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Purpose: The guarded light pipe is a recently described alternative endoillumination technique to chandelier illumination. We sought to compare the outcomes of scleral buckling (SB) under indirect ophthalmoscopy (ID) to heads-up three-dimensional visualization with a guarded light pipe (3DGLP). Methods: A retrospective comparative study was performed, including 47 eyes that underwent SB for rhegmatogenous retinal detachment (RRD) repair with either traditional ID (n = 31) or 3DGLP (n = 16). Results: The single surgery anatomic success rate was 87.0% in the ID group and 87.5% in the 3DGLP group. The final anatomic success rate was 100% in both groups. The median (interquartile range) post-operative logMAR was 0.10 (0.0-0.20) in the ID group and 0.08 (0.02-0.69) in the 3DGLP group (p = 0.51). The median operative time was 107 (94-123) minutes in the ID group and 100 (90-111) minutes in the 3DGLP group (p = 0.25). Among eyes that underwent subretinal fluid drainage, the operative time was significantly longer in the ID group compared to the 3DGLP group, 113 (100-135) minutes vs 93 (85-111) minutes (p = 0.035). There were no post-operative complications in the ID group and one complication of self-resolving vitreous hemorrhage associated with a malfunctioning cryoprobe in the 3DGLP group (p = 0.34). There were no cases of post-operative cataract progression in either group. Conclusion: Compared to traditional SB, 3DGLP improves ergonomics and educational value with similar anatomical, visual, intra and post-operative outcomes and may result in shorter operative time in cases requiring subretinal fluid drainage.

Background: To characterize contrast sensitivity function (CSF) in cataractous and pseudophakic eyes compared to healthy control eyes using a novel quantitative CSF test with active learning algorithms. Methods: This is a prospective observational study at an academic medical center. CSF was measured in eyes with visually significant cataract, at least 2+ nuclear sclerosis (NS) and visual acuity (VA) ≥ 20/50, in pseudophakic eyes and in healthy controls with no more than 1+ NS and no visual complaints, using the Manifold Contrast Vision Meter. Outcomes included Area under the Log CSF (AULCSF) and CS thresholds at 1, 1.5, 3, 6, 12, and 18 cycles per degree (cpd). A subgroup analysis as performed on cataract eyes with VA ≥ 20/25. Results: A total of 167 eyes were included, 58 eyes in the cataract group, 77 controls, and 32 pseudophakic eyes with respective median AULCSF of 1.053 (0.352) vs 1.228 (0.318) vs 1.256 (0.360). In our multivariate regression model, cataract was associated with significantly reduced AULCSF (P= 0.04, β= -0.11) and contrast threshold at 6 cpd (P= 0.01, β= -0.16) compared to controls. Contrast threshold at 6 cpd was significantly reduced even in the subgroup of cataractous eyes with VA ≥ 20/25 (P=0.02, β=-0.16). Conclusion: The novel qCSF test detected disproportionate significant contrast deficits at 6 cpd in cataract eyes; this remained significant even in the cataractous eyes with VA ≥ 20/25. CSF testing may enhance cataract evaluation and surgical decision-making, particularly in patients with subjective visual complaints despite good VA.

Non-invasive electric stimulation (ES) employing a low-intensity electric current presents a potential therapeutic modality that can be applied for treating retinal and brain neurodegenerative disorders. As neurons are known to respond directly to ES, the effects of ES on glia cells are poorly studied. A key question is if ES directly mediates microglial function or modulates their activity merely via neuron-glial signaling. Here, we demonstrated the direct effects of ES on microglia in the BV-2 cells-an immortalized murine microglial cell line. The low current ES in a biphasic ramp waveform, but not that of rectangular or sine waveforms, significantly suppressed the motility and migration of BV-2 microglia in culture without causing cytotoxicity. This was associated with diminished cytoskeleton reorganization and microvilli formation in BV-2 cultures, as demonstrated by immunostaining of cytoskeletal proteins, F-actin and β-tubulin, and scanning electron microscopy. Moreover, ES of a ramp waveform reduced microglial phagocytosis of fluorescent zymosan particles and suppressed lipopolysaccharide (LPS)-induced pro-inflammatory cytokine expression in BV-2 cells as shown by Proteome Profiler Mouse Cytokine Array. The results of quantitative PCR and immunostaining for cyclooxygenase-2, Interleukin 6, and Tumor Necrosis Factor-α corroborated the direct suppression of LPS-induced microglial responses by a ramp ES. Transcriptome profiling further demonstrated that ramp ES effectively suppressed nearly half of the LPS-induced genes, primarily relating to cellular motility, energy metabolism, and calcium signaling. Our results reveal a direct modulatory effect of ES on previously thought electrically "non-responsive" microglia and suggest a new avenue of employing ES for anti-inflammatory therapy.

