Pseudoaveraging for denoising of OCT angiography: a deep learning approach for image quality enhancement in healthy and diabetic eyes.

BACKGROUND: This study aimed to develop a deep learning (DL) algorithm that enhances the quality of a single-frame enface OCTA scan to make it comparable to 4-frame averaged scan without the need for the repeated acquisitions required for averaging. METHODS: Each of the healthy eyes and eyes from diabetic subjects that were prospectively enrolled in this cross-sectional study underwent four repeated 6 × 6 mm macular scans (PLEX Elite 9000 SS-OCT), and the repeated scans of each eye were co-registered to produce 4-frame averages. This prospective dataset of original (single-frame) enface scans and their corresponding averaged scans was divided into a training dataset and a validation dataset. In the training dataset, a DL algorithm (named pseudoaveraging) was trained using original scans as input and 4-frame averages as target. In the validation dataset, the pseudoaveraging algorithm was applied to single-frame scans to produce pseudoaveraged scans, and the single-frame and its corresponding averaged and pseudoaveraged scans were all qualitatively compared. In a separate retrospectively collected dataset of single-frame scans from eyes of diabetic subjects, the DL algorithm was applied, and the produced pseudoaveraged scan was qualitatively compared against its corresponding original. RESULTS: This study included 39 eyes that comprised the prospective dataset (split into 5 eyes for training and 34 eyes for validating the DL algorithm), and 105 eyes that comprised the retrospective test dataset. Of the total 144 study eyes, 58% had any level of diabetic retinopathy (with and without diabetic macular edema), and the rest were from healthy eyes or eyes of diabetic subjects but without diabetic retinopathy and without macular edema. Grading results in the validation dataset showed that the pseudoaveraged enface scan ranked best in overall scan quality, background noise reduction, and visibility of microaneurysms (p < 0.05). Averaged scan ranked best for motion artifact reduction (p < 0.05). Grading results in the test dataset showed that pseudoaveraging resulted in enhanced small vessels, reduction of background noise, and motion artifact in 100%, 82%, and 98% of scans, respectively. Rates of false-positive/-negative perfusion were zero. CONCLUSION: Pseudoaveraging is a feasible DL approach to more efficiently improve enface OCTA scan quality without introducing notable image artifacts.

A 27-YEAR-OLD FEMALE WITH MILD BLURRY VISION AND PROLONGED LIGHT ADJUSTMENT IN THE MORNING.

PURPOSE: The following case report highlights a rare presentation of chronic myeloid leukemia-associated hyper-viscosity syndrome and provides a brief review of expected findings and treatment outcomes. METHODS: An otherwise healthy 27-year-old woman presented to the ophthalmology clinic with mild bilateral blurriness (20/20 in both eyes) and prolonged light adaption in the morning for several months. Examination demonstrated severe bilateral venous stasis, white-centered hemorrhages, intraretinal hemorrhage, and peripheral ischemia with diffuse leakage. RESULTS: Same-day CBC demonstrated a leukocytosis of >600,000. Subsequent bone marrow biopsy confirmed the 9,22 translocation (Philadelphia chromosome). On further examination, the patient had an enlarged cardiac silhouette, cytopenia, and splenomegaly past the umbilicus, consistent with a severe and life-threatening leukostasis. CONCLUSION: Ocular involvement can occur in acute and chronic leukemia. Five to ten percentage of patients present to an eye physician first, without a known diagnosis. Prompt systemic treatment can result in near-complete reversal of any intraocular injury in most mild-to-moderate cases, as was the case here.

Hypervirulent Klebsiella pneumoniae infection in a woman with a CDH1 gene mutation.

The CDH1 gene, which encodes E-cadherin, may be associated with cancer when mutated, but the significance of mutations in the context of infection is unknown. In this report, we describe a case of disseminated hypervirulent Klebsiella pneumoniae infection in a 49 year old Caucasian woman with a documented CDH1 mutation.

Choroidal nonperfusion on optical coherence tomography angiography in a case of unilateral posterior segment ocular sarcoidosis misdiagnosed as MEWDS.

