry times, we introduced a horizontal translation factor to shift each dataset within each group. We determined the translation factor by adjusting it 1 month at a time until the r2 in weighted least squares regression (r2WLS) was maximized for the cumulative linear trend line of all datasets. Heterogeneity and study quality were assessed using the I2 statistic and Newcastle–Ottawa scale, respectively. Publication bias was evaluated by funnel plots, the Egger test, and the Begg test. Results We included 9 studies with 2134 eyes from 1835 patients. After the introduction of translation factors, the datasets in each fellow eye group fit along a straight line with a high r2WLS. The GA radius growth rate in fellow eyes with GA (0.179±0.003 mm/year) and fellow eyes with CNV (0.159±0.015 mm/year) was significantly higher than that in fellow eyes without GA or CNV (0.110±0.009 mm/year; P Conclusions We confirmed that the presence of advanced AMD in the fellow eye, defined as GA or CNV, can serve as a biomarker of the GA enlargement rate in the primary eye. This may assist the design of clinical trials and may shed light on the natural history of GA expansion.

Purpose To investigate the topographic distribution of geographic atrophy (GA) and to identify an anatomic endpoint that correlates with visual acuity (VA) in eyes with GA. Design Retrospective analysis of a multicenter, prospective, randomized controlled trial. Participants The Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. Methods We manually delineated GA on 1654 fundus photographs of 365 eyes. We measured GA areas in 9 subfields on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid and correlated them with VA via a mixed-effects model. We determined the optimal diameter for the central zone by varying the diameter from 0 to 10 mm until the highest r2 between GA area in the central zone and VA was achieved. We estimated the VA decline rate over 8 years using a linear mixed model. Main Outcome Measures Geographic atrophy area in macular subfields and VA. Results The percentage of area affected by GA declined as a function of retinal eccentricity. GA area was higher in the temporal than the nasal region (1.30 ± 1.75 mm2 vs. 1.10 ± 1.62 mm2; P = 0.005) and in the superior than the inferior region (1.26 ± 1.73 mm2 vs. 1.03 ± 1.53 mm2; P Conclusions The prevalence of GA varies significantly across different macular regions. Although total GA area was associated poorly with VA, GA area in the central 1-mm diameter zone was correlated significantly with VA and may serve as a surrogate endpoint in clinical trials.

Background/aimsBest-corrected visual acuity (BCVA) is the most common primary endpoint in treatment trials for choroideremia (CHM) but the long-term natural history of BCVA is unclear.MethodsWe searched in seven databases to identify studies that reported BCVA of untreated eyes with CHM. We sought individual-level data and performed segmented regression between BCVA and age. For eyes followed longitudinally, we introduced a horizontal translation factor to each dataset to account for different ages at onset of a rapid BCVA decline.ResultsWe included 1004 eyes from 23 studies. BCVA of the right and left eyes was moderately correlated (r=0.60). BCVA as a function of age followed a 2-phase decline (slow followed by rapid decline), with an estimated transition age of 39.1 years (95% CI 33.5 to 44.7). After the introduction of horizontal translation factors to longitudinal datasets, BCVA followed a 2-phase decline until it reached 0 letters (r2=0.90). The BCVA decline rate was 0.33 letters/year (95% CI −0.38 to 1.05) before 39 years, and 1.23 letters/year (95% CI 0.55 to 1.92) after 39 years (p=0.004).ConclusionBCVA in eyes with CHM follows a 2-phase linear decline with a transition age of approximately 39 years. Future trials enrolling young patients may not be able to use BCVA as a primary or sole endpoint, but rather, may need to employ additional disease biomarkers that change before age 39. BCVA may still have utility as a primary endpoint for patients older than 39 years who have measurable BCVA decline rates.

