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Purpose: Retinal ischemia is a major feature of diabetic retinopathy (DR). Traditional nonperfused areas measured by OCT angiography (OCTA) measure blood supply but not ischemia. We propose a novel 3-dimensional (3D) quantitative method to derive ischemia measurements from OCTA data. Design: Cross-sectional study. Participants: We acquired 223 macular OCTA volumes from 33 healthy eyes, 33 diabetic eyes without retinopathy, 7 eyes with nonreferable DR, 17 eyes with referable but nonvision-threatening DR, and 133 eyes with vision-threatening DR. Methods: Each eye was scanned using a spectral-domain OCTA system (Avanti RTVue-XR, Visionix/Optovue, Inc) with 1.6-mm scan depth in a 3 × 3-mm region (640 × 304 × 304 voxels) centered on the fovea. For each scanned OCTA volume, a custom algorithm removed flow projection artifacts. We then enhanced, binarized, and skeletonized the vasculature in each OCTA volume and generated a 3D oxygen tension map using a zero-order kinetics oxygen diffusion model. Each volume was scaled to the average retina thickness in healthy controls after foveal registration and flattening of the Bruch's membrane. Finally, we extracted 3D ischemia maps by comparison with a reference map established from scans of healthy eyes using the same processing. To assess the ability of the ischemia maps to grade DR severity, we constructed receiver operating characteristic curves for diagnosing diabetes, referable DR, and vision-threatening DR. Main Outcome Measures: Spearman correlation coefficient and area under receiver operating characteristic curve (AUC) were used to quantify the ability of the ischemia maps to DR. Results: The ischemia maps showed that the ischemic tissues were at or near pathologically nonperfused areas, but not the normally nonvascular tissue, such as the foveal avascular zone. We found multiple novel metrics, including inferred 3D-oxygen tension, ischemia index, and ischemic volume ratio, were strongly correlated with DR severity. The AUCs of ischemia index measured were 0.94 for diabetes, 0.89 for DR, 0.88 for referable DR, and 0.85 for vision-threatening DR. Conclusions: A quantitative method to infer 3D oxygen tension and ischemia using OCTA in diabetic eyes can identify ischemic tissue that are more specific to pathologic changes in DR. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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 Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract With the expansion of the aging population, age-associated sarcopenia (AAS) has become a severe clinical disease of the elderly and a key challenge for healthy aging. Regrettably, no approved therapies currently exist for treating AAS. In this study, clinical-grade human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were administrated to two classic mouse models (SAMP8 mice and D-galactose-induced aging mice), and their effects on skeletal muscle mass and function were investigated by behavioral tests, immunostaining, and western blotting. Core data results showed that hUC-MSCs significantly restored skeletal muscle strength and performance in both mouse models via mechanisms including raising the expression of crucial extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging. For the first time, the study comprehensively evaluates and demonstrates the preclinical efficacy of clinical-grade hUC-MSCs for AAS in two mouse models, which not only provides a novel model for AAS, but also highlights a promising strategy to improve and treat AAS and other age-associated muscle diseases. This study comprehensively evaluates the preclinical efficacy of clinical-grade hUC-MSCs in treating age-associated sarcopenia (AAS), and demonstrates that hUC-MSCs restore skeletal muscle strength and performance in two AAS mouse models via raising the expression of extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging, which highlights a promising strategy for AAS and other age-associated muscle diseases.

Purpose: To report the clinical utility of optical coherence tomography angiography (OCTA) for demonstrating choroidal neovascularization (CNV) associated with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) retinopathy. Methods: Thirty-three participants with LCHADD (age 7–36 years; median 17) were imaged with OCTA and the Center for Ophthalmic Optics & Lasers Angiography Reading Toolkit (COOL-ART) software was implemented to process OCTA scans. Results: Seven participants (21 %; age 17–36 years; median 25) with LCHADD retinopathy demonstrated evidence of CNV by retinal examination or presence of CNV within outer retinal tissue on OCTA scans covering 3 × 3 and/or 6 × 6-mm. These sub-clinical CNVs are adjacent to hyperpigmented areas in the posterior pole. CNV presented at stage 2 or later of LCHADD retinopathy prior to the disappearance of RPE pigment in the macula. Conclusion: OCTA can be applied as a non-invasive method to evaluate the retinal and choroidal microvasculature. OCTA can reveal CNV in LCHADD even when the clinical exam is inconclusive. These data suggest that the incidence of CNV is greater than expected and can occur even in the early stages of LCHADD retinopathy.