PURPOSE: To report a case of presumed ocular sarcoidosis initially presenting with features of multiple evanescent white dot syndrome (MEWDS) with atypical optical coherence tomography angiography (OCTA) findings. OBSERVATIONS: A 23 year-old woman presented with a unilateral central scotoma, photophobia, and decreased visual acuity after a viral illness. Examination of the right eye revealed multiple round white macular spots and stippled granularity at the fovea. Multimodal imaging with fluorescein angiography (FA), indocyanine green angiography (ICG), fundus autofluorescence (FAF), and optical coherence tomography (OCT) was consistent with a diagnosis of MEWDS. However, OCTA demonstrated choriocapillaris (CC) flow deficits, which is not typical for MEWDS. The clinical course was initially consistent with MEWDS, with spontaneous recovery of symptoms over ensuing months. The patient presented five months later with floaters and a central scotoma. Examination showed panuveitis, and systemic evaluation revealed an elevated angiotensin converting enzyme (ACE) and hilar lymphadenopathy on chest x-ray consistent with presumed sarcoidosis. CONCLUSIONS AND IMPORTANCE: A case of MEWDS atypically demonstrated CC flow deficits on OCTA and subsequently presented as uveitis secondary to presumed sarcoidosis. Atypical features in MEWDS may be a sign of another disorder masquerading early on as MEWDS and ought to prompt further investigation.

Trueness of Fit of Biphasic Transversely Isotropic Parameters Model in the Porcine Temporomandibular Joint Disc and Mandibular Condylar Cartilage and Regional Dependence.

Temporomandibular joint (TMJ) disorders (TMDs) are not well understood and the mechanical differences between the regions of the mandibular condylar cartilage (MCC) and the TMJ disc have not been thoroughly compared. As of now, there are no commercially available regenerative therapies for the TMJ. Elucidating the mechanical properties of these two structures of the articulating joint will help future efforts in developing tissue engineering treatments of the TMJ. In this study, we evaluate the compressive properties of the porcine disc and mandibular condylar cartilage by performing unconfined compression at 10% strain with 4.5%/min strain rate. Punches (4 mm biopsy) from both tissues were taken from five different regions of both the MCC and TMJ: anterior, posterior, lateral, medial, and central. Previously, theoretical models of compression in the porcine tissue did not fit the whole ramp-relaxation behavior. Thus, the data stress-relaxation was fitted to the biphasic transversely isotropic model, for both the TMJ disc and cartilage. From the results found in the disc, it was found that the posterior region had the highest values in multiple viscoelastic parameters when compared to the other regions. The mandibular condylar cartilage was only found to be significantly different in the transverse modulus between the posterior and lateral regions. Both the TMJ disc and MCC had similar magnitudes of values (for the modulus and other corresponding compressive properties) and behavior under this testing modality.

Hydrogel to guide chondrogenesis versus osteogenesis of mesenchymal stem cells for fabrication of cartilaginous tissues.

The ideal combination of hydrogel components for regeneration of cartilage and cartilaginous interfaces is a significant challenge because control over differentiation into multiple lineages is necessary. Stabilization of the phenotype of stem cell derived chondrocytes is needed to avoid undesired progression to terminal hypertrophy and tissue mineralization. A novel ternary blend hydrogel composed of methacrylated poly(ethylene glycol) (PEG), gelatin, and heparin (PGH) was designed to guide chondrogenesis by bone marrow derived mesenchymal stem cells (BMSCs) and maintenance of their cartilaginous phenotype. The hydrogel material effects on chondrogenic and osteogenic differentiation by BMSCs were evaluated in comparison to methacrylated gelatin hydrogel (GEL), a conventional bioink used for both chondrogenic and osteogenic applications. PGH and GEL hydrogels were loaded with goat BMSCs and cultured in chondrogenic and osteogenic mediums in vitro over six weeks. The PGH showed no sign of mineral deposition in an osteogenic environment in vitro. To further evaluate material effects, the hydrogels were loaded with adult human BMSCs (hBMSCs) and transforming growth factor ß-3 and grown in subcutaneous pockets in mice over eight weeks. Consistent with the in vitro results, the PGH had greater potential to induce chondrogenesis by BMSCs in vivo compared to the GEL as evidenced by elevated gene expression of chondrogenic markers, supporting its potential for stable cartilage engineering. The PGH also showed a greater percentage of GAG positive cells compared to the GEL. Unlike the GEL, the PGH hydrogel exhibited anti-osteogenic effects in vivo as evidenced by negative Von Kossa staining and suppressed gene expression of hypertrophic and osteogenic markers. By nature of their polymer composition alone, the PGH and GEL regulated BMSC differentiation down different osteochondral lineages. Thus, the PGH and GEL are promising hydrogels to regenerate stratified cartilaginous interfacial tissues in situ, such as the mandibular condyle surface, using undifferentiated BMSCs and a stratified scaffold design.

