Quantitative Evaluation of Type 1 and Type 2 Choroidal Neovascularization Components Under Treatment With Projection-Resolved OCT Angiography.

Purpose: To evaluate the response of type 1 and type 2 macular neovascularization (MNV) components under anti-vascular endothelial growth factor (VEGF) treatment in age-related macular degeneration (AMD) using projection-resolved optical coherence tomography angiography (PR-OCTA). Methods: This retrospective study included eyes with treatment-naïve exudative AMD treated with anti-VEGF injections under a pro re nata (PRN) protocol over 1 year. Two-dimensional MNV areas and three-dimensional MNV volumes were derived from macular PR-OCTA scans using an automated convolutional neural network. MNV was detected as flow signal within the outer retinal slab. Type 1 components and type 2 components were analyzed separately. Results: Of 17 enrolled eyes, 12 eyes were pure type 1 MNV and five eyes were type 2 MNV. In eyes with pure type 1, the total (sum of type 1 and type 2 components) MNV area and volume did not change from baseline to 6 months or 12 months (P > 0.05). In eyes with type 2 MNV, the total MNV area significantly decreased from the baseline to 6 months (P = 0.0074) and 12 months (P = 0.014). The total type 2 MNV volume also decreased from baseline visit to visits at 6 months and at 12 months, nearing statistical signifiicance (P = 0.061 and P = 0.074). In eyes with type 2 MNV, the type 1 component increased from 0.093 mm2 to 0.30 mm2 (P = 0.058), and the type 2 component decreased from 0.37 mm2 at 6 months to 0 at 12 months (P = 0.0087). Conclusions: Type 1 and type 2 MNV may have different response under PRN anti-VEGF treatment over 1 year.

Multi-Plexus Nonperfusion Area Segmentation in Widefield OCT Angiography Using a Deep Convolutional Neural Network.

Purpose: To train and validate a convolutional neural network to segment nonperfusion areas (NPAs) in multiple retinal vascular plexuses on widefield optical coherence tomography angiography (OCTA). Methods: This cross-sectional study included 202 participants with a full range of diabetic retinopathy (DR) severities (diabetes mellitus without retinopathy, mild to moderate non-proliferative DR, severe non-proliferative DR, and proliferative DR) and 39 healthy participants. Consecutive 6 × 6-mm OCTA scans at the central macula, optic disc, and temporal region in one eye from 202 participants in a clinical DR study were acquired with a 70-kHz OCT commercial system (RTVue-XR). Widefield OCTA en face images were generated by montaging the scans from these three regions. A projection-resolved OCTA algorithm was applied to remove projection artifacts at the voxel scale. A deep convolutional neural network with a parallel U-Net module was designed to detect NPAs and distinguish signal reduction artifacts from flow deficits in the superficial vascular complex (SVC), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). Expert graders manually labeled NPAs and signal reduction artifacts for the ground truth. Sixfold cross-validation was used to evaluate the proposed algorithm on the entire dataset. Results: The proposed algorithm showed high agreement with the manually delineated ground truth for NPA detection in three retinal vascular plexuses on widefield OCTA (mean ± SD F-score: SVC, 0.84 ± 0.05; ICP, 0.87 ± 0.04; DCP, 0.83 ± 0.07). The extrafoveal avascular area in the DCP showed the best sensitivity for differentiating eyes with diabetes but no retinopathy (77%) from healthy controls and for differentiating DR by severity: DR versus no DR, 77%; referable DR (rDR) versus non-referable DR (nrDR), 79%; vision-threatening DR (vtDR) versus non-vision-threatening DR (nvtDR), 60%. The DCP also showed the best area under the receiver operating characteristic curve for distinguishing diabetes from healthy controls (96%), DR versus no DR (95%), and rDR versus nrDR (96%). The three-plexus-combined OCTA achieved the best result in differentiating vtDR and nvtDR (81.0%). Conclusions: A deep learning network can accurately segment NPAs in individual retinal vascular plexuses and improve DR diagnostic accuracy. Translational Relevance: Using a deep learning method to segment nonperfusion areas in widefield OCTA can potentially improve the diagnostic accuracy of diabetic retinopathy by OCT/OCTA systems.