Purpose: Timely diagnosis of eye diseases is paramount to obtaining the best treatment outcomes. OCT and OCT angiography (OCTA) have several advantages that lend themselves to early detection of ocular pathology; furthermore, the techniques produce large, feature-rich data volumes. However, the full clinical potential of both OCT and OCTA is stymied when complex data acquired using the techniques must be manually processed. Here, we propose an automated diagnostic framework based on structural OCT and OCTA data volumes that could substantially support the clinical application of these technologies. Design: Cross sectional study. Participants: Five hundred twenty-six OCT and OCTA volumes were scanned from the eyes of 91 healthy participants, 161 patients with diabetic retinopathy (DR), 95 patients with age-related macular degeneration (AMD), and 108 patients with glaucoma. Methods: The diagnosis framework was constructed based on semisequential 3-dimensional (3D) convolutional neural networks. The trained framework classifies combined structural OCT and OCTA scans as normal, DR, AMD, or glaucoma. Fivefold cross-validation was performed, with 60% of the data reserved for training, 20% for validation, and 20% for testing. The training, validation, and test data sets were independent, with no shared patients. For scans diagnosed as DR, AMD, or glaucoma, 3D class activation maps were generated to highlight subregions that were considered important by the framework for automated diagnosis. Main Outcome Measures: The area under the curve (AUC) of the receiver operating characteristic curve and quadratic-weighted kappa were used to quantify the diagnostic performance of the framework. Results: For the diagnosis of DR, the framework achieved an AUC of 0.95 ± 0.01. For the diagnosis of AMD, the framework achieved an AUC of 0.98 ± 0.01. For the diagnosis of glaucoma, the framework achieved an AUC of 0.91 ± 0.02. Conclusions: Deep learning frameworks can provide reliable, sensitive, interpretable, and fully automated diagnosis of eye diseases. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Artificial intelligence (AI) has been approved for biomedical research in diverse areas from bedside clinical studies to benchtop basic scientific research. For ophthalmic research, in particular glaucoma, AI applications are rapidly growing for potential clinical translation given the vast data available and the introduction of federated learning. Conversely, AI for basic science remains limited despite its useful power in providing mechanistic insight. In this perspective, we discuss recent progress, opportunities, and challenges in the application of AI in glaucoma for scientific discoveries. Specifically, we focus on the research paradigm of reverse translation, in which clinical data are first used for patient-centered hypothesis generation followed by transitioning into basic science studies for hypothesis validation. We elaborate on several distinctive areas of research opportunities for reverse translation of AI in glaucoma including disease risk and progression prediction, pathology characterization, and sub-phenotype identification. We conclude with current challenges and future opportunities for AI research in basic science for glaucoma such as inter-species diversity, AI model generalizability and explainability, as well as AI applications using advanced ocular imaging and genomic data.

Purpose: To report the distinct pattern of retinal perfusion loss captured on optical coherence tomographic angiography (OCTA) in a case of compressive optic neuropathy associated with pituitary adenoma. Observations: A 51-year-old male had bitemporal hemianopia caused by a pituitary adenoma that compressed the optic chiasm. OCTA scans in both eyes showed peripapillary nerve fiber layer plexus defects in the nasal hemispheres and papillomacular corridors. On macular scans, the ganglion cell layer plexus showed papillomacular defects. The perfusion defects corresponded with thinning on structural OCT measurement and loss of sensitivity on visual field tests. Conclusions and importance: Chiasm compression produces a characteristic pattern of perfusion loss that can be recognized OCTA. This knowledge may be useful in the diagnosis and classification of optic neuropathies.

Abstract We investigated the time and location of retinal perfusion recovery after surgical intraocular pressure (IOP) lowering in glaucoma by using optical coherent tomography angiography (OCTA). Seventeen patients were analyzed. The 4.5 × 4.5-mm OCTA scans centered on the disc were performed preoperatively and postoperatively at 6 weeks, 3 months, and 6 months. The peripapillary retinal nerve fiber layer (NFL) thickness, NFL plexus capillary density (NFLP-CD) and visual field (VF) were measured overall and in 8 corresponding sectors. The low-perfusion area (LPA) was used to assess the cumulative area where local NFLP-CD was significantly below normal. At 6 months, the average IOP decreased 5.3 mmHg (P = 0.004), LPA decreased by 15% (P = 0.005), and NFLP-CD improved by 12% (P