Potential trade-offs between biomineralization and immunity revealed by shell properties and gene expression profiles of two closely related Crassostrea species.

Species of the Ostreidae family are key ecosystem engineers and many of them - including Crassostrea gigas and Crassostreavirginica - are commercially important aquaculture species. Despite similarities in their morphology and ecology, these two species differ in their ability to defend against pathogens, potentially reflecting species-specific differential specialization of hemocytes on immune defense versus biomineralization. To test this hypothesis, we investigated the expression levels of immune- and biomineralization-related genes as well as mineralogical and mechanical properties of the shells and the calcium sequestration ability of the hemocytes of C. gigas and C. virginica The expression of biomineralization-related genes was higher in C. virginica than in C. gigas in multiple tissues including the mantle edge and hemocytes, while the expression of immune genes was higher in the hemocytes of C. gigas Hemocytes of C. virginica contained more calcium (stored intracellularly as calcium carbonate mineral) compared with those of C. gigas Analysis of the adult shells showed that the crystallinity of calcite was higher and the laths of the foliated layer of the shell were thicker in C. virginica than in C. gigas Mechanically, the shells of C. virginica were stiffer, harder and stronger than those of C. gigas Taken together, our results show that the species-specific differences in physiology (such as disease resistance and exoskeleton properties) are reflected at the cellular and molecular levels in the differential specialization of hemocytes on potentially competing functions (immunity and biomineralization) as well as different expression profiles of other tissues involved in biomineralization (such as the mantle edge).

Regenerative Potential of Various Soft Polymeric Scaffolds in the Temporomandibular Joint Condyle.

PURPOSE: Biodegradable polymeric scaffolds have been used for tissue engineering approaches and can be used to regenerate temporomandibular joint (TMJ) tissues. Synthetic acellular polymeric poly(glycerol sebacate) (PGS) scaffolds and natural scaffolds made from gelatin are polymeric scaffold sponges that could provide a substrate for cell infiltration and remodeling. The authors studied the regenerative potential of these 2 scaffolds in addition to a bioactive signal, magnesium (Mg), in a novel fibrocartilage defect model in the goat mandibular condylar cartilage (MCC). Furthermore, in a departure from the pig model, the authors have started to develop the goat as a repeatable surgical model with easy access into the joint space in skeletally mature animals. MATERIALS AND METHODS: Bilateral osteochondral defects were created in the mandibular condyle of mature female Spanish Boer goats. A 1-mm diameter drill was used to create a trough defect on the articular surface. Four groups were evaluated: 1) an empty control without an implant, 2) PGS with Mg ions, 3) gelatin with Mg ions, and 4) gelatin with Mg ions and trimagnesium phosphate (TMP) powder. Goats were allowed to heal for 3 months, and then the tissues were harvested. RESULTS: The empty control group showed a thin fibrous layer growing within the defect. The PGS and gelatin sponge groups showed a cartilage layer with glycosaminoglycan and collagen type II and robust regeneration of the fibrous layer as exhibited by cell infiltration and collagen in the defect. TMP in the gelatin did not degrade and seemed to hamper healing. CONCLUSION: These results suggest that synthetic and natural sponges can provide a template for new tissue growth in the MCC of the TMJ. Furthermore, this study is the first to attempt to develop the goat as an in vivo TMJ tissue regeneration model.

Idiopathic Retinal Vasculitis, Aneurysms, and Neuroretinitis Syndrome Presenting With Branch Retinal Artery Occlusion.

Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) is a rare syndrome affecting the retinal and optic disc vasculature. Diffuse retinal ischemia, macular edema, and neovascularization may lead to bilateral vision loss. The authors report a case of a 36-year-old woman presenting with branch retinal artery occlusion (BRAO) in her right eye who was subsequently diagnosed with IRVAN syndrome. She was treated with panretinal photocoagulation for peripheral retinal ischemia and pars plana vitrectomy for vitreous hemorrhage. She later developed a BRAO in her left eye. This case demonstrates that BRAO may be a presenting feature of IRVAN syndrome. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:948-951.].

Distinguishing Diabetic Macular Edema From Capillary Nonperfusion Using Optical Coherence Tomography Angiography.