Glaucomatous Focal Perfusion Loss in the Macula Measured by Optical Coherence Tomographic Angiography.

PURPOSE: To measure low perfusion area (LPA) and focal perfusion loss (FPL) in the macula using optical coherence tomography (OCT) angiography (OCTA) for glaucoma. DESIGN: Prospective, cross-sectional "case-control" comparison study. METHODS: A total of 60 patients with primary open-angle glaucoma (POAG) and 37 healthy participants were analyzed. AngioVue 6 × 6-mm high-definition (400 × 400 transverse pixels) macular OCTA scans were performed on one eye of each participant. Flow signal was calculated using the split-spectrum amplitude-decorrelation angiography algorithm. En face ganglion cell layer plexus (GCLP) and superficial vascular complex (SVC) images were generated. Using custom software, vessel density (VD) maps were obtained by computing the fraction of area occupied by flow pixels after low-pass filtering by local averaging 41 × 41 pixels. LPA was defined by local VD below 0.5 percentile over a contiguous area above 98.5 percentile of the healthy reference population. The FPL was the percentage VD loss (relative to normal mean) integrated over the LPA. RESULTS: Among patients with POAG, 30 had perimetric and 30 had preperimetric glaucoma. The LPAGCLP-VD was 0.16±0.38 mm2 in normal and 5.78±6.30 mm2 in glaucoma subjects (P < .001). The FPLGCLP-VD was 0.20%±0.47% in normal and 7.52%±8.84% in glaucoma subjects (P < .001). The perimetric glaucoma diagnostic accuracy, measured by the area under the receiver operating curve, was 0.993 for LPAGCLP-VD and 0.990 for FPLGCLP-VD. The sensitivities were, respectively, 96.7% and 93.3% at 95% specificity. The LPAGCLP-VD and FPLGCLP-VD had good repeatability (0.957 and 0.952 by intraclass correlation coefficient). Diagnostic accuracy was better than GCLP VD (AROC 0.950, sensitivity 83.3%) and OCT ganglion cell complex (GCC) thickness (AROC 0.927, sensitivity 80.0%) and GCC focal loss volume (AROC 0.957, sensitivity 80.0%). The LPAGCLP-VD and FPLGCLP-VD correlated well with central VF mean deviations (Pearson r = -0.716 and -0.705 respectively, both P < .001). CONCLUSION: Assessment of macular FPL using OCTA is useful in evaluating glaucomatous damage.

Selenium enhancement strategy under precise fertilization in foxtail millet rhizosphere.

Enhancing selenium content in millet is a crucial strategy to address malnutrition due to selenium deficiency. Jingu 21 was used as the experimental material in this study. The effects of selenium fertilizer application amount, vertical position of fertilization, and horizontal position of fertilization on the selenium content in various millet organs were assessed using a three-factor, five-level quadratic rotation combination design. The results indicate that selenium fertilizer application amount, vertical fertilization position, and horizontal fertilization position significantly affected the selenium content in various millet organs. Analysis of the selenium accumulation for different millet organs show that the recommended optimal agronomic strategy for producing selenium-enriched millet comprises a selenium fertilizer application amount ranging from 100.65 to 120.15 kg/hm2, a vertical fertilization position of 10.28-11.76 cm, and a horizontal fertilization position of 6.74-7.29 cm. This study elucidates the patterns of selenium content accumulation under precise fertilization measures of millet and provides valuable insights for implementing selenium enhancement techniques in the production of selenium-enriched millet.

Pseudorabies virus hijacks the Rab6 protein to promote viral assembly and egress.