Purpose To evaluate the images produced in an initial surgical series of intraoperative near–real-time volumetric swept-source (SS) OCT imaging. Design Prospective translational study. Participants Forty-one consecutive adult patients undergoing vitreoretinal surgery between July 22, 2014, and July 1, 2015, at the Duke University Eye Center who agreed to participate. Methods A novel microscope-integrated SS-OCT prototype captured volumetric renderings of imaging of macular surgery in near-real-time and showed them to the surgeon via a heads-up display through the microscope oculars. Then the images were analyzed formally after surgery. Main Outcome Measures Image quality, successful capture of surgical instruments, maneuvers and associated retinal deformation volumetrically over time, and qualitative image analysis. Results Volumetric SS-OCT images were graded as acceptable in 92% of patients. Volumetric imaging of scraping and peeling procedures was achieved in 75% and 78% of patients in whom it was performed, respectively. Imaging provided the surgeon with near–real-time volumetric visualization of the position of the instrument relative to the retinal surface, flap initiation, flap removal, and retinal deformation during instrumentation via a heads-up display. Conclusions This volumetric, microscope-integrated SS-OCT prototype seems to provide high-detail, near–real-time volumetric imaging of delicate maneuvers during macular surgery.

Purpose To establish a continuous topography of retinal vessel density in normal eyes using optical coherence tomography angiography (OCTA). Methods A retrospective chart review was performed, and 8-mm × 8-mm OCTA images from 22 normal eyes were analyzed. Vessel density was plotted as a continuous function of distance from the foveal center (radial vessel density) and directional meridians (directional vessel density) for the superficial capillary plexus and deep capillary plexus. Results Continuous radial and directional vessel density plots for the superficial and deep capillary plexus were generated. Radial vessel density analysis revealed transition points at 657 microns (95% confidence interval [CI], 619-696) and 950 microns (95% CI, 903-997) from the foveal center for the superficial plexus and deep plexus, respectively. Directional vessel density analysis demonstrated significant vessel density variations in these vascular layers and provided greater detail compared to traditional quadrant analysis. Conclusions There are significant topographic variations of retinal vessel density in normal eyes. Continuous vessel density analysis offers greater sensitivity in detecting topographic vessel density changes compared to traditional methods of analysis. Translational relevance This study establishes a normative continuous vessel density topography that may help elucidate the role of the vascular bed in different chorioretinal diseases.

Purpose To conduct a systematic review and meta-analysis of the natural history of atrophy secondary to choroideremia (CHM). Clinical Relevance A sensitive and reliable anatomic measure to monitor disease progression is needed in treatment trials for CHM. However, the long-term natural history of the residual retinal pigment epithelium (RPE) is unclear, with reported RPE area decline rates varying widely among patients. Methods We searched in 7 literature databases up through July 17, 2019, to identify studies that assessed the residual RPE area in untreated eyes with CHM using fundus autofluorescence (FAF). We sought individual-eye data and investigated the RPE decline pattern using 3 models: the area linear model (ALM), radius linear model (RLM), and area exponential model (AEM), in which the area, radius, and log-transformed area of RPE change linearly with time, respectively. To account for different eyes’ entry times into the studies, we added a horizontal translation factor to each dataset. The RPE decline rate was estimated using a 2-stage random-effects meta-analysis. We assessed the risk of bias using the Quality In Prognosis Studies tool. Results Of 807 articles screened, we included 9 articles containing cross-sectional data (257 eyes) from 6 studies and longitudinal data (229 visits from 68 eyes) from 5 studies. The residual RPE area followed a trend of exponential decay as a function of patient age. After the introduction of horizontal translation factors to longitudinal datasets of individual eyes, the datasets fit along a straight line in the AEM over nearly 60 years (r2 = 0.997). The decline rate of log-transformed RPE area was 0.050 (95% confidence interval, 0.046–0.055) log(mm2)/year and was independent of the baseline RPE area (r = −0.18; P = 0.15) and age (r = 0.06; P = 0.63). In contrast, the decline rates of the area and effective radius of residual RPE strongly correlated with the baseline RPE area (r = 0.90 and 0.61, respectively; P Conclusions The loss of residual RPE area in untreated eyes with CHM follows the AEM over approximately 60 years. Log-transformed residual RPE area measured by FAF can serve as an anatomic endpoint to monitor CHM.