Optical coherence tomography (OCT) has changed the standard of care for diagnosis and management of macular diseases in adults. Current commercially available OCT systems, including handheld OCT for pediatric use, have a relatively narrow field of view (FOV), which has limited the potential application of OCT to retinal diseases with primarily peripheral pathology, including many of the most common pediatric retinal conditions. More broadly, diagnosis of all types of retinal detachment (exudative, tractional, and rhegmatogenous) may be improved with OCT-based assessment of retinal breaks, identification of proliferative vitreoretinopathy (PVR) membranes, and the pattern of subretinal fluid. Intraocular tumors both benign and malignant often occur outside of the central macula and may be associated with exudation, subretinal and intraretinal fluid, and vitreoretinal traction. The development of wider field OCT systems thus has the potential to improve the diagnosis and management of myriad diseases in both adult and pediatric retina. In this paper, we present a case series of pediatric patients with complex vitreoretinal pathology undergoing examinations under anesthesia (EUA) using a portable widefield (WF) swept-source (SS)-OCT device.

Purpose: To propose a deep-learning−based method to differentiate arteries from veins in montaged widefield OCT angiography (OCTA). Design: Cross-sectional study. Participants: A total of 232 participants, including 109 participants with diabetic retinopathy (DR), 64 participants with branch retinal vein occlusion (BRVO), 27 participants with diabetes but without DR, and 32 healthy participants. Methods: We propose a convolutional neural network (CAVnet) to classify retinal blood vessels on montaged widefield OCTA en face images as arteries and veins. A total of 240 retinal angiograms from 88 eyes were used to train CAVnet, and 302 retinal angiograms from 144 eyes were used for testing. This method takes the OCTA images as input and outputs the segmentation results with arteries and veins down to the level of precapillary arterioles and postcapillary venules. The network also identifies their intersections. We evaluated the agreement (in pixels) between segmentation results and the manually graded ground truth using sensitivity, specificity, F1-score, and Intersection over Union (IoU). Measurements of arterial and venous caliber or tortuosity are made on our algorithm’s output of healthy and diseased eyes. Main Outcome Measures: Classification of arteries and veins, arterial and venous caliber, and arterial and venous tortuosity. Results: For classification and identification of arteries, the algorithm achieved average sensitivity of 95.3%, specificity of 99.6%, F1 score of 94.2%, and IoU of 89.3%. For veins, the algorithm achieved average sensitivity of 94.4%, specificity of 99.7%, F1 score of 94.1%, and IoU of 89.2%. We also achieved an average sensitivity of 76.3% in identifying intersection points. The results show CAVnet has high accuracy on differentiating arteries and veins in DR and BRVO cases. These classification results are robust across 2 instruments and multiple scan volume sizes. Outputs of CAVnet were used to measure arterial and venous caliber or tortuosity, and pixel-wise caliber and tortuosity maps were generated. Differences between healthy and diseased eyes were demonstrated, indicating potential clinical utility. Conclusions: The CAVnet can classify arteries and veins and their branches with high accuracy and is potentially useful in the analysis of vessel type-specific features on diseases such as branch retinal artery occlusion and BRVO.

To investigate the issues related to significant environmental damage and poor resource utilization of soda residue (SR), the composition and microstructure of hydration products of the GGBS (ground granulated blast-furnace slag) synergistically activated by NaOH-SR are characterized by an X-ray diffraction (XRD), Fourier-transform infrared spectrometry (FTIR), thermogravimetric–differential thermogravimetric (TG-DTG) analysis, and scanning electron microscope X-ray energy dispersive spectrometry (SEM-EDS). The effect of SR proportion, activator dosage, and water-to-binder ratio on the hydration process is studied. Results indicate that the hydration products mainly include hydrated calcium chloroaluminate (3CaO·Al2O3·CaCl2·10H2O, FS), hydrated calcium aluminosilicate (Ca2Al3(SiO4)3OH, C-A-S-H), halite (NaCl), calcite (CaCO3), and C-S-H gel. With the increase in SR proportion (especially from 80% to 90%), the C-S-H gel yield decreases significantly, while the FS yield rapidly increases, and the T-O-Si (T = Al or Si) peak shifts to a higher wavenumber range (955 cm−1 to 975 cm−1). With the decrease in activator dosage (40% to 15%), the hydration reaction gradually weakens, and the FTIR band of the T-O-Si (T = Al or Si) shifts to the lower wavenumber range (968 cm−1 to 955 cm−1). Then, cemented paste backfills (CPBs) are prepared with iron tailings as the aggregate. At mass content of 75%, SR proportion of 80%, and activator dosage of 30%, the fluidity of the CPB reaches 267.5 mm with a 28-day unconfined compressive strength (UCS) of 2.4 MPa, confirming that SR- and NaOH-synergistically-activated GGBS has great application prospects in backfill mining.