Pseudorabies virus (PRV) is recognized as the aetiological agent responsible for Aujeszky's disease, or pseudorabies, in swine populations. Rab6, a member of the small GTPase family, is implicated in various membrane trafficking processes, particularly exocytosis regulation. Its involvement in PRV infection, however, has not been documented previously. In our study, we observed a significant increase in the Rab6 mRNA and protein levels in both PK-15 porcine kidney epithelial cells and porcine alveolar macrophages, as well as in the lungs and spleens of mice infected with PRV. The overexpression of wild-type Rab6 and its GTP-bound mutant facilitated PRV proliferation, whereas the GDP-bound mutant form of Rab6 had no effect on viral propagation. These findings indicated that the GTPase activity of Rab6 was crucial for the successful spread of PRV. Further investigations revealed that the reduction in Rab6 levels through knockdown significantly hampered PRV proliferation and disrupted virus assembly and egress. At the molecular level, Rab6 was found to interact with the PRV glycoproteins gB and gE, both of which are essential for viral assembly and egress. Our results collectively suggest that PRV exploits Rab6 to expedite its assembly and egress and identify Rab6 as a promising novel target for therapeutic treatment for PRV infection.

Visualizing features with wide-field volumetric OCT angiography.

Optical coherence tomography (OCT) and its extension OCT angiography (OCTA) have become essential clinical imaging modalities due to their ability to provide depth-resolved angiographic and tissue structural information non-invasively and at high resolution. Within a field of view, the anatomic detail available is sufficient to identify several structural and vascular pathologies that are clinically relevant for multiple prevalent blinding diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and vein occlusions. The main limitation in contemporary OCT devices is that this field of view is limited due to a fundamental trade-off between system resolution/sensitivity, sampling density, and imaging window dimensions. Here, we describe a swept-source OCT device that can capture up to a 12 × 23-mm field of view in a single shot and show that it can identify conventional pathologic features such as non-perfusion areas outside of conventional fields of view. We also show that our approach maintains sensitivity sufficient to visualize novel features, including choriocapillaris morphology beneath the macula and macrophage-like cells at the inner limiting membrane, both of which may have implications for disease.

Optimizing numerical k-sampling for swept-source optical coherence tomography angiography.

High-quality swept-source optical coherence tomography (SS-OCT) requires accurate k-sampling, which is equally vital for optical coherence tomography angiography (OCTA). Most SS-OCT systems are equipped with hardware-driven k-sampling. However, this conventional approach raises concerns over system cost, optical alignment, imaging depth, and stability in the clocking circuit. This work introduces an optimized numerical k-sampling method to replace the additional k-clock hardware. Using this method, we can realize high axial resolution (4.9-µm full-width-half-maximum, in air) and low roll-off (2.3 dB loss) over a 4-mm imaging depth. The high axial resolution and sensitivity achieved by this simple numerical method can reveal anatomic and microvascular structures with structural OCT and OCTA in both macular and deeper tissues, including the lamina cribrosa, suggesting its usefulness in imaging retinopathy and optic neuropathy.

A new andrographolide derivative ADA targeting SIRT3-FOXO3a signaling mitigates cognitive impairment by activating mitophagy and inhibiting neuroinflammation in Apoe4 mice.

BACKGROUND: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and mitophagy deficit was identified as the typical abnormality in early stage of AD. The neuroprotective effect of andrographolide (AGA) has been confirmed, anda acetylated derivative of AGA (3,14,19-triacetylandrographolide, ADA) was considered to have stronger efficacy. PURPOSE: The current study aims to investigate the impact of ADA on cognitive ability in a sporadic AD model and explore its potential mechanism. STUDY DESIGN/ METHODS: Apoe4 mouse was adopted for evaluating the impact of AGA on cognitive impairment through a serious of behavioral tests. The molecular mechanism of ADA involved in mitophagy and neuroinflammation was investigated in detailby Western blot, ELISA, immunofluorescence and transmission electron microscopy in Apoe4 mice, as well as Apoe4-transfected BV2 cells and HT22 cells. RESULTS: ADA application significantly improved cognitive impairment of Apoe4 mice, and lessened Aß load and neuronal damage, which has stronger activity than its prototype AGA. Accumulated mitophagy markers LC3II, P62, TOM20, PINK1 and Parkin, and decreased mitophagy receptor BNIP3 in hippocampus of Apoe4 mice were greatly reversed after ADA treatment. Meanwhile, ADA promoted the recruitment of BNIP3 to mitochondria, and the transport of damaged mitochondria to lysosome, indicating that disturbed mitophagy in AD mice was restored by ADA. Inhibited SIRT3 and FOXO3a in Apoe4 mice brains were elevated after ADA treatment. ADA also lightened the neuroinflammation caused by NLRP3 inflammasome activation. Additionally, damaged mitophagy and/or activated NLRP3 inflammasome were also observed in BV2 cells and HT22 cells transfected with Apoe4, all of which were rescued by ADA incubation. Noteworthily, SIRT3 inhibitor 3-TYP could abolish the impact of ADA on mitophagy and NLRP3 inflammasome in vitro. CONCLUSION: ADA exerted stronger cognition-enhancing ability in relative to AGA, and ADA could repaire mitophagy deficiency via SIRT3-FOXO3a pathway, and subsequently inhibite NLRP3 inflammasome to mitigate AD pathology.

