The Emerging Role of Gut Microbiota in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a progressive, degenerative retinal disease that is a leading cause of blindness globally. Although multiple risk factors have been identified regarding disease incidence and progression, including smoking, genetics, and diet, the understanding of AMD pathogenesis remains unclear. As such, primary prevention is lacking, and current treatments have limited efficacy. More recently, the gut microbiome has emerged as an influential player in various ocular pathologies. As mediators of metabolism and immune regulation, perturbations in gut microbiota may impart significant effects distally on the neuroretina and its adjacent tissues, termed the gut-retina axis. In this review, key studies over the past several decades are summarized, both in humans and in animal models, which shed insight on the relationships between the gut microbiome and retinal biology and their implications for AMD. The literature linking gut dysbiosis with AMD is examined, along with preclinical animal models and techniques apt for studying the role of gut microbiota in AMD pathogenesis, which include interactions with systemic inflammation, immune regulation, chorioretinal gene expression, and diet. As understanding of the gut-retina axis continues to advance, so too will the possibility for more accessible and effective prevention and therapy of this vision-threatening condition.

FULL-THICKNESS MACULAR HOLE CLOSURE WITH TOPICAL MEDICAL THERAPY.

PURPOSE: To examine the efficacy and clinical characteristics of successful full-thickness macular hole closure with topical therapy. METHODS: Retrospective case series of full-thickness macular holes managed by a single retinal physician (DS) diagnosed and treated from 2017 to 22. RESULTS: Of 168 patients with full-thickness macular holes, 71 patients were started on steroid, carbonic anhydrase inhibitor, and nonsteroidal antiinflammatory (NSAID) drops. 49 patients (mean 67 years, 59% women) were included in the analysis, and 22 patients were excluded for poor follow-up. In total, 7/49 were secondary post-PPV holes and 42/49 were idiopathic. In addition, 18/49 eyes (36.7%) achieved closure on topical therapy, of which 13 were idiopathic. Hole size was directly correlated with odds of closure: for every 10 µm decrease in size and odds of closure increased by 1.2× ( P = 0.001, CI 1.1-1.4). Average time to closure was 107.2 days (range 20-512 days) and was not correlated with hole size ( P = 0.217, CI -0.478 to +1.938). The presence of VMT was found to be inversely related to successful closure (OR 6.1, P = 0.029, CI 1.2-31.3). There was no significant difference in final best-corrected visual acuity for eyes undergoing primary pars plana vitrectomy versus those trialing drops before undergoing pars plana vitrectomy ( P = 0.318, CI -0.094 to +0.112). CONCLUSION: In the first study to date to report the overall efficacy and clinical characteristics of successful macular hole closure with topical therapy, drops achieved an overall closure rate of 36.7%, with higher efficacy in smaller holes and those without VMT. Rates of MH narrowing and reduction in central foveal thickness acted as predictors of effectiveness of drop therapy.

Molecular pathology of adverse local tissue reaction caused by metal-on-metal implants defined by RNA-seq.

Total hip arthroplasty (THA) alleviates hip pain and improves joint function. Current implant design permits long-term survivorship of THAs, but certain metal-on-metal (MoM) articulations can portend catastrophic failure due to adverse local tissue reactions (ALTR). Here, we identified biological and molecular differences between periacetabular synovial tissues of patients with MoM THA failure undergoing revision THA compared to patients undergoing primary THA for routine osteoarthritis (OA). Analysis of tissue biopsies by RNA-sequencing (RNA-seq) revealed that MoM patient samples exhibit significantly increased expression of immune response genes but decreased expression of genes related to extracellular matrix (ECM) remodeling. Thus, interplay between local tissue inflammation and ECM degradation may account for the pathology and compromised clinical outcomes in select patients with MoM implants. We conclude that adverse responses of host tissues to implant materials result in transcriptomic modifications in patients with MoM implants that permit consideration of strategies that could mitigate ECM damage.

Bleb revision with Tenon's transposition flap: Case report.

