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Trimethylamine N-oxide (TMAO) is a gut microbiota–derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe–dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host. Mechanism-based small-molecule inhibitors targeting a gut microbial enzyme lower circulating levels of the prothrombotic metabolite trimethylamine-N-oxide and suppress diet-induced thrombosis in mice.

The Ang/Tie2 pathway complements VEGF-mediated activity in retinal vascular diseases such as DME, AMD, and RVO by decreasing vascular integrity, increasing neovascularization, and increasing inflammatory signaling. Faricimab is a bispecific antibody that has been developed as an inhibitor of both VEGF and Ang2 that has shown positive results in phase I, II and III trials. Recent Year 1 data from phase III clinical trials YOSEMITE, RHINE, TENAYA, and LUCERNE have confirmed the efficacy, safety, durability, and superiority of faricimab in patients with DME and nAMD. Faricimab, if approved, may significantly decrease treatment burden in patients with retinal vascular diseases to a greater extent than would current standard of care anti-VEGF injections.

Photobiomodulation therapy (PBT) has emerged as a possible treatment for age-related macular degeneration (AMD) and diabetic retinopathy (DR). This review seeks to summarize the application of PBT in AMD and DR. The National Clinical Trial (NCT) database and PubMed were queried using a literature search strategy and reviewed by the authors. Fourteen studies examining the application of PBT for AMD and nine studies examining the application of PBT for diabetic macular edema (DME) were extracted from 60 candidate publications. Despite notable methodological differences between studies, PBT has been reported to treat certain DR and AMD patients. DR patients with center involving DME and VA ≥ 20/25 have demonstrated response to treatment. AMD patients at Age-Related Eye Disease Study Stages 2-4 with VA ≥20/200 have also shown response to treatment. Results of major clinical trials are pending. PBT remains an emergent therapy with possible applications in DR and AMD. Further, high powered studies monitored by a neutral party with standard devices, treatment delivery and treatment timing are needed.

Background/Objectives While dyslipidaemia has been suggested as a potential risk factor for diabetic retinopathy (DR), previous studies have reported conflicting findings. This study aimed to better characterize the relationship between abnormal serum levels of various lipid markers and the risk of the development and progression of DR. Subjects/Methods This retrospective cohort study utilized a United States national database of electronic medical records. Adults with a history of type 2 diabetes mellitus without type 1 diabetes mellitus were divided into cohorts based on the presence of abnormal serum levels of various lipid markers. Propensity score matching was performed to match cohorts with abnormal lipid levels to those with normal lipid levels on covariates. The cohorts were then compared to evaluate the hazard ratios (HR) of receiving a new DR diagnosis, pars plana vitrectomy, panretinal photocoagulation, vitreous haemorrhage, proliferative diabetic retinopathy, diabetic macular oedema (DMO), and traction retinal detachment. Results The database contained 1,126,231 eligible patients (mean age: 60.8 [14.2] years; 46.0% female). Among patients without prior DR, low HDL (HR = 0.94, CI = 0.90–0.98), total cholesterol (HR = 0.88, CI = 0.85–0.91), and high triglyceride (HR = 0.91, CI = 0.86–0.97) levels were associated with a decreased risk of receiving a DR diagnosis. Among patients with preexisting DR, high LDL levels was associated with an increased risk of DMO (HR = 1.42, CI = 1.15–1.75), whereas low HDL levels was associated with a marginally decreased risk (HR = 0.92, CI = 0.85–0.99). Conclusions Elevated levels of markers of dyslipidaemia are inversely associated with the risk of receiving a DR diagnosis, but this relationship is blunted after the onset of DR.

Background/Objectives Bariatric surgery, as indicated for treatment of morbid obesity, has been studied in association with short term effects on ocular pathology. However, effects of surgery on postoperative disease incidence is largely unknown. Subjects/Methods In this retrospective cohort study, the TriNetX United States Collaborative Network national database, was queried for patients with an ICD-10 code for morbid obesity and a procedural code for bariatric surgery. Patients were propensity score matched across baseline demographics at the time of surgery and compared to those presenting with an ICD10 code for morbid obesity with no records of a procedural code for bariatric surgery, identifying 42,408 patients per cohort. New diagnoses or procedural codes found after the surgical index date for diabetic retinopathy, age-related macular degeneration, glaucoma, low vision, and blindness along with pertinent treatment metrics were monitored. Results Bariatric surgery was found to be associated with reduced future risk of diabetic retinopathy (RR: 0.283; 95% CI: 0.252–0.319), macular edema (RR: 0.224; 95% CI: 0.170–0.297), vitreous hemorrhage (RR: 0.459; 95% CI: 0.323–0.653), ocular hypertension (RR: 0.387; 95% CI: 0.387–0.487), glaucoma (RR: 0.360; 95% CI: 0.326–0.399), use of ocular pressure lowering medications (RR: 0.565; 95% CI: 0.496–0.644), age-related macular degeneration (RR: 0.628; 95% CI: 0.447–0.882), cataract surgery (RR: 0.524; 95% CI: 0.448–0.612), and low vision and blindness (RR: 0.328; 95% CI: 0.294–0.365) compared to patients not surgically managed. Conclusions The present analysis comprising a large US cohort of patients suggests that bariatric surgery is associated with a decreased risk of future ocular morbidity and mortality.