To reclassify fundus autofluorescence (FAF) patterns around geographic atrophy (GA) based on GA progression rates.MEDLINE, EMBASE, Cochrane Library, Clinicaltrials.gov, and PubMed were searched for studies reporting GA progression rates among different FAF patterns, such as "None," "Focal," "Banded," "Patchy," "Diffuse Nontrickling," and "Diffuse Trickling." The GA radius growth rate among different FAF patterns was compared, and a GA growth function for each group was derived. To account for the patients' different entry times, a horizontal translation factor was introduced to shift each data subset from "time after enrollment" to "duration of GA."Seven studies with 496 eyes were included. Based on GA radius growth rates, the six FAF patterns were clustered into four groups with a high correlation coefficient within each group: Group 1, None, 0.061 mm/year (r = 0.996), Group 2, Focal, 0.105 mm/year (r = 0.987), Group 3, Banded, Patchy, and Diffuse Nontrickling, 0.149 mm/year (r = 0.993), and Group 4, "Diffuse Trickling, 0.245 mm/year (r = 0.997).This meta-analysis suggested that the six FAF patterns can be coalesced into four groups based on lesion progression rates. Simplification of the reclassified FAF patterns may shed light on the GA natural history and assist in the design of clinical trials.

Current-generation software for rendering volumetric OCT data sets based on ray casting results in volume visualizations with indistinct tissue features and sub-optimal depth perception. Recent developments in hand-held and microscope-integrated intrasurgical OCT designed for real-time volumetric imaging motivate development of rendering algorithms which are both visually appealing and fast enough to support real time rendering, potentially from multiple viewpoints for stereoscopic visualization. We report on an enhanced, real time, integrated volumetric rendering pipeline which incorporates high performance volumetric median and Gaussian filtering, boundary and feature enhancement, depth encoding, and lighting into a ray casting volume rendering model. We demonstrate this improved model implemented on graphics processing unit (GPU) hardware for real-time volumetric rendering of OCT data during tissue phantom and live human surgical imaging. We show that this rendering produces enhanced 3D visualizations of pathology and intraoperative maneuvers compared to standard ray casting.

Proton exchange membranes (PEM) are critical components of low temperature fuel cells. Most PEMs are made of perfluorinated sulfonic acid polymers such as Nafion®. However, Nafion has a high methanol permeability which is limiting its applicability in direct methanol fuel cells (DMFCs). Here, we report on novel sulfonated pillar[5]arene/Nafion composite membranes with improved properties for application in DMFCs. The properties of the novel composite membranes were investigated under a range of synthesis and operating conditions. Under most conditions, the novel composite membranes exhibited properties far superior than Nafion. For example, the proton conductivity of the sulfonated pillar[5]arene's (10 wt.%)/Nafion composite membrane was 0.145 × 10−4 S cm−1 at 80 °C, while methanol permeability was 2.43 × 10−6 cm2/s. Proton selectivity was increased up to two-fold compared to Nafion-recast membrane. The likely mechanisms for improvements were discussed. Overall, these results indicate that these novel composite membranes are promising for application in DMFCs.

Systematic review and meta-analysis of the natural history of geographic atrophy (GA).Several different models have been used to describe the natural history of GA in untreated eyes, and the reported progression rates vary widely across clinical trials.We searched in MEDLINE, EMBASE, Cochrane Library, Clinicaltrials.gov, and PubMed for studies that measured GA size in untreated eyes over a follow-up period ranging from the start dates of the databases through June 6, 2017. Data were analyzed using 3 models: (1) the area linear model, in which the lesion area enlarges linearly with time; (2) the radius linear model (RLM), in which the lesion radius expands linearly with time; and (3) the area exponential model, in which the lesion area changes exponentially with time. A horizontal translation factor was added to shift each data set to correct for the differences in participant entry time into the studies. The model that best fit data was determined by performing residual analyses, determining the dependence of growth rate on time, and the predicted age of GA onset. The risk of bias was assessed using the Newcastle-Ottawa scale.We included 25 studies with data from 2942 eyes. The RLM yielded the best goodness of fit and predictive performance of GA progression. Cumulative data for untreated eyes fit a straight line in the RLM (rIn this meta-analysis, the progression pattern of GA was uniform across a wide range of studies, and best fit the RLM. Our analysis may shed light on the natural history of GA and may influence the design of future clinical trials.