Purpose: To determine whether handheld widefield OCT can be used to document retinopathy of prematurity (ROP) stage while using scleral depression to improve peripheral views. Design: Prospective, observational study. Participants: Consecutive neonates admitted to the neonatal intensive care unit in a single academic medical center who also met criteria for ROP screening and whose parents or guardians consented for them to undergo research imaging. Methods: Scleral depression was combined with widefield OCT using an investigational 400-kHz, 55° field of view, handheld OCT during routine ROP screening from October 28, 2020, through March 3, 2021. Main Outcome Measures: Acquisition of en face and B-scan imaging of the peripheral retina to assess early vitreoretinal pathologic features objectively, including the demarcation between vascularized and anterior avascular retina, the presence of early ridge formation, and small neovascular tufts. Results: Various stages of ROP were detected using a rapid-acquisition OCT system. In 1 neonate, serial OCT imaging over a 5-week period demonstrated accumulation of neovascular tufts with progression to stage 3 ROP with extraretinal fibrovascular proliferation along the ridge. Videography of this technique is included in this report for instructional purposes. Conclusions: Serial examinations using widefield OCT and scleral depression are feasible and may improve detection and documentation of ROP disease progression. Earlier detection of ROP-related proliferation may prevent vitreoretinal traction, retinal detachment, and blindness.

Abstract Background Although cord blood (CB) offers promise for treatment of patients with high-risk hematological malignancies and immune disorders, the limited numbers of hematopoietic stem cell (HSC)/progenitor cell in a CB unit and straitened circumstances in expanding ex vivo make it quite challenging to develop the successful cell therapies. Methods In this study, a novel strategy has been developed to support ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs) by coculture with engineered human umbilical arterial endothelial cells (HuAECs-E4orf1-GFP), which expresses E4ORF1 stably by using a retroviral system. Results Coculture of CD34+ hCB cells with HuAECs-E4orf1-GFP resulted in generation of considerably more total nucleated cells, CD34+CD38−, and CD34+CD38−CD90+ HSPCs in comparison with that of cytokines alone or that of coculture with human umbilical vein endothelial cells (HuVECs) after 14-day amplification. The in vitro multilineage differentiation potential and in vivo repopulating capacity of the expanded hematopoietic cells cocultured with HuAECs-E4orf1-GFP were also markedly enhanced compared with the other two control groups. DLL4, a major determinant of arterial endothelial cell (EC) identity, was associated with CD34+ hCB cells amplified on HuAECs-E4orf1-GFP. Conclusions Collectively, we demonstrated that HuAECs acted as a permissive niche in facilitating expansion of HSPCs. Our study further implicated that the crucial factors and related pathways presented in HuAECs may give a hint to maintain self-renewal of bona fide HSCs.

Recent advances in portable optical coherence tomography (OCT) and OCT angiography (OCTA) have resulted in wider fields of view (FOV) and shorter capture times, further expanding the potential clinical role of OCT technology in the diagnosis and management of retinopathy of prematurity (ROP). Using a prototype, handheld OCT device, retinal imaging was obtained in non-sedated infants in the neonatal intensive care unit (NICU) as well as sedated infants in the operating room of Oregon Health & Science University (OHSU) Hospital. In this observational study, we provide an overview of potential advantages of OCT-based disease assessment in ROP. We observed that next-generation OCT imaging (a) may be sufficient for objective diagnosis and zone/stage/plus disease categorization, (b) allows for minimally-invasive longitudinal monitoring of disease progression and post-treatment course, (c) provides three-dimensional mapping of the vitreoretinal interface, and (d) with OCTA, enables dye-free visualization of normal and pathologic vascular development.

