The association between altered intestinal microbiome, impaired systemic and ocular surface immunity, and impaired wound healing response after corneal alkaline-chemical injury in diabetic mice.

Purpose: We aim to investigate the effect of sustained hyperglycemia on corneal epithelial wound healing, ocular surface and systemic immune response, and microbiome indices in diabetic mice compared to controls after alkaline chemical injury of the eye. Methods: Corneal alkaline injury was induced in the right eye of Ins2Akita (Akita) mice and wild-type mice. The groups were observed at baseline and subsequently days 0, 3, and 7 after injury. Corneal re-epithelialization was observed under slit lamp with fluorescein staining using a cobalt blue light filter. Enucleated cornea specimens were compared at baseline and after injury for changes in cornea thickness under hematoxylin and eosin staining. Tear cytokine and growth factor levels were measured using protein microarray assay and compared between groups and time points. Flow cytometry was conducted on peripheral blood and ocular surface samples to determine CD3+CD4+ cell count. Fecal samples were collected, and gut microbiota composition and diversity pattern were measured using shotgun sequencing. Results: Akita mice had significantly delayed corneal wound healing compared to controls. This was associated with a reduction in tear levels of vascular endothelial growth factor A, angiopoietin 2, and insulin growth factor 1 on days 0, 3, and 7 after injury. Furthermore, there was a distinct lack of upregulation of peripheral blood and ocular surface CD3+CD4+ cell counts in response to injury in Akita mice compared to controls. This was associated with a reduction in intestinal microbiome diversity indices in Akita mice compared to controls after injury. Specifically, there was a lower abundance of Firmicutes bacterium M10-2 in Akita mice compared to controls after injury. Conclusion: In diabetic mice, impaired cornea wound healing was associated with an inability to mount systemic and local immune response to ocular chemical injury. Baseline and post-injury differences in intestinal microbial diversity and abundance patterns between diabetic mice and controls may potentially play a role in this altered response.

Virtual reality and augmented reality- emerging screening and diagnostic techniques in ophthalmology: A systematic review.

In health care, virtual reality (VR) and augmented reality (AR) have been applied extensively for many purposes. Similar to other technologies such as telemedicine and artificial intelligence, VR and AR may improve clinical diagnosis and screening services in ophthalmology by alleviating current problems, including workforce shortage, diagnostic error, and underdiagnosis. In the past decade a number of studies and products have used VR and AR concepts to build clinical tests for ophthalmology, but comprehensive reviews on these studies are limited. Therefore, we conducted a systematic review on the use of VR and AR as a diagnostic and screening tool in ophthalmology. We identified 26 studies that implemented a variety of VR and AR tests on different conditions, including VR cover tests for binocular vision disorder, VR perimetry for glaucoma, and AR slit lamp biomicroscopy for retinal diseases. In general, while VR and AR tools can become standardized, automated, and cost-effective tests with good user experience, several weaknesses, including unsatisfactory accuracy, weak validation, and hardware limitations, have prevented these VR and AR tools from having wider clinical application. Also, a comparison between VR and AR is made to explain why studies have predominantly used VR rather than AR.

Sex Hormones Related Ocular Dryness in Breast Cancer Women.

BACKGROUND: Dry eye syndrome (DES) is strictly connected to systemic and topical sex hormones. Breast cancer treatment, the subsequent hormonal therapy, the subsequent hyperandrogenism and the early sudden menopause, may be responsible for ocular surface system failure and its clinical manifestation as dry eye disease. This local dryness is part of the breast cancer iatrogenic dryness, which affects overall mucosal tissue in the fragile population of those with breast cancer. METHODS: A literature review regarding the role of sex hormone changes and systemic hormonal replacement treatments (SHRT) in DES available on PubMed and Web of Science was made without any restriction of language. RESULTS: Androgens exert their role on the ocular surface supporting meibomian gland function and exerting a pro-sebaceous effect. Estrogen seems to show a pro/inflammatory role on the ocular surface, while SHRT effects on dry eye are still not well defined, determining apparently contradictory consequences on the ocular surface homeostasis. The role of sex hormones on dry eye pathogenesis is most likely the result of a strict crosstalk between the protective androgens effects and the androgen-modulating effects of estrogens on the meibomian glands. CONCLUSIONS: Patients with a pathological or iatrogenic hormonal imbalance, such as in the case of breast cancer, should be assessed for dry eye disease, as well as systemic dryness, in order to restore their social and personal quality of life.

Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions.

We systematically reviewed published translational research on gene-based therapy for retinal ganglion cell (RGC) neuroprotection. A search was conducted on Entrez PubMed on 23 December 2020 using the keywords "gene therapy", "retinal ganglion cell" and "neuroprotection". The initial search yielded 82 relevant articles. After restricting publications to those with full text available and in the English language, and then curating for only original articles on gene-based therapy, the final yield was 18 relevant articles. From the 18 papers, 17 of the papers utilized an adeno-associated viral (AAV) vector for gene therapy encoding specific genes of interest. Specifically, six of the studies utilized an AAV vector encoding brain-derived neurotrophic factor (BDNF), two of the studies utilized an AAV vector encoding erythropoietin (EPO), the remaining 10 papers utilized AAV vectors encoding different genes and one microRNA study. Although the literature shows promising results in both in vivo and in vitro models, there is still a significant way to go before gene-based therapy for RGC neuroprotection can proceed to clinical trials. Namely, the models of injury in many of the studies were more acute in nature, unlike the more progressive and neurodegenerative pathophysiology of diseases, such as glaucoma. The regulation of gene expression is also highly unexplored despite the use of AAV vectors in the majority of the studies reviewed. It is also expected that with the successful launch of messenger ribonucleic acid (mRNA)-based vaccinations in 2020, we will see a shift towards this technology for gene-based therapy in glaucoma neuroprotection.

Sociodemographic, behavioral, and medical risk factors associated with visual impairment among older adults: a community-based pilot survey in Southern District of Hong Kong.

BACKGROUND: The last visual survey of older adults in Hong Kong was a district-level study in 2002, with no assessment of behavioral and medical risk factors for visual impairment (VI). Our objectives were to determine the latest VI prevalence among older adults, significance of any spatial and temporal differences on the prevalence, and any associations of sociodemographic, behavioral and medical risk factors with VI from a multi-perspective analysis. METHODS: Community-based pilot survey of residents from a suburb of Hong Kong, aged ≥50, using a standardized questionnaire, was conducted in 2016. RESULTS: Of the 222 subjects, crude rates of bilateral and unilateral VI were 9.46 and 32.88%, respectively, or corresponding age-and-gender-adjusted rates of 6.89 and 30.5%. Older age and lower educational were associated with higher risk for unilateral VI, while older age, temporary housing, obesity and hyperlipidemia were associated with higher risk for bilateral VI. Smoking and alcohol-drinking status were not associated with unilateral or bilateral VI. Relative changes in ORs of hypertension or educational level on unilateral or bilateral VI were >  10% after adjusting for age. Interaction term between hyperlipidemia and gender or obesity was significant for unilateral VI. Gender, hypertension and cataract were not associated with unilateral or bilateral VI in general population of pooled analysis but were identified as risk factors in specific subgroups of stratified analysis. Refractive error (myopia or hyperopia) was significantly associated with VI in the eye-level analysis after adjusting the inter-eye correlation. CONCLUSIONS: Sociodemographic and medical risk factors contributed to VI, but behavioral risk factors did not. Sociodemographic disparities of visual health existed. Age was the confounders of the VI-hypertension or VI-educational level relationships. Gender and obesity were more likely to have multiplicative effect on unilateral VI when combined with hyperlipidemia. Stratified analysis should be conducted to provide further insight into the risk factors for VI in specific populations. Uncorrected refractive error remains a significant cause of impaired vision. The spatial and temporal differences in bilateral VI prevalence from the previous local study indicates a territory-wide survey is needed to assess regional differences and overall prevalence of VI in Hong Kong.

Amphiphilic additives in silicone oil tamponade and emulsification: an eye-on-a-chip study.