Immunological dynamic characteristics in acute myeloid leukemia predict the long-term outcomes and graft-versus host-disease occurrences post-transplantation.

To investigate the relationship between immune dynamic and graft-versus-host-disease (GVHD) risk, 111 initial diagnostic acute myeloid leukemia patients were reviewed. The flow cytometry data of 12 major lymphocyte subsets in bone marrow (BM) from 60 transplant patients at four different time points were analyzed. Additionally, 90 immune subsets in peripheral blood (PB) of 11 post-transplantation on day 100 were reviewed. Our results demonstrated that transplant patients had longer OS compared to non-transplant patients (P < 0.001). Among transplant patients, those who developed GVHD showed longer OS than those without GVHD (P < 0.05). URD donors and CMV-negative status donors were associated with improved OS in transplant patients (P < 0.05). Importantly, we observed a decreased Th/Tc ratio in BM at initial diagnostic in patients with GVHD compared to those without GVHD (P = 0.034). Receiver operating characteristic analysis indicated that a low Th/Tc ratio predicted an increased risk of GVHD with a sensitivity of 44.44% and specificity of 87.50%. Moreover, an increased T/NK ratio in BM of post-induction chemotherapy was found to be associated with GVHD, with a sensitivity of 75.76% and specificity of 65.22%. Additionally, we observed a decreased percentage of NK1 (CD56-CD16+NK) in PB on day 100 post-transplantation in the GVHD group (P < 0.05). These three indicators exhibit promising potential as specific and useful biomarkers for predicting GVHD. These findings provide valuable insights for the early identification and management of GVHD risk, thereby facilitating the possibility of improving patient outcomes.

Interpretable Diabetic Retinopathy Diagnosis Based on Biomarker Activation Map.

OBJECTIVE: Deep learning classifiers provide the most accurate means of automatically diagnosing diabetic retinopathy (DR) based on optical coherence tomography (OCT) and its angiography (OCTA). The power of these models is attributable in part to the inclusion of hidden layers that provide the complexity required to achieve a desired task. However, hidden layers also render algorithm outputs difficult to interpret. Here we introduce a novel biomarker activation map (BAM) framework based on generative adversarial learning that allows clinicians to verify and understand classifiers' decision-making. METHODS: A data set including 456 macular scans were graded as non-referable or referable DR based on current clinical standards. A DR classifier that was used to evaluate our BAM was first trained based on this data set. The BAM generation framework was designed by combing two U-shaped generators to provide meaningful interpretability to this classifier. The main generator was trained to take referable scans as input and produce an output that would be classified by the classifier as non-referable. The BAM is then constructed as the difference image between the output and input of the main generator. To ensure that the BAM only highlights classifier-utilized biomarkers an assistant generator was trained to do the opposite, producing scans that would be classified as referable by the classifier from non-referable scans. RESULTS: The generated BAMs highlighted known pathologic features including nonperfusion area and retinal fluid. CONCLUSION/SIGNIFICANCE: A fully interpretable classifier based on these highlights could help clinicians better utilize and verify automated DR diagnosis.

Perfused and Nonperfused Microaneurysms Identified and Characterized by Structural and Angiographic OCT.