Purpose: To evaluate the performance of a federated learning framework for deep neural network-based retinal microvasculature segmentation and referable diabetic retinopathy (RDR) classification using OCT and OCT angiography (OCTA). Design: Retrospective analysis of clinical OCT and OCTA scans of control participants and patients with diabetes. Participants: The 153 OCTA en face images used for microvasculature segmentation were acquired from 4 OCT instruments with fields of view ranging from 2 × 2-mm to 6 × 6-mm. The 700 eyes used for RDR classification consisted of OCTA en face images and structural OCT projections acquired from 2 commercial OCT systems. Methods: OCT angiography images used for microvasculature segmentation were delineated manually and verified by retina experts. Diabetic retinopathy (DR) severity was evaluated by retinal specialists and was condensed into 2 classes: non-RDR and RDR. The federated learning configuration was demonstrated via simulation using 4 clients for microvasculature segmentation and was compared with other collaborative training methods. Subsequently, federated learning was applied over multiple institutions for RDR classification and was compared with models trained and tested on data from the same institution (internal models) and different institutions (external models). Main Outcome Measures: For microvasculature segmentation, we measured the accuracy and Dice similarity coefficient (DSC). For severity classification, we measured accuracy, area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve, balanced accuracy, F1 score, sensitivity, and specificity. Results: For both applications, federated learning achieved similar performance as internal models. Specifically, for microvasculature segmentation, the federated learning model achieved similar performance (mean DSC across all test sets, 0.793) as models trained on a fully centralized dataset (mean DSC, 0.807). For RDR classification, federated learning achieved a mean AUROC of 0.954 and 0.960; the internal models attained a mean AUROC of 0.956 and 0.973. Similar results are reflected in the other calculated evaluation metrics. Conclusions: Federated learning showed similar results to traditional deep learning in both applications of segmentation and classification, while maintaining data privacy. Evaluation metrics highlight the potential of collaborative learning for increasing domain diversity and the generalizability of models used for the classification of OCT data.

Purpose: To examine the efficacy of a deep learning-based algorithm to quantify the nonperfusion area (NPA) on montaged widefield OCT angiography (OCTA) for assessment of diabetic retinopathy (DR) severity. Design: Cross-sectional study. Participants: One hundred thirty-seven participants with a full range of DR severity and 26 healthy participants. Methods: A deep learning-based algorithm was developed for detecting and quantifying NPA in the superficial vascular complex on widefield OCTA comprising 3 horizontally montaged 6 × 6-mm OCTA scans from the nasal, macular, and temporal regions. We trained the algorithm on 978 volumetric OCTA scans from all participants using 5-fold cross-validation. The algorithm can distinguish NPA from shadow artifacts. The F1 score evaluated segmentation accuracy. The area under the receiver operating characteristic curve and sensitivity with specificity fixed at 95% quantified network performance to distinguish patients with diabetes from healthy control participants, referable DR from nonreferable DR (nonproliferative DR [NPDR] less than moderate severity), and severe DR (severe NPDR, proliferative DR, or DR with edema) from nonsevere DR (mild to moderate NPDR). Main Outcome Measures: Widefield OCTA NPA, visual acuity (VA), and DR severities. Results: Automatically segmented NPA showed high agreement with the manually delineated ground truth, with a mean ± standard deviation F1 score of 0.78 ± 0.05 in nasal, 0.82 ± 0.07 in macular, and 0.78 ± 0.05 in temporal scans. The extrafoveal avascular area (EAA) in the macular scan showed the best sensitivity at 54% for differentiating those with diabetes from healthy control participants, whereas montaged widefield OCTA scan showed significantly higher sensitivity than macular scans (P < 0.0001, McNemar’s test) for detecting eyes with DR at 66%, referable DR at 63%, and severe DR at 62%. Montaged widefield OCTA showed the highest correlation (Spearman ρ = 0.74; P < 0.0001) between EAA and DR severity. The macular scan showed the strongest negative correlation (Pearson ρ = –0.42; P < 0.0001) between EAA and best-corrected VA. Conclusions: A deep learning-based algorithm for montaged widefield OCTA can detect NPA accurately and can improve the detection of clinically important DR.