PURPOSE To investigate the relationship between intraocular pressure (IOP) and big bubble (BB) formation in a model of deep anterior lamellar keratoplasty (DALK). DESIGN Ex-vivo. METHODS Corneoscleral buttons from human donors were loaded onto an artificial anterior chamber connected to a column of balanced salt solution. A surgeon-in-training learned to perform DALK via the BB technique using swept-source microscope-integrated optical coherence tomography (SS-MIOCT) with heads-up display (HUD). DALK procedures were performed at 6 different IOPs (5, 10, 15, 20, 30, or 40 mm Hg; n = 6 per group) in a randomized fashion, with the surgeon-in-training masked to the pressure and guided by SS-MIOCT with HUD. For a subset of corneas within each pressure group, DALK was performed on matching donor tissue at a control IOP. BB diameter was recorded, and a diameter exceeding the trephine diameter was considered optimal. RESULTS Wilcoxon rank sum test showed a difference in BB diameter among the different pressure groups (mean ± SD of 7.75 ± 1.60, 8.33 ± 1.99, 10.9 ± 0.92, 9.08 ± 1.07, 6.67 ± 3.33, and 3.42 ± 3.77 mm in the 5, 10, 15, 20, 30, and 40 mm Hg groups, respectively; P = 0.0014). Per Tukey test, this difference was attributable to comparisons between the 40 mm Hg group and the 5, 10, 15, or 20 mm Hg groups (P = 0.04, 0.02, 0.0001, 0.004, respectively). CONCLUSIONS In this ex-vivo model of DALK, the BB technique guided by SS-MIOCT with HUD yielded bubbles of optimal diameters only at physiologic pressures (10‒20 mm Hg). Extremely high IOP (40 mm Hg) resulted in BBs of significantly smaller diameter than BBs obtained at physiologic and low (5 mm Hg) IOPs.

Minimally-invasive microsurgery has resulted in improved outcomes for patients. However, operating through a microscope limits depth perception and fixes the visual perspective, which result in a steep learning curve to achieve microsurgical proficiency. We introduce a surgical imaging system employing four-dimensional (live volumetric imaging through time) microscope-integrated optical coherence tomography (4D MIOCT) capable of imaging at up to 10 volumes per second to visualize human microsurgery. A custom stereoscopic heads-up display provides real-time interactive volumetric feedback to the surgeon. We report that 4D MIOCT enhanced suturing accuracy and control of instrument positioning in mock surgical trials involving 17 ophthalmic surgeons. Additionally, 4D MIOCT imaging was performed in 48 human eye surgeries and was demonstrated to successfully visualize the pathology of interest in concordance with preoperative diagnosis in 93% of retinal surgeries and the surgical site of interest in 100% of anterior segment surgeries. In vivo 4D MIOCT imaging revealed sub-surface pathologic structures and instrument-induced lesions that were invisible through the operating microscope during standard surgical maneuvers. In select cases, 4D MIOCT guidance was necessary to resolve such lesions and prevent post-operative complications. Our novel surgical visualization platform achieves surgeon-interactive 4D visualization of live surgery which could expand the surgeon’s capabilities.

Optical coherence tomography (OCT) allows for micron scale imaging of the human retina and cornea. Current generation research and commercial intrasurgical OCT prototypes are limited to live B-scan imaging. Our group has developed an intraoperative microscope integrated OCT system capable of live 4D imaging. With a heads up display (HUD) 4D imaging allows for dynamic intrasurgical visualization of tool tissue interaction and surgical maneuvers. Currently our system relies on operator based manual tracking to correct for patient motion and motion caused by the surgeon, to track the surgical tool, and to display the correct B-scan to display on the HUD. Even when tracking only bulk motion, the operator sometimes lags behind and the surgical region of interest can drift out of the OCT field of view. To facilitate imaging we report on the development of a fast volume based tool segmentation algorithm. The algorithm is based on a previously reported volume rendering algorithm and can identify both the tool and retinal surface. The algorithm requires 45 ms per volume for segmentation and can be used to actively place the B-scan across the tool tissue interface. Alternatively, real-time tool segmentation can be used to allow the surgeon to use the surgical tool as an interactive B-scan pointer.