Purpose: To determine if extraocular muscles (EOMs) from mice with nystagmus show abnormalities in myofiber composition and innervation, as seen in EOMs from human nystagmus patients, and to determine when in development those changes occur. Methods: Balb/c albino mice were crossed to pigmented mice to generate heterozygous mice, which were mated to create experimental litters containing albinos and wild-type controls. Orbits were harvested from adult animals (12 weeks old); on postnatal day (P)0, P10, P14, and P21; and from 6-week-old animals. EOM sections were collected from the intraorbital portion of the muscles. Sections were immunostained for slow and fast myosin and for neuromuscular junctions (NMJs). The proportion of each myofiber subtype and the density and size of NMJs were quantified. Initial innervation patterns were assessed using whole-mount immunostaining of embryonic day (E)13.5 embryos expressing IslMN:GFP. Results: Adult albino EOMs display an increased proportion of slow myofibers, larger slow myofibers, and a decreased density of NMJs-similar to human nystagmus patients. The percentage of NMJs on slow myofibers is also lower in albino animals. The initial innervation pattern of the incoming ocular motor neurons is normal in E13.5 albino embryos. Differences in the proportion of slow and fast myofiber subtypes are present as early as P14, and a lower percentage of NMJs on slow myofibers is present by P21. There is a lower density of NMJs on albino EOMs as early as P10, prior to eye opening. Conclusions: Changes in NMJ development observed before eye opening indicate that nystagmus is not solely secondary to poor vision.

PURPOSE: Serum lipids are modifiable, routinely collected blood test features associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) with intraocular pressure (IOP). DESIGN: Cross-sectional study in the UK Biobank and European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohorts. PARTICIPANTS: We included 94 323 participants from the UK Biobank (mean age, 57 years) and 6230 participants from the EPIC-Norfolk (mean age, 68 years) cohorts with data on TC, HDL-C, LDL-C, and triglycerides collected between 2006 and 2009. METHODS: Multivariate linear regression adjusting for demographic, lifestyle, anthropometric, medical, and ophthalmic covariables was used to examine the associations of serum lipids with corneal-compensated IOP (IOPcc). MAIN OUTCOME MEASURES: Corneal-compensated IOP. RESULTS: Higher levels of TC, HDL-C, and LDL-C were associated independently with higher IOPcc in both cohorts after adjustment for key demographic, medical, and lifestyle factors. For each 1-standard deviation increase in TC, HDL-C, and LDL-C, IOPcc was higher by 0.09 mmHg (95% confidence interval [CI], 0.06-0.11 mmHg; P < 0.001), 0.11 mmHg (95% CI, 0.08-0.13 mmHg; P < 0.001), and 0.07 mmHg (95% CI, 0.05-0.09 mmHg; P < 0.001), respectively, in the UK Biobank cohort. In the EPIC-Norfolk cohort, each 1-standard deviation increase in TC, HDL-C, and LDL-C was associated with a higher IOPcc by 0.19 mmHg (95% CI, 0.07-0.31 mmHg; P = 0.001), 0.14 mmHg (95% CI, 0.03-0.25 mmHg; P = 0.016), and 0.17 mmHg (95% CI, 0.06-0.29 mmHg; P = 0.003). An inverse association between triglyceride levels and IOP in the UK Biobank (-0.05 mmHg; 95% CI, -0.08 to -0.03; P < 0.001) was not replicated in the EPIC-Norfolk cohort (P = 0.30). CONCLUSIONS: Our findings suggest that serum TC, HDL-C, and LDL-C are associated positively with IOP in 2 United Kingdom cohorts and that triglyceride levels may be associated negatively. Future research is required to assess whether these associations are causal in nature.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

Purpose: To report a case of systemic diffuse large B cell lymphoma presenting with ocular manifestations and neurologic findings resembling Vogt-Koyanagi-Harada syndrome. Observations: A 51-year-old Caucasian man presented with headache, ear pain, and blurry vision in both eyes. He was found to have bilateral exudative retinal detachments. After a short period of initial improvement with high dose systemic corticosteroid, his condition significantly worsened. An extensive work-up, including a kidney biopsy, led to a diagnosis of systemic diffuse large B cell lymphoma. He had excellent recovery following treatment with appropriate chemotherapy. Conclusions and Importance: Systemic malignancy may present with ocular manifestations and may masquerade as another diagnosis. An unexpected clinical course may suggest an alternative diagnosis. A broad systemic work-up including an evaluation for malignancy should be considered for patients presenting with unexplained exam or systemic findings.