PURPOSE: Microaneurysms (MAs) have distinct, oval-shaped, hyperreflective walls on structural OCT, and inconsistent flow signal in the lumen with OCT angiography (OCTA). Their relationship to regional macular edema in diabetic retinopathy (DR) has not been quantitatively explored. DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: A total of 99 participants, including 23 with mild, nonproliferative DR (NPDR), 25 with moderate NPDR, 34 with severe NPDR, and 17 with proliferative DR. METHODS: We obtained 3 × 3-mm scans with a commercial device (Solix, Visionix/Optovue) in 99 patients with DR. Trained graders manually identified MAs and their location relative to the anatomic layers from cross-sectional OCT. Microaneurysms were first classified as perfused if flow signal was present in the OCTA channel. Then, perfused MAs were further classified into fully and partially perfused MAs based on the flow characteristics in en face OCTA. The presence of retinal fluid based on OCT near MAs was compared between perfused and nonperfused types. We also compared OCT-based MA detection to fundus photography (FP)- and fluorescein angiography (FA)-based detection. MAIN OUTCOME MEASURES: OCT-identified MAs can be classified according to colocalized OCTA flow signal into fully perfused, partially perfused, and nonperfused types. Fully perfused MAs may be more likely to be associated with diabetic macular edema (DME) than those without flow. RESULTS: We identified 308 MAs (166 fully perfused, 88 partially perfused, 54 nonperfused) in 42 eyes using OCT and OCTA. Nearly half of the MAs identified in this study straddle the inner nuclear layer and outer plexiform layer. Compared with partially perfused and nonperfused MAs, fully perfused MAs were more likely to be associated with local retinal fluid. The associated fluid volumes were larger with fully perfused MAs compared with other types. OCT/OCTA detected all MAs found on FP. Although not all MAs seen with FA were identified with OCT, some MAs seen with OCT were not visible with FA or FP. CONCLUSIONS: OCT-identified MAs with colocalized flow on OCTA are more likely to be associated with DME than those without flow. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Early Sign of Retinal Neovascularization Evolution in Diabetic Retinopathy: A Longitudinal OCT Angiography Study.

Purpose: To assess whether the combination of en face OCT and OCT angiography (OCTA) can capture observable, but subtle, structural changes that precede clinically evident retinal neovascularization (RNV) in eyes with diabetic retinopathy (DR). Design: Retrospective, longitudinal study. Participants: Patients with DR that had at least 2 visits. Methods: We obtained wide-field OCTA scans of 1 eye from each participant and generated en face OCT, en face OCTA, and cross-sectional OCTA. We identified eyes with RNV sprouts, defined as epiretinal hyperreflective materials on en face OCT with flow signals breaching the internal limiting membrane on the cross-sectional OCTA without recognizable RNV on en face OCTA and RNV fronds, defined as recognizable abnormal vascular structures on the en face OCTA. We examined the corresponding location from follow-up or previous visits for the presence or progression of the RNV. Main Outcome Measures: The characteristics and longitudinal observation of early signs of RNV. Results: From 71 eyes, we identified RNV in 20 eyes with the combination of OCT and OCTA, of which 13 (65%) were photographically graded as proliferative DR, 6 (30%) severe nonproliferative DR, and 1 (5%) moderate nonproliferative diabetic retinopathy. From these eyes, we identified 38 RNV sprouts and 26 RNV fronds at the baseline. Thirty-four RNVs (53%) originated from veins, 24 (38%) were from intraretinal microabnormalities, and 6 (9%) were from a nondilated capillary bed. At the final visit, 53 RNV sprouts and 30 RNV fronds were detected. Ten eyes (50%) showed progression, defined as having a new RNV lesion or the development of an RNV frond from an RNV sprout. Four (11%) RNV sprouts developed into RNV fronds with a mean interval of 7.0 months. Nineteen new RNV sprouts developed during the follow-up, whereas no new RNV frond was observed outside an identified RNV sprout. The eyes with progression were of younger age (P = 0.014) and tended to be treatment naive (P = 0.07) compared with eyes without progression. Conclusions: Longitudinal observation demonstrated that a combination of en face OCT and cross-sectional OCTA can identify an earlier form of RNV before it can be recognized on en face OCTA. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Single-shot OCT and OCT angiography for slab-specific detection of diabetic retinopathy.

