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This document is a response to a comment on an article titled "Single-Cell Transcriptomics Reveals Novel Role of Microglia in Fibrovascular Membrane of Proliferative Diabetic Retinopathy." The authors address the comment and concerns raised by Corano Scheri and Fawzi. They explain that microglia, a type of myeloid cell, express macrophage-related genes and exhibit heterogeneous disease-associated profiles. The authors acknowledge that further experiments are needed to determine the ontogeny of profibrotic retinal myeloid cells. They also discuss the expression of certain markers in FVM-resident myeloid cells and their similarity to scar-associated macrophages in other fibrotic diseases. The authors emphasize the importance of understanding the immunopathogenic nature of FVM for the development of targeted therapeutic strategies. [Extracted from the article]

Scheduling virtual machines is a major research topic for cloud computing, because it directly influences the performance, the operation cost and the quality of services. A large cloud center is normally equipped with several hundred thousand physical machines. The mission of the scheduler is to select the best one to host a virtual machine. This is an NPhard global optimization problem with grand challenges for researchers. This work studies the Virtual Machine (VM) scheduling problem on the cloud. Our primary concern with VM scheduling is the energy consumption, because the largest part of a cloud center operation cost goes to the kilowatts used. We designed a scheduling algorithm that allocates an incoming virtual machine instance on the host machine, which results in the lowest energy consumption of the entire system. More specifically, we developed a new algorithm, called vision cognition, to solve the global optimization problem. This algorithm is inspired by the observation of how human eyes see directly the smallest/largest item without comparing them pairwisely. We theoretically proved that the algorithm works correctly and converges fast. Practically, we validated the novel algorithm, together with the scheduling concept, using a simulation approach. The adopted cloud simulator models different cloud infrastructures with various properties and detailed runtime information that can usually not be acquired from real clouds. The experimental results demonstrate the benefit of our approach in terms of reducing the cloud center energy consumption

Diabetic retinopathy (DR) is currently one of the common causes of vision loss in working-age adults. It is clinically diagnosed and classified according to the vascular changes in the fundus. However, the activation of immune cells occurs before these vascular changes become detectable. These, together with molecular studies and the positive clinical outcomes of anti-inflammatory treatment, highlight the pivotal involvement of the immune system. The role of innate immunity in DR pathophysiology has been studied in depth, but the contribution of adaptive immunity remains largely elusive. This review aims to summarize our current understanding of the activation mechanism of adaptive immunity in DR microenvironments and to discuss the relationship between adaptive immunity and local vascular units or innate immunity, which opens new avenues for clinical applications in DR treatment. [ABSTRACT FROM AUTHOR]

Retinal laser therapy such as panretinal photocoagulation can be associated with complications, including rare cases of choroidal detachment. This report describes high-resolution optical coherence tomography (OCT) imaging after retinal laser panretinal photocoagulation (PRP) in patients with proliferative diabetic retinopathy (PDR) demonstrating choroidal detachment. A series of three sequential patients with high-risk proliferative diabetic retinopathy who were PRP laser naïve were examined with spectral-domain OCT immediately after green solid-state laser or PASCAL® PRP treatment. All three patients demonstrated a significant choroidal detachment immediately after PRP treatment. By one month after PRP, the choroidal detachment resolved spontaneously in all patients. OCT examinations were performed to detect and evaluate the severity and the change of choroidal detachment and thickness measurements were quantified and demonstrated a mean decrease in choroidal thickness of 122 µm (p < 0.05 in all patients). Conventional green solid-state laser and PASCAL® laser both have the risk of developing complications such as choroidal detachment. While the rate of choroidal detachment has been reported to be quite low, this could be due to subclinical, self-limited, choroidal detachments. The risk could be larger than previously reported using modern high-resolution clinical optical imaging such as OCT. [ABSTRACT FROM AUTHOR]

Objectives: Stem cell‐derived photoreceptor replacement therapy is a promising strategy for the treatment of retinal degenerative disease. The development of 3D retinal organoids has permitted the production of photoreceptors. However, there is no strategy to enrich a specific photoreceptor subtype due to inadequate knowledge of the molecular mechanism underlying the photoreceptor fate determination. Hence, our aim is to explore the uncharacterized function of somatostatin signalling in human pluripotent stem cell‐derived photoreceptor differentiation. Materials and Methods: 3D retinal organoids were achieved from human embryonic stem cell. The published single‐cell RNA‐sequencing datasets of human retinal development were utilized to further investigate the transcriptional regulation of photoreceptor differentiation. The assays of immunofluorescence staining, lentivirus transfection, real‐time quantitative polymerase chain reaction and western blotting were performed. Results: We identified that the somatostatin receptor 2 (SSTR2)‐mediated signalling was essential for rod photoreceptor differentiation at the precursor stage. The addition of the cognate ligand somatostatin in human 3D retinal organoids promoted rod photoreceptor differentiation and inhibited cone photoreceptor production. Furthermore, we found that the genesis of rod photoreceptors was modulated by endogenous somatostatin specifically secreted by developing retinal ganglion cells. Conclusions: Our study identified SSTR2 signalling as a novel extrinsic regulator for rod photoreceptor fate determination in photoreceptor precursors, which expands the repertoire of functional signalling pathways in photoreceptor development and sheds light on the optimization of the photoreceptor enrichment strategy. [ABSTRACT FROM AUTHOR]