Ophthalmic surgeons manipulate micron-scale tissues using stereopsis through an operating microscope and instrument shadowing for depth perception. While ophthalmic microsurgery has benefitted from rapid advances in instrumentation and techniques, the basic principles of the stereo operating microscope have not changed since the 1930’s. Optical Coherence Tomography (OCT) has revolutionized ophthalmic imaging and is now the gold standard for preoperative and postoperative evaluation of most retinal and many corneal procedures. We and others have developed initial microscope-integrated OCT (MIOCT) systems for concurrent OCT and operating microscope imaging, but these are limited to 2D real-time imaging and require offline post-processing for 3D rendering and visualization. Our previously presented 4D MIOCT system can record and display the 3D surgical field stereoscopically through the microscope oculars using a dual-channel heads-up display (HUD) at up to 10 micron-scale volumes per second. In this work, we show that 4D MIOCT guidance improves the accuracy of depth-based microsurgical maneuvers (with statistical significance) in mock surgery trials in a wet lab environment. Additionally, 4D MIOCT was successfully performed in 38/45 (84%) posterior and 14/14 (100%) anterior eye human surgeries, and revealed previously unrecognized lesions that were invisible through the operating microscope. These lesions, such as residual and potentially damaging retinal deformation during pathologic membrane peeling, were visualized in real-time by the surgeon. Our integrated system provides an enhanced 4D surgical visualization platform that can improve current ophthalmic surgical practice and may help develop and refine future microsurgical techniques.

Systematic experiments have been carried out to study the performance of the novel sodium titanate (Na 2 Ti 3 O 7 ) nanotube/Nafion ® composite membrane (5 wt% Na 2 Ti 3 O 7 ) in a single direct methanol fuel cell (DMFC) at different operating temperatures, methanol concentrations, air flow rates, methanol flow rates, and cathode humidification temperatures. The experimental results showed that the composite membrane outperform pure Nafion ® membranes with the same thickness, Nafion ® 112, under all the operating conditions. Furthermore, under some operating conditions, the new composite membranes even outperform Nafion ® 117, a much thicker membrane. These experimental results have proved that the new composite membrane is superior to pure Nafion ® membrane in DMFCs and the addition of Na 2 Ti 3 O 7 nanotubes into Nafion ® is an effective way to improve membrane performances.

Novel nanocomposite membrane of sodium titanate/Nafion based on sodium titanate nanotubes with Nafion ® were prepared by solvent casting techniques. Nanotubes of sodium titanate were synthesized by hydrothermal method. TEM, XRD, and FTIR were employed to characterize the crystal phase, microstructure, and other physicochemical properties of the membrane and the nanotube samples. FTIR results showed us that the nanotube material of Na 2 Ti 3 O 7 has existed in the nanocomposite membrane of Na 2 Ti 3 O 7 /Nafion. The existence of sodium titanate nanotubes in Nafion ® improves the methanol crossover and makes promising practical value of blocking methanol in direct methanol fuel cells.

In this study, novel sodium titanate (Na 2 Ti 3 O 7 ) nanotube/Nafion ® composite membranes were prepared by a solution casting method. The properties of these composite membranes were studied using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Additionally, the water uptake, methanol permeability, proton conductivity, and selectivity of the composite membranes were measured to evaluate the applicability of these membranes in DMFCs. It was found that the addition of Na 2 Ti 3 O 7 nanotubes enhanced the water uptake and reduced the methanol permeability of the composite membranes. The proton conductivity and methanol permeability depend on the Na 2 Ti 3 O 7 nanotube content. Using the selectivity, the optimal nanotube contents was found to be 5 wt%. The new composite membrane was found to have significantly higher selectivity than a pure Nafion ® membrane and thus has good potential to outperform Nafion ® in DMFCs.

Carbon-supported PtAuSn/C nanoparticle catalyst was synthesized by a microwave-assisted polyol process. The process is a quick process that only requires a few minutes to complete. The catalyst thus obtained was characterized by transmission electron microscopy and X-ray diffraction analysis. The electrochemical performance of the catalyst, for the ethanol oxidation reaction, was also investigated. The results indicated that the PtAuSn/C catalyst was uniformly dispersed on carbon and was in the nano-size range. The electrochemical measurements indicated that PtAuSn/C nanoparticle catalyst synthesized by the microwave-assisted polyol method demonstrated a significantly higher electrochemically active area and higher catalytic activity than Pt/C for the ethanol oxidation reaction.