PURPOSE: To validate the international chronic ocular graft-versus-host disease (GVHD) diagnostic criteria (ICCGVHD) compared to the National Institute of Health diagnostic criteria 2014 (NIH2014) for chronic ocular GVHD. METHODS: Between 2013 and 2019, the study enrolled 233 patients with or without chronic ocular GVHD combined with the presence or absence of systemic chronic GVHD in an internationally prospective multicenter and observational cohort from 9 institutions. All patients were evaluated for four clinical parameters of ICCGVHD. RESULTS: The relation between the ICCGVHD score (0-11) and NIH2014 eye score (0-4) was relatively high (r = 0.708, 95% CI: 0.637-0.767, p < 0.001). The sensitivity and specificity of ICCGVHD for NIH 2014 for 233 patients were 94.3% (95% CI: 89.6%-98.1%) and 71.7% (95% CI: 63.0-79.5%), respectively (cutoff value of the ICCGVHD score = 6). The positive predictive value was 77.1% (95% CI: 71.1%-82.1%), and the negative predictive value was 87.0% (95% CI:81.6-92.5%). For the patients with systemic GVHD (n = 171), the sensitivity and specificity were 94.2% and 67.2%, respectively (ICCGVHD-score cutoff value = 6). By receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.903 (95% CI: 0.859-0.948). For patients without systemic GVHD (n = 62), the sensitivity and specificity were 100% and 76.7%, respectively (ICCGVHD-score cutoff value = 6). The AUC was 0.891 (95% CI 0.673-1.000). CONCLUSIONS: Good sensitivity, specificity, predictive value and correlation were found between ICCGVHD and NIH2014. ICCGVHD scores ≥6 can be useful to diagnose ocular GVHD with or without systemic GVHD for clinical research.

Retinoblastoma is the most common primary intraocular malignancy in children. Although traditional chemotherapy has shown some success in retinoblastoma management, there are several shortcomings to this approach, including inadequate pharmacokinetic parameters, multidrug resistance, low therapeutic efficiency, nonspecific targeting, and the need for adjuvant therapy, among others. The revolutionary developments in biomaterials for drug delivery have enabled breakthroughs in cancer management. Today, biomaterials are playing a crucial role in developing more efficacious retinoblastoma treatments. The key goal in the evolution of drug delivery biomaterials for retinoblastoma therapy is to resolve delivery-associated obstacles and lower nonlocal exposure while ameliorating certain adverse effects. In this review, we will first delve into the historical perspective of retinoblastoma with a focus on the classical treatments currently used in clinics to enhance patients' quality of life and survival rate. As we move along, we will discuss biomaterials for drug delivery applications. Various aspects of biomaterials for drug delivery will be dissected, including their features and recent advances. In accordance with the current advances in biomaterials, we will deliver a synopsis on the novel chemotherapeutic drug delivery strategies and evaluate these approaches to gain new insights into retinoblastoma treatment.

Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer's disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina. Here, we discovered the presence and increased populations of Clec7a+ and Galectin-3+ MGnD microglia in retinas of transgenic APPSWE/PS1L166P AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible CreERT2 system in APPSWE/PS1L166P mice diminished retinal Clec7a+ and Galectin-3+ microglial populations while increasing homeostatic P2ry12+ microglia. Retinal MGnD microglia were often adhering to microvessels; their depletion protected the inner blood-retina barrier and reduced vascular amyloidosis. Microglial miR-155 depletion further limits retinal inflammation. Mass spectrometry analysis revealed enhanced retinal PI3K-Akt signaling and predicted IL-8 and Spp1 decreases in mice with microglia-specific miR-155 knockout. Overall, this study identified MGnD microglia in APPSWE/PS1L166P mouse retina. Transcriptional regulation of these dysfunctional microglia mitigated retinal inflammation and vasculopathy. The protective effects of microglial miR-155 ablation should shed light on potential treatments for retinal inflammation and vascular damage during AD and other ocular diseases.

Subspecialty exposure during residency can influence the future pursuit of fellowship training. In this study, we compared the trends in strabismus surgical experience reported by graduating ophthalmology residents in the United States with other categories of ophthalmic surgery. Over the 10-year period (2010-2019), there was a decline in the total number of strabismus procedures performed during residency by ophthalmology residents graduating in a given year (1.4 fewer cases per year; 95% CI, 1.1-1.6 [P < 0.001]). Although several surgical categories experienced a decrease in cases performed in the assistant role, strabismus surgery was the only category with a decrease in cases performed in the surgeon role (0.4 fewer cases per year; 95% CI, 0.3-0.5 [P < 0.001]).