Purpose: To monitor the intraocular proangiogenic and profibrotic cytokine profiles within 7 days after intravitreous injection of conbercept (IVC) for patients with proliferative diabetic retinopathy (PDR). Methods: This prospective, randomized controlled, consecutive, comparative study included 157 eyes with PDR. Participant eyes underwent sham IVC or IVC and subsequent vitrectomy at days 2, 3, 4, 5, 6, 7 postinjection. The intraocular cytokines profiles were measured using beaded assay methods. Results: After IVC, the vascular endothelial growth factor (VEGF)‐A level in PDR vitreous decreased rapidly by approximately 10 times at day 2 (p = 0.00001) and kept at a low level at days 3, 4, 5, 6, 7 (p < 0.001, each compared with IVC‐sham group). Similar tendency of the change in VEGF‐A was observed in aqueous humour. The level of placenta growth factor (PIGF) in aqueous humour decreased 2 days after IVC whereas returned to baseline level after 5 days. The vitreous profibrotic cytokines, tissue growth factor (TGF)‐β1, TGF‐β2, TGF‐β3 and connective tissue growth factor did not increase after IVC in each group. Conclusion: We observed a remarkable and rapid decrease in intraocular VEGF‐A, temporal decrease in PIGF from day 2 to day 4, increase in VEGF‐C and VEGF‐D from day 2 onwards, but no profibrotic switch in PDR eyes after IVC. The findings might suggest that ideal vitrectomy timing might be around 3 days after IVC. [ABSTRACT FROM AUTHOR]

Vitreous fibrovascular membranes (FVMs), the hallmark of proliferative diabetic retinopathy (PDR), cause retinal hemorrhage, detachment, and eventually blindness. However, little is known about the pathophysiology of FVM. In this study, we used single-cell RNA sequencing on surgically harvested PDR-FVMs and generated a comprehensive cell atlas of FVM. Eight cellular compositions were identified, with microglia as the major cell population. We identified a GPNMB+ subpopulation of microglia, which presented both profibrotic and fibrogenic properties. Pseudotime analysis further revealed the profibrotic microglia was uniquely differentiated from retina-resident microglia and expanded in the PDR setting. Ligand-receptor interactions between the profibrotic microglia and cytokines upregulated in PDR vitreous implicated the involvement of several pathways, including CCR5, IFNGR1, and CD44 signaling, in the microglial activation within the PDR microenvironment. Collectively, our description of the novel microglia phenotypes in PDR-FVM may offer new insight into the cellular and molecular mechanism underlying the pathogenesis of DR, as well as potential signaling pathways amenable to disease-specific intervention. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the influence of preoperative adjunctive anti-VEGF drug (Conbercept) on vitreous inflammatory cytokines and chemokines profiles and whether those cytokines were associated with early macular edema (ME) after surgery for patients with proliferative diabetic retinopathy (PDR). Methods: In this post hoc analysis of the CONCEPT clinical trial, subjects with PDR underwent vitrectomy were included and vitreous samples were collected at the start of vitrectomy. Levels of vitreous VEGF, 17 inflammatory cytokines, and 11 chemokines were measured using Luminex multiplex technology. Subjects were then divided into groups based on with (Pre-IV) or without (No-Pre-IV) preoperative intravitreous injection of Conbercept; with or without early ME after surgery. Results: There was no difference between Pre-IV (13/30) and No-Pre-IV (7/29) concerning the ratio of patients with early ME (p = 0.17). After preoperative intravitreous injection of Conbercept, VEGF level dramatically decreased (p = 0.001), TNF-α (p = 0.002), and IP-10 (p = 0.018) increased in Pre-IV group. In patients with early ME after surgery, however, a number of cytokines increased, including IL-1β (p = 0.008), IL-2 (p = 0.023), IL-4 (p = 0.030), IL-9 (p = 0.02), IL-10 (p = 0.002), IL-12 (p = 0.001), IL-13 (p = 0.031), IL-17A (p = 0.008), TNF-α (p = 0.012), CXCL9 (p = 0.023), G-CSF (p = 0.019), MCP-1 (p = 0.048), and RANTES (p = 0.016). Conclusion: We found the preoperative adjunctive Conbercept injection has limited influence on the levels of vitreous inflammatory cytokines and chemokines in PDR. The elevated levels of a series of cytokines might be associated with early inflammation after vitrectomy, which may lead to postoperative ME. [ABSTRACT FROM AUTHOR]