AIMS: Recently, chemically modified silicone oil has been demonstrated as a reservoir for sustained release of intraocular drugs, many of which might be amphiphilic in nature. In this work, we study the effect of amphiphilic additives in silicone oil on emulsification under eye-like movements. METHODS: Three silicone-oil-soluble surfactants, namely DC749, MQ1640 and FZ2233, were used as model amphiphilic additives. The change of viscosity was measured by a rheometer in the cone-and-plate geometry. The interfacial tension (IFT) between silicone oil and model aqueous phase was measured by pendant drop tensiometry. Emulsification of silicone oil was induced by simulated saccadic eye movements on a cell-coated eye-on-a-chip platform for 4 days. The number of emulsified silicone oil droplets observed in the aqueous phase was assessed daily by optical microscopy. RESULTS: Significantly more emulsified droplets were formed in silicone oil with DC749 or MQ1640 (P < 0.05). However, such increase was not directly related to the change in IFT nor viscosity. Moreover, water droplets were also found in the silicone oil, but not in the control silicone oil without additive. CONCLUSIONS: The amphiphilic substances in silicone oil promoted emulsification. Besides typical oil-in-water drops that normally affect the eye, water-in-oil drops were also formed. Before silicone oil could be considered as a vehicle for drug delivery, the nature of the drug and its possible effect on emulsification and therefore on the pharmacokinetics needs to be investigated. An additional concern is that water-in-oil droplets in the eye would affect the optical clarity of silicone oil and might cause visual symptoms.

Role of tear film biomarkers in the diagnosis and management of dry eye disease.

In recent years, there has been increasing scientific interest in the use of tear film biomarkers in the diagnosis and management of dry eye disease (DED), owing to their potential important roles in the pathogenesis of ocular surface damage, as well as the technical feasibility of tear sample collection techniques. An Entrez PubMed search was conducted on March 2, 2019, to include papers investigating the use of tear film biomarkers in DED, and the results were classified according to whether the DED is associated with systemic inflammatory disease or not and further classified within each section according to the molecular nature of the biomarker for further discussion. A total of 58 relevant articles were reviewed. Certain cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha, IL-17, and IL-8, were found by a number of studies to consistently reflect disease severity well and had strong correlations with tear film metrics and tests for ocular surface damage in dry eye without systemic inflammatory disease. For dry eye with systemic inflammatory disease, IL-17, IL-8, and IL-1 receptor antagonists were shown to be consistently higher in affected eyes and correlated well with ocular surface disease severity in more than one type of inflammatory disease. With the advancement in technology and lowered costs in the future, tear film biomarker counts would allow better diagnosis and monitoring of DED, as well as facilitate personalized treatment strategies.

Comparison of Visual, Refractive and Ocular Surface Outcomes Between Small Incision Lenticule Extraction and Laser-Assisted In Situ Keratomileusis for Myopia and Myopic Astigmatism.

Laser-assisted in situ keratomileusis (LASIK) is the most commonly performed laser refractive surgical technique worldwide for the treatment of myopia and myopic astigmatism. In recent years, small incision lenticule extraction (SMILE) has emerged as a promising alternative to LASIK, requiring only a single femtosecond laser to create an intrastromal lenticule, which is then removed via a small incision. The technique obviates the need for a corneal flap. A number of published studies have compared the two techniques in terms of visual, refractive and ocular surface outcomes. This review compares the clinical outcomes between LASIK and SMILE in treating myopia and myopic astigmatism based on studies published in the last 5 years. Twenty-two studies were included, all of which were observational in nature. Results suggest that the two techniques have comparable visual outcomes in terms of safety, efficacy and predictability, although recovery in visual acuity may be slower in SMILE-treated than LASIK-treated eyes. SMILE is found to result in less severe postoperative dry eye symptoms and faster recovery of corneal sensitivity than LASIK. It is important to note, however, that the SMILE technique is limited by the lack of a cyclotorsion-compensation system and option for customized treatment profile. The heterogeneity of results in this review may be attributable to the use of different LASIK platforms in different studies. Few studies compared the outcomes regarding severity of myopia. Future prospective randomized controlled trials with a larger sample size and longer follow-up period will be highly beneficial for progress in this field.