INTRODUCTION: To describe the use and technique of a Tenon's transposition flap without overlying conjunctiva to cover bare sclera following bleb excision and tube shunt implantation. PRESENTATION OF CASE: A 76-year-old man with severe stage primary open-angle glaucoma in both eyes presented with a nonfunctioning trabeculectomy with a thin-walled, cystic bleb overhanging the cornea. A Baerveldt-350 Glaucoma Implant in the ciliary sulcus was recommended for further lowering of intraocular pressure, along with concurrent excision of the bleb due to patient dissatisfaction with the cosmesis of the bleb and to prevent future bleb-associated complications. Conjunctiva could be closed without tension over the new tube entry site; however, a defect remained at the prior trabeculectomy site. A Tenon's transposition flap without overlying conjunctiva was created to cover this site. By postoperative week 6, new conjunctiva had grown over the Tenon's transposition graft, appearing as if there had never been a bleb. DISCUSSION: This case illustrates the use of a Tenon's transposition flap to cover bare sclera following bleb excision. This technique proves valuable when conjunctiva is limited, offering an alternative when adjacent conjunctiva cannot be mobilized. CONCLUSION: In cases requiring non-water-tight coverage of bare sclera with limited available conjunctiva, a Tenon's transposition flap can be used, permitting new conjunctiva to safely grow over bare Tenon's. This technique is useful during a variety of scenarios, including tube shunt and trabeculectomy revisions, where conjunctival closure may be difficult.

Reflux hyphema from transient hypotony after Ozurdex® in eyes with prior GATT.

Purpose: To report on delayed-onset hyphema following intravitreal injection of dexamethasone implant Ozurdex® in eyes with a history of gonioscopy-assisted transluminal trabeculotomy (GATT). Observations: We describe two cases of hyphema occurring within one day following Ozurdex® implantation in eyes that had undergone GATT at least one year prior. One case responded well to medical management, while the other required anterior chamber paracentesis for intraocular pressure (IOP) control. Both patients achieved normalization of IOP following resolution of the hyphema, and have not had recurrence. Conclusions and importance: We propose that transient hypotony immediately after Ozurdex® injection may lead to a reflux of blood from the episcleral venous network into the anterior chamber in eyes with prior ab interno trabeculotomy. Glaucoma and retina specialists should be aware of this potential complication to guide follow up and management in the post-injection period for these patients.

Oral Metformin Inhibits Choroidal Neovascularization by Modulating the Gut-Retina Axis.

Purpose: Emerging data indicate that metformin may prevent the development of age-related macular degeneration (AMD). Whereas the underlying mechanisms of metformin's anti-aging properties remain undetermined, one proposed avenue is the gut microbiome. Using the laser-induced choroidal neovascularization (CNV) model, we investigate the effects of oral metformin on CNV, retinal pigment epithelium (RPE)/choroid transcriptome, and gut microbiota. Methods: Specific pathogen free (SPF) male mice were treated via daily oral gavage of metformin 300 mg/kg or vehicle. Male mice were selected to minimize sex-specific differences to laser induction and response to metformin. Laser-induced CNV size and macrophage/microglial infiltration were assessed by isolectin and Iba1 immunostaining. High-throughput RNA-seq of the RPE/choroid was performed using Illumina. Fecal pellets were analyzed for gut microbiota composition/pathways with 16S rRNA sequencing/shotgun metagenomics, as well as microbial-derived metabolites, including small-chain fatty acids and bile acids. Investigation was repeated in metformin-treated germ-free (GF) mice and antibiotic-treated/GF mice receiving fecal microbiota transplantation (FMT) from metformin-treated SPF mice. Results: Metformin treatment reduced CNV size (P < 0.01) and decreased Iba1+ macrophage/microglial infiltration (P < 0.005). One hundred forty-five differentially expressed genes were identified in the metformin-treated group (P < 0.05) with a downregulation in pro-angiogenic genes Tie1, Pgf, and Gata2. Furthermore, metformin altered the gut microbiome in favor of Bifidobacterium and Akkermansia, with a significant increase in fecal levels of butyrate, succinate, and cholic acid. Metformin did not suppress CNV in GF mice but colonization of microbiome-depleted mice with metformin-derived FMT suppressed CNV. Conclusions: These data suggest that oral metformin suppresses CNV, the hallmark lesion of advanced neovascular AMD, via gut microbiome modulation.

High-Fat Diet Alters the Retinal Pigment Epithelium and Choroidal Transcriptome in the Absence of Gut Microbiota.

Relationships between retinal disease, diet, and the gut microbiome have started to emerge. In particular, high-fat diets (HFDs) are associated with the prevalence and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR). These effects are thought to be partly mediated by the gut microbiome, which modulates interactions between diet and host homeostasis. Nevertheless, the effects of HFDs on the retina and adjacent retinal pigment epithelium (RPE) and choroid at the transcriptional level, independent of gut microbiota, are not well-understood. In this study, we performed the high-throughput RNA-sequencing of germ-free (GF) mice to explore the transcriptional changes induced by HFD in the RPE/choroid. After filtering and cleaning the data, 649 differentially expressed genes (DEGs) were identified, with 616 genes transcriptionally upregulated and 33 genes downregulated by HFD compared to a normal diet (ND). Enrichment analysis for gene ontology (GO) using the DEGs was performed to analyze over-represented biological processes in the RPE/choroid of GF-HFD mice relative to GF-ND mice. GO analysis revealed the upregulation of processes related to angiogenesis, immune response, and the inflammatory response. Additionally, molecular functions that were altered involved extracellular matrix (ECM) binding, ECM structural constituents, and heparin binding. This study demonstrates novel data showing that HFDs can alter RPE/choroid tissue transcription in the absence of the gut microbiome.