BACKGROUND AND OBJECTIVE: To describe the appearance of diabetic macular edema (DME) using optical coherence tomography angiography (OCTA) and distinguish it from capillary nonperfusion. PATIENTS AND METHODS: Patients with DME were recruited for OCTA imaging. Eyes with confounding retinal diseases were excluded. Using 3 mm × 3 mm OCT angiograms segmented into the superficial and deep inner retinal vascular plexuses, two graders described the appearance of DME and confirmed the diagnosis with structural OCT and fluorescein angiography. RESULTS: DME was evaluated in 17 eyes of 12 patients. The cystoid spaces in DME appeared completely devoid of flow on the OCT angiograms and were oblong in shape with smooth borders that did not follow the distribution of surrounding capillaries, whereas areas of capillary nonperfusion were a greyer hue and had irregular borders. CONCLUSIONS: The cystoid spaces in DME can be differentiated from capillary nonperfusion using OCTA. OCTA may help to guide treatment decisions in the future.

Outer Retinal Changes Preceding Secondary Macular Hole Formation Years After Vitreomacular Traction Release Demonstrated on Spectral-Domain OCT.

This report describes changes documented on spectral-domain optical coherence tomography (SD-OCT) in the right eye of a 58-year-old woman who eventually developed a secondary full-thickness macular hole (FTMH). She had a history of vitreomacular traction (VMT) that had resolved spontaneously with a complete posterior vitreous detachment. Despite VMT resolution, a hyperreflective band from the internal to the external limiting membrane and evidence of photoreceptor disruption persisted on SD-OCT for 2 years, at which point an FTMH developed. Despite VMT release, the unexpected FTMH coupled with the preceding outer retinal changes suggest persistent secondary damage to Müller cells as a potential factor.

CHARACTERIZING THE EFFECT OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY ON TREATMENT-NAIVE CHOROIDAL NEOVASCULARIZATION USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To use optical coherence tomography angiography (OCTA) to characterize the effects of anti-VEGF injections on treatment-naive choroidal neovascularization (CNV). METHODS: From August 2014 to May 2015, treatment-naive eyes with CNV were scanned using a prototype OCTA system on a commercially available SD-OCT device (Optovue Inc, Fremont, CA). Optical coherence tomography angiography scans were obtained before anti-VEGF injection and at follow-up visits. The CNV area and greatest linear dimension (GLD) were measured along with the maximum retinal pigment epithelial detachment (RPED) height. Changes in subretinal and/or intraretinal fluid were also assessed. RESULTS: Six eyes of six patients with treatment-naive CNV were included. Diagnoses included neovascular age-related macular degeneration, idiopathic polypoidal choroidal vasculopathy, CNV secondary to central serous chorioretinopathy and multifocal choroiditis, and macular telangiectasia Type 2 with subretinal neovascularization. After treatment, all patients with fluid on OCT initially showed a decrease in the amount of fluid. Five of six patients demonstrated decreases in CNV GLD and area with an average reduction of 23.6% and 29.8% respectively. CONCLUSION: Both CNV greatest linear dimension and area measured using OCTA decreased after anti-VEGF treatment in most patients. Optical coherence tomography angiography may be a useful tool for monitoring and quantifying the response of CNV to treatment.

DETECTION OF MICROVASCULAR CHANGES IN EYES OF PATIENTS WITH DIABETES BUT NOT CLINICAL DIABETIC RETINOPATHY USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To evaluate the ability of optical coherence tomography angiography to detect early microvascular changes in eyes of diabetic individuals without clinical retinopathy. METHODS: Prospective observational study of 61 eyes of 39 patients with diabetes mellitus and 28 control eyes of 22 age-matched healthy subjects that received imaging using optical coherence tomography angiography between August 2014 and March 2015. Eyes with concomitant retinal, optic nerve, and vitreoretinal interface diseases and/or poor-quality images were excluded. Foveal avascular zone size and irregularity, vessel beading and tortuosity, capillary nonperfusion, and microaneurysm were evaluated. RESULTS: Foveal avascular zone size measured 0.348 mm² (0.1085-0.671) in diabetic eyes and 0.288 mm² (0.07-0.434) in control eyes (P = 0.04). Foveal avascular zone remodeling was seen more often in diabetic than control eyes (36% and 11%, respectively; P = 0.01). Capillary nonperfusion was noted in 21% of diabetic eyes and 4% of control eyes (P = 0.03). Microaneurysms and venous beading were noted in less than 10% of both diabetic and control eyes. Both diabetic and healthy control eyes demonstrated tortuous vessels in 21% and 25% of eyes, respectively. CONCLUSION: Optical coherence tomography angiography was able to image foveal microvascular changes that were not detected by clinical examination in diabetic eyes. Changes to the foveal avascular zone and capillary nonperfusion were more prevalent in diabetic eyes, whereas vessel tortuosity was observed with a similar frequency in normal and diabetic eyes. Optical coherence tomography angiography may be able to detect diabetic eyes at risk of developing retinopathy and to screen for diabetes quickly and noninvasively before the systemic diagnosis is made.