Abstract Stem cells have emerged as a potential therapy for a range of neural insults, but their application in Alzheimer's disease (AD) is still limited and the mechanisms underlying the cognitive benefits of stem cells remain to be elucidated. Here, the effects of clinical‐grade human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) on the recovery of cognitive ability in SAMP8 mice, a senescence‐accelerated mouse model of AD is explored. A functional assay identifies that the core functional factor hepatocyte growth factor (HGF) secreted from hUC‐MSCs plays critical roles in hUC‐MSC‐modulated recovery of damaged neural cells by down‐regulating hyperphosphorylated tau, reversing spine loss, and promoting synaptic plasticity in an AD cell model. Mechanistically, structural and functional recovery, as well as cognitive enhancements elicited by exposure to hUC‐MSCs, are at least partially mediated by HGF in the AD hippocampus through the activation of the cMet‐AKT‐GSK3β signaling pathway. Taken together, these data strongly implicate HGF in mediating hUC‐MSC‐induced improvements in functional recovery in AD models.

Primary arterial endothelial cell (AEC) is an attractive source of tissue-engineered blood vessels for therapeutic transplantation in vascular disease. However, scarcity of donor tissue, inability of proliferation and undergo de-differentiation in culture remain major obstacles. We derived a stable induced pluripotent stem cell (iPSC) line possessed all the characteristics of pluripotent state from human umbilical arterial endothelial cells by transduction of four human transcription factors (Oct4, Sox2, Klf4, and c-Myc) using sendai virus vectors. It will likely facilitate to lineage differentiate and generate sufficient AECs for clinical use in cardiovascular disease based on epigenetic memory of the tissue of origin.

Purpose: The purpose of this study is to analyze early retinal angiomatous proliferation (RAP) utilizing a novel imaging modality, Projection-Resolved Optical Coherence Tomography Angiography (PR-OCTA). Observations: Five months prior to the diagnosis of a RAP lesion, cross-sectional PR-OCTA demonstrated flow in the outer retina contiguous with the deep retinal capillary plexus (DCP) and adjacent to a small pigment epithelial detachment. After development of a clinically visible RAP lesion, cross-sectional PR-OCTA demonstrated the RAP lesion connecting DCP and sub-retinal pigment epithelial neovascularization. Conclusions & importance: This is the first report of PR-OCTA demonstrating abnormal flow in the outer retina prior to the development of a clinically detectable RAP lesion. PR-OCTA may be useful for surveillance and to help further characterize and stage RAP lesions.

Optical coherence tomography angiography (OCTA) is a functional extension of OCT that provides information on retinal and choroidal circulations without the need for dye injections. With the recent development of high-speed OCT systems and efficient algorithms, OCTA has become clinically feasible. In this review article, we discuss the technical principles of OCTA, including image processing and artifacts, and its clinical applications in ophthalmology. We summarize recent studies which qualitatively or quantitatively assess disease presentation, progression, and/or response to treatment.

Purpose: To report two cases of pediatric choroidal neovascularization (CNV) and the associated neovascular and retinal findings identified on Optical Coherence Tomography Angiography (OCTA) imaging. Methods: A 14-year-old boy with handheld laser-induced maculopathy-related CNV and a 13-year-old boy with idiopathic CNV were evaluated with visual acuity testing, slit-lamp exam, fundus photography, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and OCTA. Results: Macular CNV were identified in both pediatric patients using OCTA imaging. The first case demonstrated a classic pediatric type II CNV with a “tree-like” pattern and a single vessel in-growth site, while the second case demonstrated a type I CNV with a “glomerular” pattern. Conclusion: Distinct choroidal neovascular patterns were visualized in these two cases of pediatric CNV when compared to adult subtypes. OCTA is a noninvasive imaging modality capable of evaluating and characterizing pediatric CNV and their associated vascular patterns.

Cord blood (CB) is an attractive source of hematopoietic stem cells (HSCs) for hematopoietic cell transplantation. However, its application remains limited due to the low number of HSCs/progenitors in a single CB unit and its notoriously difficulty in expanding ex vivo. Here, we demonstrated that the human fetal liver sinusoidal endothelial cells engineered to constitutively express the adenoviral E4orf1 gene (hFLSECs-E4orf1) is capable of efficient expansion ex vivo for human CB hematopoietic stem and progenitor cells (HSPCs). Coculture of CD34+ hCB cells with hFLSECs-E4orf1 resulted in generation of substantially more total nucleated cells, CD34+CD38− and CD34+ CD38−CD90+ HSPCs in comparison with that of cytokines alone after 14 days. The multilineage differentiation potential of the expanded hematopoietic cells in coculture condition, as assessed by in vitro colony formation, was also significantly heightened. The CD34+ hCB cells amplified on hFLSECs-E4orf1 were capable of engraftment in vivo. Furthermore, hFLSECs-E4orf1 highly expressed hematopoiesis related growth factor and Notch receptors. Accordingly, the CD34+ hCB cells amplified on hFLSECs-E4orf1 exhibited Notch signaling activation. Taken together, our findings indicated that FLSECs may potentially be the crucial component of the microenvironment to support recapitulation of embryonic HSC amplification in vitro and allow identification of new growth factors responsible for collective regulation of hematopoiesis.