A Systematic Review of Potential Therapeutic Use of Lycium Barbarum Polysaccharides in Disease.

OBJECTIVE: To evaluate the effect of Lycium barbarum polysaccharides in the treatment and/or prevention of diseases of different etiologies and systems. METHODS: We performed an Entrez PubMed literature search using keywords "lycium", "barbarum", "polysaccharides", "anti-fibrotic", "anti-apoptotic", "anti-oxidizing", "anti-aging", "neuroprotection", "metabolism", "diabetes", "hyperlipidemia", "neuroprotection", and "immunomodulation" on the 14th of August 2018, resulting in 207 papers, of which 20 were chosen after filtering for 'English language' and 'published within 10 years' as well as curation for relevance by the authors. RESULTS: The 20 selected papers included 2 randomized control trials (1 double-blinded RCT and 1 double-blinded placebo-controlled RCT), 11 in vivo studies, 5 in vitro studies, 1 study with both in vivo and in vitro results, and 1 chemical study. There is good evidence from existing studies on the antifibrotic, antioxidizing, neuroprotective, anticancer, and anti-inflammatory effects of Lycium barbarum polysaccharides. However, there is a need for further studies in the form of large-scale clinical trials to support its use in humans. There is also significant potential for LBP as a safe and effective topical treatment in ocular surface diseases, owing to promising in vitro results and a lack of demonstrated toxic effects to corneal epithelial cells. CONCLUSION: Results from existing studies suggest that LBP is a promising therapeutic agent, particularly in the management of liver disease, hyperlipidemia, and diabetes. One major limitation of current research is a lack of standardization and quality control for the LBP used. The availability of research-grade LBP will inevitably promote future research in this field worldwide.

Ciliochoroidal detachment after Ahmed glaucoma valve implantation: a retrospective study.

BACKGROUND: To investigate the occurrence of ciliochoroidal detachment (CCD), its risk factors and its impact on the success rate after Ahmed glaucoma valve (AGV) implantation. METHODS: This is a retrospective observational study carried out at Eye Hospital of Wenzhou Medical University, Zhejiang, China. Patients with uncontrolled glaucoma who underwent AGV implantation alone or combined with phacoemulsification (AGV-Phaco) in the hospital from April 1, 2013 to July 31, 2016 were included. The preoperative and postoperative CCD was defined when the detachment between ciliary body and choroid was detected by the ultrasound biomicroscopy (UBM) and anterior segment optical coherence tomography (AS-OCT) respectively. The main outcomes included the incidence of CCD and the success rate at 6 months after surgery. RESULTS: In total, 97 male and 56 female patients were included. CCD was observed in 92 (57.8%) eyes. The glaucoma diagnosis in the Non-CCD and CCD group included primary open angle glaucoma (21(31.3%) vs 33(35.9%)), primary angle closure glaucoma (10(14.9%) vs 13(14.1%)), secondary glaucoma (25(37.3%) vs (28(30.4%)) and so on. The preoperative median IOP (interquartile range) were 21.7(16.0,32.0) mmHg and 23.0(16.0,33.0) mmHg in the Non-CCD group and CCD group. Previous surgical history (95% confidence interval (CI), 1.24 to 13.34; odds ratio (OR) 4.06; p = 0.02) and shorter axial length (95% CI, 0.62 to 0.97 OR 0.78; p = 0.02) were the two risk factors of CCD. The success rate between the CCD and Non-CCD group was not significantly different (64.3% vs 62.5%, p = 0.86) at 6 months. CONCLUSIONS: The incidence of CCD is 57.8% after AGV surgery. Eyes with previous surgical procedure was prone to CCD occurrence and longer axial length was protective against CCD. But at 6 months postoperatively, CCD did not reduce the success rate of AGV surgery and may not be a worrisome complication.

Adhesion of silicone oil and emulsification: an in vitro assessment using a microfluidic device and 'Eye-on-a-Chip'.