The first generation of intrasurgical optical coherence tomography (OCT) systems displayed OCT data onto a separate computer monitor, requiring surgeons to look away from the surgical microscope. In order to provide real-time OCT feedback without requiring surgeons to look away during surgeries, recent prototype research and commercial intrasurgical OCT systems have integrated heads-up display (HUD) systems into the surgical microscopes to allow the surgeons to access the OCT data and the surgical field through the oculars concurrently. However, all current intrasurgical OCT systems with a HUD are only capable of imaging through one ocular limiting the surgeon’s depth perception of OCT volumes. Stereoscopy is an effective technology to dramatically increase depth perception by presenting an image from slightly different angles to each eye. Conventional stereoscopic HUD use a pair of micro displays which require bulky optics. Several new approaches for HUDs are reported to use only one micro display at the expense of image brightness or increased footprint. Therefore, these techniques for HUD are not suitable to be integrated into microscopes. We have developed a novel stereoscopic HUD which uses spatial multiplexing to project stereo views into both oculars simultaneously with only one micro-display and three optical elements for our microscope-integrated OCT system. Simultaneous stereoscopic views of OCT volumes are computed in real time by GPU-enabled OCT system software. We present, to our knowledge, the first microscope integrated stereoscopic HUD used for intrasurgical OCT with a novel optical design for stereoscopic viewing devices and report on its preliminary use in human vitreoretinal surgeries.

Magnification of the surgical field using the operating microscope facilitated profound innovations in retinal surgery in the 1970s, such as pars plana vitrectomy. Although surgical instrumentation and illumination techniques are continually developing, the operating microscope for vitreoretinal procedures has remained essentially unchanged and currently limits the surgeon's depth perception and assessment of subtle microanatomy. Optical coherence tomography (OCT) has revolutionized clinical management of retinal pathology, and its introduction into the operating suite may have a similar impact on surgical visualization and treatment. In this article, we review the evolution of OCT for retinal surgery, from perioperative analysis to live volumetric (four-dimensional, 4D) image-guided surgery. We begin by briefly addressing the benefits and limitations of the operating microscope, the progression of OCT technology, and OCT applications in clinical/perioperative retinal imaging. Next, we review intraoperative OCT (iOCT) applications using handheld probes during surgical pauses, two-dimensional (2D) microscope-integrated OCT (MIOCT) of live surgery, and volumetric MIOCT of live surgery. The iOCT discussion focuses on technological advancements, applications during human retinal surgery, translational difficulties and limitations, and future directions.

Intra-operative optical coherence tomography (OCT) requires a display technology which allows surgeons to visualize OCT data without disrupting surgery. Previous research and commercial intrasurgical OCT systems have integrated heads-up display (HUD) systems into surgical microscopes to provide monoscopic viewing of OCT data through one microscope ocular. To take full advantage of our previously reported real-time volumetric microscope-integrated OCT (4D MIOCT) system, we describe a stereoscopic HUD which projects a stereo pair of OCT volume renderings into both oculars simultaneously. The stereoscopic HUD uses a novel optical design employing spatial multiplexing to project dual OCT volume renderings utilizing a single micro-display. The optical performance of the surgical microscope with the HUD was quantitatively characterized and the addition of the HUD was found not to substantially effect the resolution, field of view, or pincushion distortion of the operating microscope. In a pilot depth perception subject study, five ophthalmic surgeons completed a pre-set dexterity task with 50.0% (SD = 37.3%) higher success rate and in 35.0% (SD = 24.8%) less time on average with stereoscopic OCT vision compared to monoscopic OCT vision. Preliminary experience using the HUD in 40 vitreo-retinal human surgeries by five ophthalmic surgeons is reported, in which all surgeons reported that the HUD did not alter their normal view of surgery and that live surgical maneuvers were readily visible in displayed stereoscopic OCT volumes.