Spectral-domain optical coherence tomography angiography of choroidal neovascularization.

PURPOSE: To describe the characteristics as well as the sensitivity and specificity of detection of choroidal neovascularization (CNV) on optical coherence tomography angiography (OCTA) using spectral-domain optical coherence tomography. DESIGN: Observational, retrospective study. PARTICIPANTS: Seventy-two eyes of 61 subjects (48 eyes of 43 subjects with CNV, 24 eyes of 18 subjects without CNV). METHODS: Patients imaged using the prototype AngioVue OCTA system (Optovue, Inc, Fremont, CA) between August 2014 and October 2014 at New England Eye Center were assessed. Patients in whom CNV was identified on OCTA were evaluated to define characteristics of CNV on OCTA: size using greatest linear dimension (small, <1 mm; medium, 1-2 mm; large, >2 mm), appearance (well-circumscribed, poorly circumscribed), and presence of subretinal and intraretinal fluid. Concurrently, an overlapping second cohort of patients who underwent same-day OCTA and fluorescein angiography (FA) for suspected CNV was evaluated to estimate sensitivity and specificity of OCTA in detecting CNV using FA as ground truth. MAIN OUTCOME MEASURES: Choroidal neovascularization appearance, CNV size, and presence of subretinal and intraretinal fluid. RESULTS: In 48 eyes, CNV was visualized on OCTA. Thirty-one eyes had CNV associated with neovascular age-related macular degeneration. Size of CNV was small in 23% (7/31), medium in 42% (13/31), and large in 35% (11/31). Poorly circumscribed vessels, subretinal fluid, and intraretinal fluid each were seen in 71% (22/31). Seven eyes had CNV associated with central serous chorioretinopathy. Size of CNV was small in 71% (5/7) and large in 29% (2/7). Seventy-one percent (5/7) had well-circumscribed vessels, 86% (6/7) had subretinal fluid, and 14% (1/7) had intraretinal fluid. Thirty eyes with OCTA and same-day FA were evaluated to determine sensitivity and specificity of CNV detection on OCTA. Sensitivity was 50% (4/8) and specificity was 91% (20/22). CONCLUSIONS: Using OCTA allows the clinician to visualize CNV noninvasively and may provide a method for identifying and guiding treatment of CNV. The specificity of CNV detection on OCTA compared with FA seems to be high. Future studies with larger sample sizes are needed to elaborate better on the sensitivity and specificity of CNV detection and to illustrate clinical usefulness.

Elevated cleavage of human immunoglobulin gamma molecules containing a lambda light chain mediated by iron and histidine.

Monoclonal antibodies in liquid formulation undergo nonenzymatic hydrolysis when stored at 5 degrees C for extended periods. This hydrolysis is enhanced at extreme pH and high temperature. In this study we discover that iron in the presence of histidine also enhanced cleavage of human immunoglobulin gamma (IgG) molecules containing a lambda light chain when incubated at 40 degrees C. The level of cleavage was concentration dependent on both iron and histidine levels. Enhanced cleavage with iron and histidine was not observed on IgG molecules containing a kappa light chain. Using CE-SDS to quantify levels of Fab+Fc, the Fab arm, and free light chain (LC) and heavy chain (HC) fragments, we show that cleavage resulted in elevated levels of free light and heavy chain fragments. Using MS we find elevated scission between residues E/C on the LC resulting in LC fragment 1-215. We also observed enhanced cleavage between S/C residues of the HC resulting in HC fragment 1-217. The corresponding Fab+Fc fragment beginning with cys-218 was not found. Instead, we find elevation of a Fab+Fc fragment that began with aspartic acid (cleavage between C/D). Further studies to understand how iron and histidine enhance cleavage of lambda light chain IgG molecules are ongoing.