PURPOSE: Silicone oil (SiO) with additives of high-molecular-weight (HMW) SiO molecules, eases both the injection and removal. When used inside an eye, it remains unclear how increasing extensional viscosity of SiO might reduce emulsification. Using cell-lined models, this study aims to understand the reason why SiO with HMW is less prone to emulsification. METHODS: The adhesion of SiO was studied and recorded in a cell-coated microchannel by optical microscopy. The resistance of SiO against emulsification was tested on another cell-coated eye-on-a-chip platform, which was subject to simulated saccadic eye movements, for 4 days. Silicone oil (SiO) candidates with HMW, SiOHMW 2000 and SiOHMW 5000 , and their counterparts SiO2000 and SiO5000 without HMW, were tested. The quantity of the SiO emulsified droplets formed was assessed daily by optical microscopy. RESULTS: When flowing in the microchannel, SiO adheres on the cell-coated substrate. The number of droplets is generally lower in SiO with HMW than their counterparts. At the end of the experiment, the average numbers of droplets in SiO2000 (29.1 ± 41.0) and SiO5000 (9.1 ± 19.5) are higher than those in SiOHMW 2000 (6.0 ± 4.5) and SiOHMW 5000 (5.6 ± 4.1). CONCLUSION: A new mechanism of emulsification of SiO is proposed: SiO adheres to ocular tissue to form emulsified droplets. The presence of HMW, which increases the extensional viscosity, may resist the break-up of SiO from the substrate to form emulsified droplets. When tested in a physiologically representative platform, the use of HMW in SiO generally reduces the number of droplets formed in vitro.

Transcorneal Electrical Stimulation Inhibits Retinal Microglial Activation and Enhances Retinal Ganglion Cell Survival After Acute Ocular Hypertensive Injury.

PURPOSE: To investigate the effect of transcorneal electrical stimulation (TcES) on retinal ganglion cell (RGC) function and survival after acute ocular hypertension-related retinal injury in gerbil eyes. METHODS: Gerbil eyes were subjected to acute ocular hypertensive injury (80 mm Hg for 60 minutes). In the treatment group, TcES was applied to the surgical eye immediately and then twice weekly for a total of 1 month. In the control group, sham TcES was given to the surgical eye at the same time points. Retinal function was assessed and compared between groups using flash electroretinography. For histological analysis, the number of RGC and microglial cells were counted by immunofluorescence staining after the gerbils were sacrificed on day 7 and day 28. Real-time polymerase chain reaction and western blot analysis were conducted to compare expression of interleukin (IL)-10, IL-6, COX-2, tumor necrosis factor (TNF)-α, and NF-κB phosphorylation among groups. RESULTS: TcES-treated eyes had significantly higher RGC survival at 1 month compared to controls. This was associated with RGC function. Furthermore, TcES-treated eyes were shown to have increased IL-10 expression, with a corresponding reduction in IL-6 and COX-2 expression as well as reduction in NF-κB phosphorylation. This was associated with a suppression in microglial cell activation in TcES-treated eyes. CONCLUSIONS: Early treatment with TcES in gerbils protected the RGC from secondary damage and preserved retinal function in acute ocular hypertensive injury through modulation of the microglial-cell activated local inflammatory response. TRANSLATIONAL RELEVANCE: Our study strengthens the argument for translating TcES as a viable treatment in acute glaucoma.

Preoperative optimization of ocular surface disease before cataract surgery.

An impaired ocular surface adversely affects preoperative planning for cataract surgery, including intraocular lens (IOL) calculations, toric IOL axis and magnitude estimates, keratometry, and topography measurements. It also increases surgical difficulty. We performed a review to evaluate the connection between cataract surgery and dry eye and to determine the best management for these patients. Of the 16 papers included in this review, 6 were randomized controlled trials. Cataract surgery was shown to worsen ocular parameters and aggravate dry-eye disease. Physicians should recognize and aggressively treat cataract patients with poor prognostic factors and/or with existing dry-eye disease. Increased incision extent, operation time, irrigation, and microscopic-light exposure time decreased the tear breakup time and mean goblet cell density. Postoperatively, the use of eyedrops was associated with worsening of goblet cell density; hence, these medications should be tapered off when no longer needed.