Purpose: To robustly segment retinal layers that are affected by complex variety of retinal diseases for optical coherence tomography angiography (OCTA) en face projection generation. Methods: In this paper, we propose a robust retinal layer segmentation model to reduce the impact of multifarious abnormalities on model performance. OCTA vascular distribution that is regarded as the supplements of spectral domain optical coherence tomography (SD‐OCT) structural information is introduced to improve the robustness of layer region encoding. To further reduce the sensitivity of region encoding to retinal abnormalities, we propose a multitask layer‐wise refinement (MLR) module that can refine the initial layer region segmentation results layer‐by‐layer. Finally, we design a region‐to‐surface transformation (RtST) module without additional training parameters to convert the encoding layer regions to their corresponding layer surfaces. This transformation from layer regions to layer surfaces can remove the inaccurate segmentation regions, and the layer surfaces are easier to be used to protect the retinal layer natures than layer regions. Results: Experimental data includes 273 eyes, where 95 eyes are normal and 178 eyes contain complex retinal diseases, including age‐related macular degeneration (AMD), diabetic retinopathy (DR), central serous chorioretinopathy (CSC), choroidal neovascularization (CNV), and so forth. The dice similarity coefficient (DSC: %) of superficial, deep and outer retina achieves 98.92, 97.48, and 98.87 on normal eyes and 98.35, 95.33, and 98.17 on abnormal eyes. Compared with other commonly used layer segmentation models, our model achieves the state‐of‐the‐art layer segmentation performance. Conclusions: The final results prove that our proposed model obtains outstanding performance and has enough ability to resist retinal abnormalities. Besides, OCTA modality is helpful for retinal layer segmentation. [ABSTRACT FROM AUTHOR]

Objectives. Idiopathic epiretinal membrane (iERM) or idiopathic macular hole (iMH) is frequently used as a "healthy" control in comparison of vitreous cytokines with other vitreoretinal diseases. This study aimed to investigate if there is a difference in vitreal cytokines expression between patients with iERM and iMH. Methods. In this prospective study, all subjects received standard pars plana vitrectomy surgery, and 0.5 ml of native vitreous sample was extracted during the vitrectomy. Luminex technology and enzyme-linked immunosorbent assay were used to profile the concentration of 52 classic angiogenic, inflammatory, and profibrotic cytokines and chemokines. Statistical analyses were performed by the Mann–Whitney U test, followed by multiple comparisons by the Bonferroni correction. Results. Vitreal samples from 13 iERM and 24 iMH were studied. Of the 52 tested cytokines, 41 were similar in expression, and 5 were under the detection limit, while 6 cytokines (MMP-8, Eotaxin, MIP-1a, RANTES, TGF-β2, and IL-4) were differently expressed between two groups (p < 0.05). Nevertheless, these significances disappeared after the adjustment of Bonferroni correction. Conclusion. The tested cytokines showed similar expression between iERM and iMH patients. This indicates that eyes with iERM or iMH can be together served as "healthy" controls. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the changes in vessel density in patients with unilateral congenital cataract after cataract extraction. Materials and Methods: Children with unilateral congenital cataract were enrolled in our study. All of the patients underwent congenital cataract extraction and intraocular lens (IOL) implantation successfully. Optical coherence tomography angiography (OCTA) was performed to image the retinal vasculature in the macular and optic disc areas before and after surgery. The differences in vessel density and retinal thickness between groups were compared. Results: We found that the best corrected visual acuity (BCVA) was significantly improved one month after surgery compared with that before surgery (t=5.179, p< 0.001). The axial length was also changed one month after surgery (t=5.350, p< 0.001). The vessel density in the macular and optic disc areas of the affected eyes was significantly lower than that in the normal eyes, while the vessel density at the posterior pole was significantly improved one month after cataract extraction. Conclusion: The decrease in vessel density in the macular and optic disc areas might be a consequence of the congenital cataract. Cataract extraction can relieve the form deprivation of the affected eye and increase the vessel density at the posterior pole of the affected eye significantly. [ABSTRACT FROM AUTHOR]