In this study, we present an optical coherence tomographic angiography (OCTA) prototype using a 500 kHz high-speed swept-source laser. This system can generate a 75-degree field of view with a 10.4 µm lateral resolution with a single acquisition. With this prototype we acquired detailed, wide-field, and plexus-specific images throughout the retina and choroid in eyes with diabetic retinopathy, detecting early retinal neovascularization and locating pathology within specific retinal slabs. Our device could also visualize choroidal flow and identify signs of key biomarkers in diabetic retinopathy.

Targeting mitophagy for depression amelioration: a novel therapeutic strategy.

Major depressive disorder is a global psychiatric condition characterized by persistent low mood and anhedonia, which seriously jeopardizes the physical and mental well-being of affected individuals. While various hypotheses have been proposed to explicate the etiology of depression, the precise pathogenesis and effective treatment of this disorder remain elusive. Mitochondria, as the primary organelles responsible for cellular energy production, possess the ability to meet the essential energy demands of the brain. Research indicated that the accumulation of damaged mitochondria is associated with the onset of depression. Mitophagy, a type of cellular autophagy, specifically targets and removes excess or damaged mitochondria. Emerging evidence demonstrated that mitophagy dysfunction was involved in the progression of depression, and several pharmacological interventions that stimulating mitophagy exerted excellent antidepressant actions. We provided an overview of updated advancements on the regulatory mechanism of mitophagy and the mitophagy abnormality in depressed patients and animals, as well as in cell models of depression. Meanwhile, various therapeutic strategies to restore mitophagy for depression alleviation were also discussed in this review.

Perfused and Nonperfused Microaneurysms Identified and Characterized by Structural and Angiographic OCT.

Purpose: Microaneurysms (MAs) have distinct, oval-shaped, hyperreflective walls on structural OCT, and inconsistent flow signal in the lumen with OCT angiography (OCTA). Their relationship to regional macular edema in diabetic retinopathy (DR) has not been quantitatively explored. Design: Retrospective, cross-sectional study. Participants: A total of 99 participants, including 23 with mild, nonproliferative DR (NPDR), 25 with moderate NPDR, 34 with severe NPDR, and 17 with proliferative DR. Methods: We obtained 3 × 3-mm scans with a commercial device (Solix, Visionix/Optovue) in 99 patients with DR. Trained graders manually identified MAs and their location relative to the anatomic layers from cross-sectional OCT. Microaneurysms were first classified as perfused if flow signal was present in the OCTA channel. Then, perfused MAs were further classified into fully and partially perfused MAs based on the flow characteristics in en face OCTA. The presence of retinal fluid based on OCT near MAs was compared between perfused and nonperfused types. We also compared OCT-based MA detection to fundus photography (FP)- and fluorescein angiography (FA)-based detection. Main Outcome Measures: OCT-identified MAs can be classified according to colocalized OCTA flow signal into fully perfused, partially perfused, and nonperfused types. Fully perfused MAs may be more likely to be associated with diabetic macular edema (DME) than those without flow. Results: We identified 308 MAs (166 fully perfused, 88 partially perfused, 54 nonperfused) in 42 eyes using OCT and OCTA. Nearly half of the MAs identified in this study straddle the inner nuclear layer and outer plexiform layer. Compared with partially perfused and nonperfused MAs, fully perfused MAs were more likely to be associated with local retinal fluid. The associated fluid volumes were larger with fully perfused MAs compared with other types. OCT/OCTA detected all MAs found on FP. Although not all MAs seen with FA were identified with OCT, some MAs seen with OCT were not visible with FA or FP. Conclusions: OCT-identified MAs with colocalized flow on OCTA are more likely to be associated with DME than those without flow. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Ophthalmology Retina 2023;■:1-8 © 2023 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated Macular Fluid Volume As a Treatment Indicator for Diabetic Macular Edema.