Use of anti-vascular endothelial growth factor in the management of pterygium.

The rising success of anti-vascular endothelial growth factor (VEGF) therapies in ocular disease has stimulated the use of such treatments in the surgical management of pterygium. We reviewed the literature to better understand the safety and efficacy of the adjunctive role of anti-VEGF treatments for pterygium excision. Without surgery, anti-VEGF alone may favourably alter symptoms and vascularity, but does not cause pterygium regression. Some evidence supports the use of anti-VEGF as an adjuvant therapy to surgery, especially when using a higher dose and a more frequent dosing regimen. Overall, anti-VEGF is generally safe and well tolerated in patients with pterygium. Currently, the evidence does not conclusively support the use of anti-VEGF in pterygium surgery. However, further research may guide unanswered questions regarding the interaction between VEGF and other factors responsible for pterygium growth. In addition, the optimal route and dosage of anti-VEGF administration is not yet known.

Molecular signature linked to acute phase injury and tumor invasiveness in small-for-size liver grafts.

OBJECTIVE: We aimed to explore the precise molecular mechanism of early and invasive tumor growth in a small-for-size graft after liver transplantation and to identify the distinct molecular signature linked to acute-phase injury and late-phase tumor invasiveness. SUMMARY BACKGROUND DATA: Acute phase small-for-size liver graft injury plays an important role in tumor recurrence after liver transplantation. For prevention of such recurrence, understanding of its underlying mechanism will be important in developing novel therapeutic strategies. METHODS: An orthotopic rat liver transplantation model was applied using whole grafts and small-for-size (50%) grafts. The recipients were injected with hepatoma cell lines via the portal vein to mimic tumor recurrence after liver transplantation. Tumor invasive properties were compared between the tumor developed from small and whole graft. Gene signatures of acute phase graft injury (days 1 and 3) and late phase tumor recurrence (days 14 and 21) were screened using cDNA microarray analysis and further confirmed by quantitative RT-PCR. The potential gene candidate CXCL10 was singled out for further functional studies to investigate its role in tumor progression. RESULTS: A number of genes linked to inflammatory responses and tumor invasiveness were found over-expressed in small-for-size liver grafts and/or tumors developed in small liver grafts by cDNA microarray screening. Real-time RT-PCR also confirmed that the gene CXCL10 was over-expressed not only in small-for-size graft at the early phase, but also in tumor from small-for-size graft at the late phase after liver transplantation. In vitro functional studies further confirmed that CXCL10 promoted tumor-invasion-related properties and tumor-associated macrophage activation. CONCLUSION: CXCL10 over-expression, the distinct gene signature of acute-phase graft injury and tumor invasiveness in small-for-size liver grafts, may contribute to early tumor recurrence after liver transplantation. CXCL10 and its downstream signals may be potential therapeutic targets in the prevention of tumor recurrence after liver transplantation using small-for-size graft.

Small-for-size liver graft injury--impact on tumor behavior.

The success of liver transplantation has led to an ever-increasing demand for liver grafts. Since the first successful living donor liver transplantation, this surgical innovation has been well established in children and has significantly relieved the crisis of donor organ shortage for children. However, the extension of living donor liver transplantation to adult recipients is limited by the graft volume. The major concern of adult-to-adult living donor liver transplantation is the adequate graft that can be harvested from a living donor. Small-for-size graft injury is frequently observed. To develop novel effective treatments attenuating small-for-size liver graft injury during living donor liver transplantation, it is important to explore the precise mechanism of acute phase small-for-size graft damage. Recently, a number of clinical studies and animal experiments have been conducted to investigate the possible key issues on acute phase small-for-size liver graft injury, such as mechanical injury from shear stress, subsequent inflammatory responses, and imbalance of vasoregulatory factors. This review focuses on the mechanism of small-for-size liver graft injury based on the number of clinical and experimental studies. The latest research findings of the significance of acute phase liver graft injury on late phase tumor recurrence and metastasis are also addressed.