The eye and the kidney share structural and developmental similarities on a cellular and clinical level, and they are often affected by the same disease processes. Performing an eye exam to look for signs of conditions such as hypertension and diabetes can provide a helpful window into the health of the kidney. Patients with kidney transplants (KT) are a unique population that require close monitoring. These patients are maintained on a number of immunosuppressive medications and may face complications such as medication side effects, infections, and graft rejection. Patients with KT are at higher risk of both infectious and noninfectious eye conditions related to underlying systemic disease or use of immunosuppressive medications. Screening for eye conditions is important because preserving visual function is integral to quality of life, and also because the eye exam can help with early detection and treatment of systemic conditions. Here we describe some of the common eye findings and conditions in patients with KT. We recommend that patients with KT receive annual eye exams, and we hope that the information provided here can help nephrologists become more familiar with eye findings and identify situations where a referral to ophthalmology is warranted.

Purpose: To investigate the clinical response to infliximab in ocular inflammation patients who develop anti-infliximab antibodies (AIA) vs. those patients who do not develop AIA. Observations: A retrospective review was performed of patients treated with infliximab for noninfectious uveitis (NIU) or scleritis. Clinical response was determined as a composite clinical endpoint and classified as complete, partial, or absent. Nine of 32 infliximab-treated patients (28%) were found to develop AIA. Among the AIA-positive patients, clinical response was complete in 7 patients (78%) and partial in 2 patients (22%). Among the AIA-negative patients, clinical response was complete in 15 patients (65%), partial in 6 patients (26%) and absent in 2 patients (9%). Serum infliximab levels tended to decrease with appearance of AIA but rarely became undetectable. Conclusions and Importance: In this pilot study, AIA-positive patients did not have diminished clinical response to infliximab when compared with AIA-negative patients. There was a high rate of complete clinical response to infliximab in this group of NIU and scleritis patients. Approximately a quarter of patients developed AIA. AIA-positive patients did not have diminished rates of clinical response when compared with AIA-negative patients. This suggests that routine AIA monitoring may not be clinically useful, although validation of this finding in larger cohorts is necessary.

The mucin layer of the tear film is produced by goblet cells in the conjunctiva to protect the ocular surface and maintain homeostasis. The pro-resolving lipid mediator resolvin D2 (RvD2) biosynthesized from an omega 3 fatty acid actively terminates inflammation and regulates mucin secretion from conjunctival goblet cells. Our objective was to determine which Ca2+ -dependent signaling pathways RvD2 uses to stimulate conjunctival goblet cell function (CGC). We hypothesize that RvD2 activates multiple intracellular Ca2+ signaling pathways to stimulate CGC secretion. Rat and human CGCs were cultured from conjunctival explants. The amount of RvD2 receptor GPR18/DRV2 message and protein were determined. The intracellular concentration of Ca2+ ([Ca2+ ]i ) was measured in CGCs using a fluorescent Ca2+ dye and mucin secretion was determined by measuring protein secretion enzymatically with a lectin. Goblet cells were incubated with signaling pathway inhibitors before stimulation with RvD2 and [Ca2+ ]i or secretion was measured. In rat and human CGCs RvD2 receptor and in rat CGCs IP3 (a molecule that releases Ca2+ from intracellular organelles) receptors 1-3 were detected. In both species of CGC RvD2 increased [Ca2+ ]i similarly to RvD1. In rat CGCs, the increase in [Ca2+ ]i and secretion stimulated by RvD2 was significantly blocked by inhibitors to phospholipase (PL-) C and IP3 -receptor, but not protein kinase C. Increase in [Ca2+ ]i was blocked by the PLD inhibitor, but not the PLA2 inhibitor. Secretion was blocked by PLA2 inhibitor, but not the PLD inhibitor. An inhibitor of the epidermal growth factor receptor blocked the increase in [Ca2+ ]i by RvD2 in both species of CGCs. In CGCs RvD2 activates multiple intracellular signaling pathways that are Ca2+ -dependent, along with one Ca2+ -independent and one cAMP/protein kinase A-dependent pathway. Activation of these pathways stimulate mucin secretion from rat and human CGCs into the tear film contributing to ocular surface homeostasis and health.

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve vision after traumatic or ischemic optic nerve injury or in neurodegenerative diseases such as glaucoma, dominant optic neuropathy, or optic pathway gliomas. Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. This review primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field provides hope that clinically effective strategies to improve vision in patients with currently untreatable losses could become a reality in 5-10 years.