Introduction: To assess the diagnostic accuracy of automatically quantified macular fluid volume (MFV) for treatment-required diabetic macular edema (DME). Methods: This retrospective cross-sectional study included eyes with DME. The commercial software on optical coherence tomography (OCT) produced the central subfield thickness (CST), and a custom deep-learning algorithm automatically segmented the fluid cysts and quantified the MFV from the volumetric scans of an OCT angiography system. Retina specialists treated patients per standard of care based on clinical and OCT findings without access to the MFV. The main outcome measures were the area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of the CST, MFV, and visual acuity (VA) for treatment indication. Results: Of 139 eyes, 39 (28%) were treated for DME during the study period and 101 (72%) were previously treated. The algorithm detected fluid in all eyes; however, only 54 eyes (39%) met the DRCR.net criteria for center-involved ME. The AUROC of MFV predicting a treatment decision of 0.81 was greater than that of CST (0.67) (P = .0048). Untreated eyes that met the optimal threshold for treatment-required DME based on MFV (>0.031 mm3) had better VA than treated eyes (P = .0053). A multivariate logistic regression model showed that MFV (P = .0008) and VA (P = .0061) were significantly associated with a treatment decision, but CST was not. Conclusions: MFV had a higher correlation with the need for treatment for DME than CST and may be especially useful for ongoing management of DME.

Loganin alleviated cognitive impairment in 3×Tg-AD mice through promoting mitophagy mediated by optineurin.

ETHNOPHARMACOLOGICAL RELEVANCE: Corni Fructus is a traditional Chinese herb and widely applied for treatment of age-related disorders in China. Iridoid glycoside was considered as the active ingredient of Corni Fructus. Loganin is one of the major iridoid glycosides and quality control components of Corni Fructus. Emerging evidence emphasized the beneficial effect of loganin on neurodegenerative disorders, such as Alzheimer's disease (AD). However, the detailed mechanism underlying the neuroprotective action of loganin remains to be unraveled. AIM OF THE STUDY: To explore the improvement of loganin on cognitive impairment in 3 × Tg-AD mice and reveal the potential mechanism. MATERIALS AND METHODS: Eight-month 3 × Tg-AD male mice were intraperitoneally injected with loganin (20 and 40 mg/kg) for consecutive 21 days. Behavioral tests were used to evaluated the cognition-enhancing effects of loganin, and Nissl staining and thioflavine S staining were performed to analyze neuronal survival and Aß pathology. Western blot analysis, transmission electron microscopy and immunofluorescence were utilized to explore the molecular mechanism of loganin in AD mice involved mitochondrial dynamics and mitophagy. Aß25-35-induced SH-SY5Y cells were applied to verify the potential mechanism in vitro. RESULTS: Loganin significantly mitigated the learning and memory deficit and amyloid ß-protein (Aß) deposition, and recovered synaptic ultrastructure in 3 × Tg-AD mice. Perturbed mitochondrial dynamics characterized by excessive fission and insufficient fusion were restored after loganin treatment. Meanwhile, loganin reversed the increase of mitophagy markers (LC3II, p62, PINK1 and Parkin) and mitochondrial markers (TOM20 and COXIV) in hippocampus of AD mice, and enhanced the location of optineurin (OPTN, a well-known mitophagy receptor) to mitochondria. Accumulated PINK1, Parkin, p62 and LC3II were also revealed in Aß25-35-induced SH-SY5Y cells, which were ameliorated by loganin. Increased OPTN in Aß25-35-treated SH-SY5Y cells was further upregulated by loganin incubation, along with the reduction of mitochondrial ROSand elevation ofmitochondrial membrane potential (MMP). Conversely, OPTN silence neutralized the effect of loganin on mitophagy and mitochondrial function, which is consistent with the finding that loganin presented strong affinity with OPTN measured by molecular docking in silico. CONCLUSIONS: Our observations confirmed that loganin enhanced cognitive function and alleviated AD pathology probably by promoting OPTN-mediated mitophagy,. Loganin might be a potential drug candidate for AD therapy via targeting mitophagy.

Utility of En Face OCT for the Detection of Clinically Unsuspected Retinal Neovascularization in Patients with Diabetic Retinopathy.