Defeating Cancel Culture in Surgical Site Infection Research: A Plea to Include Microbial Cultures and Antibiotic Sensitivity Data.

Background: Despite advances in infection control measures, surgical site infections (SSIs) remain a real and present danger to patients. In most studies addressing SSI prevention measures, recommendations are often made in the absence of information such as culture results, the antibiotic agents used for prophylaxis, and antibiotic sensitivity data. The aim of this study is to document this latter claim by reviewing studies published in the last five years in highly read and cited surgical journals. Methods: A systematic review evaluating SSIs from four highly cited surgical journals, Annals of Surgery, the British Journal of Surgery, JAMA Surgery, and the Journal of the American College of Surgeons was conducted for articles published between 2016 and 2021. We focused our analysis on the following key features: how SSI is defined; bacterial culture information; antibiotic sensitivity data; and identification of the antibiotic chosen for prophylaxis. We hypothesized that, in most cases among the journals queried, this information would be unavailable. Results: Of the 71 studies included, 32 diagnosed SSIs based on criteria developed by the U.S. Centers for Disease Control and Prevention while five provided no definition of SSI. Of the 27 articles recommending increasing antibiotic usage, only one study performed antibiotic sensitivity testing to guide the antibiotic choice. Of 71 studies reviewed, only one reported all key features we considered to be important for SSI antibiotic decision-making; 46 reported none of the key features. Conclusions: Among publications addressing SSIs in four highly cited surgical journals, key information regarding diagnosis and with which to base antibiotic recommendations, is routinely unavailable.

A molecular atlas of the human postmenopausal fallopian tube and ovary from single-cell RNA and ATAC sequencing.

As part of the Human Cell Atlas Initiative, our goal is to generate single-cell transcriptomics (single-cell RNA sequencing [scRNA-seq], 86,708 cells) and regulatory (single-cell assay on transposase accessible chromatin sequencing [scATAC-seq], 59,830 cells) profiles of the normal postmenopausal ovary and fallopian tube (FT). The FT contains 11 major cell types, and the ovary contains 6. The dominating cell type in the FT and ovary is the stromal cell, which expresses aging-associated genes. FT epithelial cells express multiple ovarian cancer risk-associated genes (CCDC170, RND3, TACC2, STK33, and ADGB) and show active communication between fimbrial epithelial cells and ovarian stromal cells. Integrated single-cell transcriptomics and chromatin accessibility data show that the regulatory landscape of the fimbriae is different from other anatomic regions. Cell types with similar gene expression in the FT display transcriptional profiles. These findings allow us to disentangle the cellular makeup of the postmenopausal FT and ovary, advancing our knowledge of gynecologic diseases in menopause.

The Effects of Chemotherapeutics on the Ovarian Cancer Microenvironment.

High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor-stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.

High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota.

The relationship between retinal disease, diet, and the gut microbiome has shown increasing importance over recent years. In particular, high-fat diets (HFDs) are associated with development and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy. However, the complex, overlapping interactions between diet, gut microbiome, and retinal homeostasis are poorly understood. Using high-throughput RNA-sequencing (RNA-seq) of whole retinas, we compare the retinal transcriptome from germ-free (GF) mice on a regular diet (ND) and HFD to investigate transcriptomic changes without influence of gut microbiome. After correction of raw data, 53 differentially expressed genes (DEGs) were identified, of which 19 were upregulated and 34 were downregulated in GF-HFD mice. Key genes involved in retinal inflammation, angiogenesis, and RPE function were identified. Enrichment analysis revealed that the top 3 biological processes affected were regulation of blood vessel diameter, inflammatory response, and negative regulation of endopeptidase. Molecular functions altered include endopeptidase inhibitor activity, protease binding, and cysteine-type endopeptidase inhibitor activity. Human and mouse pathway analysis revealed that the complement and coagulation cascades are significantly affected by HFD. This study demonstrates novel data that diet can directly modulate the retinal transcriptome independently of the gut microbiome.