We used optical coherence tomography (OCT) angiography with a high-speed swept-source OCT system to investigate retinal blood flow changes induced by visual stimulation with a reversing checkerboard pattern. The split-spectrum amplitude-decorrelation angiography (SSADA) algorithm was used to quantify blood flow as measured with parafoveal flow index (PFI), which is proportional to the density of blood vessels and the velocity of blood flow in the parafoveal region of the macula. PFI measurements were taken in 15 second intervals during a 4 minute period consisting of 1 minute of baseline, 2 minutes with an 8 Hz reversing checkerboard pattern stimulation, and 1 minute without stimulation. PFI measurements increased 6.1±4.7% (p = .001) during the first minute of stimulation, with the most significant increase in PFI occurring 30 seconds into stimulation (p

Oxygen availability is regarded as a critical factor to metabolically regulate systemic blood flow. There is a debate as to how peripheral blood flow (PBF) is affected and modulated during hypoxia and hyperoxia; however in vivo evaluating of functional PBF under oxygen-related physiological perturbation remains challenging. Microscopic observation, the current frequently used imaging modality for PBF characterization often involves the use of exogenous contrast agents, which would inevitably perturb the intrinsic physiologic responses of microcirculation being investigated. In this paper, optical micro-angiography (OMAG) was employed that uses intrinsic optical scattering signals backscattered from blood flows for imaging PBF in skeletal muscle challenged by the alteration of oxygen concentration. By utilizing optical reflectance signals, we demonstrated that OMAG is able to show the response of hemodynamic activities upon acute hypoxia and hyperoxia, including the modulation of macrovascular caliber, microvascular density, and flux regulation within different sized vessels within skeletal muscle in mice in vivo. Our results suggest that OMAG is a promising tool for in vivo monitoring of functional macro- or micro-vascular responses within peripheral vascular beds.

Understanding how hepatic precursor cells can generate differentiated bile ducts is crucial for studies on epithelial morphogenesis and for development of cell therapies for hepatobiliary diseases. Epimorphin (EPM) is a key morphogen for duct morphogenesis in various epithelial organs. The role of EPM in bile duct formation (DF) from hepatic precursor cells, however, is not known. To address this issue, we used WB-F344 rat epithelial stem-like cells as model for bile duct formation. A micropattern and a uniaxial static stretch device was used to investigate the effects of EPM and stress fiber bundles on the mitosis orientation (MO) of WB cells. Immunohistochemistry of liver tissue sections demonstrated high EPM expression around bile ducts in vivo. In vitro, recombinant EPM selectively induced DF through upregulation of CK19 expression and suppression of HNF3alpha and HNF6, with no effects on other hepatocytic genes investigated. Our data provide evidence that EPM guides MO of WB-F344 cells via effects on stress fiber bundles and focal adhesion assembly, as supported by blockade EPM, beta1 integrin, and F-actin assembly. These blockers can also inhibit EPM-induced DF. These results demonstrate a new biophysical action of EPM in bile duct formation, during which determination of MO plays a crucial role.

This research presents the development of an innovative electrochemical detection platform using a graphene-zinc oxide (G-ZnO) nanocomposite for the quantification of 17β-estradiol in milk. The G-ZnO nanocomposite, synthesized via a facile one-pot method, exhibited a unique wrinkled structure with a high specific surface area of 143 m²/g. Characterization through SEM, TEM, and XRD confirmed the effective integration of ultrafine ZnO nanoparticles onto graphene sheets. The electrochemical performance of the G-ZnO modified glassy carbon electrode was evaluated, revealing a notably low detection limit of 8.3 nM for 17β-estradiol, a significant improvement over traditional sensors. The sensor demonstrated a wide linear range of 0.05–100 μM and exceptional reproducibility with less than 3.5 % RSD over repeated measurements. Recovery studies in spiked milk samples yielded highly accurate results, with recovery percentages ranging from 97.8 % to 104.6 %. These findings underscore the potential of G-ZnO nanocomposites in creating sensitive, efficient, and reliable sensors for healthcare and environmental applications.