Background and Objective Management of hypercoagulable states with systemic anticoagulation is standard of care. The risk of future retinal vein occlusion (RVO) development with direct oral anticoagulation agents (DOACs) has yet to be investigated in a large United States cohort. Patients and Methods Retrospective cohort study using a large ICD-10 coded database. The database was queried for patients being managed with warfarin or DOACs. Propensity score matching was then used to create comparable groups. Risk ratios for RVO and intraocular bleed development in patients without a prior diagnosis of RVO were calculated. Results Patients managed with warfarin were found to be at significantly increased risk of developing a new diagnosis of all RVO (risk ratio [RR]: 1.49, 1.42–1.57), vitreous hemorrhage (RR: 2.14, 1.98–2.30), retinal hemorrhage (RR: 1.84, 1.71–1.97) and choroidal hemorrhage (RR: 2.06, 1.53–2.79), compared to patients managed with DOACs. Conclusion These findings suggest DOACs are associated with significantly reduced retinal vein occlusion and intraocular bleeding risk compared to warfarin.

Background/Objectives Vision loss is a top disability in the United States (US). Patients commonly present with multiple ocular diseases, but the extent to which this places them at risk for vision loss, and if sex and race impacts this, is poorly understood. This exploratory analysis evaluated which ocular comorbidities and demographics are at highest risk for visual impairment. Subjects/Methods A retrospective cross-sectional study was conducted through the TriNetX Analytics Network, an aggregated network encompassing over 90 million insured and uninsured patients across 50 healthcare organizations from all regions in the US. Patients with diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal vein occlusion (RVO), glaucoma, and uveitis were included in this study. Ocular diseases and visual impairment were determined through ICD-10 codes. Prevalence and odds ratios were calculated while stratifying by sex and racial demographics. Statistical analyses were completed using RStudio and Excel with 95% confidence intervals calculated. Results The comorbid conditions with the highest prevalence of visual impairment were uveitis and RVO (39.94%), uveitis and neovascular AMD (37.61%), and uveitis and glaucoma (33.23%). The comorbidity with the highest odds for visual impairment was uveitis and RVO (POR 4.86; 95% CI 4.49, 5.26). Compared to white males, Black and Hispanic males were disproportionately affected by visual impairment across ocular comorbidities. Conclusion This study quantified the prevalence and odds of visual impairment for unilateral and comorbid ocular disease, with the addition of uveitis causing the greatest increase. Black and Hispanic males were disproportionately affected by visual impairment across comorbid conditions.

Background and Objective: This study assesses long-term outcomes following surgical repair of idiopathic full-thickness macular holes (FTMHs) in patients with at least 5 years of postoperative follow-up. Patients and Methods: A retrospective study evaluated patients diagnosed with idiopathic FTMH who received surgical repair at a single tertiary center with at least 5 years of postoperative follow-up. Data collection included demographic and preoperative characteristics along with macular hole structural integrity as determined by spectral-domain optical coherence tomography (OCT). Functional and structural improvement were assessed by collection of visual acuity and findings on OCT at determined time points until 9 years of follow-up. Results: The study comprised 90 eyes of 80 patients with a mean age of 67.2 ± 6.8 years, with an average postoperative follow-up of 80.8 ± 17.4 months (range 54 to 130 months). The mean macular hole diameter was 239.7 µm ± 92.2. Macular hole reoperation occurred in four eyes (4%) at a mean duration of 5.5 ± 6 months (range 0.3 to 13 months). Over the study duration, ellipsoid zone (EZ) integrity was maintained in 67.8% of eyes, with an absence of intraretinal fluid (IRF) in 96% on final OCT. The preoperative mean Early Treatment Diabetic Retinopathy Study (ETDRS) best visual acuity (BVA) of 51 improved to a mean BVA of 76 at 5 years postoperatively, with an average gain of 24 letters at one year that remained stable over 5 years (P < 0.05). Eight years after surgical repair, more than 80% of patients achieved a BVA > 65. Conclusions: Vitreoretinal surgery for idiopathic FTMH resulted in successful hole closure and sustained visual acuity improvement over long-term follow-up. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX–XX.]

Clinical trials targeting the gut microbiome to mitigate ocular disease are now on the horizon. A review of clinical data thus far is essential to determine future directions in this novel promising field. This review examines recent clinical trials that support the plausibility of a gut-eye axis, and may form the basis of novel clinical interventions. PubMed was queried for English language clinical studies examining the relationships between gut microbiota and ocular pathology. 25 studies were extracted from 828 candidate publications, which suggest that gut imbalance is associated with ocular pathology. Of these, only four interventional studies exist which suggest probiotic supplementation or fecal microbiota transplant can reduce symptoms of chalazion or uveitis. The gut-eye axis appears to hold clinical relevance, but current data is limited in sample size and design. Further investigation via longitudinal clinical trials may be warranted.

Background and Objective: Our aim was to assess long-term outcomes following surgical repair of idiopathic epiretinal membrane (ERM) with pars plana vitrectomy (PPV) and membrane peel (MP). Patients and Methods: A retrospective study evaluated patients with idiopathic ERM who underwent surgical repair at a single academic tertiary center with five to nine years of postoperative follow-up, assessing preoperative characteristics, surgical techniques, best visual acuity (BVA), and optical coherence tomography biomarkers at various time points. Results: The study involved 67 patients (72 eyes) with an average postoperative follow-up of 82.8 ± 18.8 months. Patients with cone outer segment tips integrity at initial presentation and 1-year follow-up and patients with external limiting membrane and ellipsoid zone integrity at 1-year follow-up were noted to have significantly better long-term visual acuity than those without. More than 85% of patients achieved a BVA > 70 seven years after surgical repair. Conclusions: Vitreoretinal surgery for idiopathic ERM resulted in improved anatomical recovery and sustained visual acuity gain over long-term follow-up. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX–XX.]