PURPOSE: To assess the value of en face OCT for detecting clinically unsuspected retinal neovascularization (RNV) in patients with nonproliferative diabetic retinopathy (NPDR). DESIGN: A retrospective, cross-sectional study. PARTICIPANTS: Treatment-naïve patients clinically graded as NPDR in an ongoing prospective observational OCT angiography (OCTA) study at a tertiary care center. METHODS: Each patient underwent imaging of 1 eye with a spectral-domain OCTA, generating a 17 × 17-mm widefield image by montaging four 9 × 9-mm scans. Two independent graders examined a combination of en face OCT, en face OCTA with a custom vitreoretinal interface slab, and cross-sectional OCTA to determine the presence of RNV. We measured the area of RNV flow within RNV lesions on en face OCTA. MAIN OUTCOME MEASURES: Detection rate of clinically occult RNV with OCT and OCTA. RESULTS: Of 63 enrolled eyes, 27 (43%) were clinically graded as severe NPDR, 16 (25%) as moderate NPDR, and 20 (32%) as mild NPDR. Using the combination of en face OCT, en face OCTA, and cross-sectional OCTA, the graders detected 42 RNV lesions in 12 (19%) eyes, of which 8 (67%) were graded as severe NPDR, 2 (17%) as moderate NPDR, and 2 (17%) as mild NPDR. The sensitivity of en face OCT alone for detecting eyes with RNV was similar to that of en face OCTA alone (100% vs. 92%; P = 0.32), whereas the specificity of en face OCT alone was significantly lower than that of en face OCTA alone (32% vs. 73%; P < 0.001). For detecting individual RNV lesions, the en face OCT was 100% sensitive, compared with 67% sensitivity for the en face OCTA (P < 0.001). The area of RNV lesions that manual grading with en face OCTA alone missed was significantly smaller than that of manually detectable RNV (Mean [standard deviation] RNV flow area, 0.015 [0.020] mm2 vs. 0.16 [0.36] mm2; P < 0.001). CONCLUSION: The combination of en face OCT and OCTA can detect clinically occult RNV with high sensitivity. For screening these small lesions, en face OCT may be a useful imaging modality. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Deep learning-based signal-independent assessment of macular avascular area on 6×6 mm optical coherence tomography angiogram in diabetic retinopathy: a comparison to instrument-embedded software.

SYNOPSIS: A deep-learning-based macular extrafoveal avascular area (EAA) on a 6×6 mm optical coherence tomography (OCT) angiogram is less dependent on the signal strength and shadow artefacts, providing better diagnostic accuracy for diabetic retinopathy (DR) severity than the commercial software measured extrafoveal vessel density (EVD). AIMS: To compare a deep-learning-based EAA to commercial output EVD in the diagnostic accuracy of determining DR severity levels from 6×6 mm OCT angiography (OCTA) scans. METHODS: The 6×6 mm macular OCTA scans were acquired on one eye of each participant with a spectral-domain OCTA system. After excluding the central 1 mm diameter circle, the EAA on superficial vascular complex was measured with a deep-learning-based algorithm, and the EVD was obtained with commercial software. RESULTS: The study included 34 healthy controls and 118 diabetic patients. EAA and EVD were highly correlated with DR severity (ρ=0.812 and -0.577, respectively, both p<0.001) and visual acuity (r=-0.357 and 0.420, respectively, both p<0.001). EAA had a significantly (p<0.001) higher correlation with DR severity than EVD. With the specificity at 95%, the sensitivities of EAA for differentiating diabetes mellitus (DM), DR and severe DR from control were 80.5%, 92.0% and 100.0%, respectively, significantly higher than those of EVD 11.9% (p=0.001), 13.6% (p<0.001) and 15.8% (p<0.001), respectively. EVD was significantly correlated with signal strength index (SSI) (r=0.607, p<0.001) and shadow area (r=-0.530, p<0.001), but EAA was not (r=-0.044, p=0.805 and r=-0.046, p=0.796, respectively). Adjustment of EVD with SSI and shadow area lowered sensitivities for detection of DM, DR and severe DR. CONCLUSION: Macular EAA on 6×6 mm OCTA measured with a deep learning-based algorithm is less dependent on the signal strength and shadow artefacts, and provides better diagnostic accuracy for DR severity than EVD measured with the instrument-embedded software.