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Intraocular pressure (IOP) is the most important modifiable risk factor for glaucoma and fluctuates considerably within patients over short and long time periods. Our field's understanding of IOP has evolved considerably in recent years, driven by tonometric technologies with increasing accuracy, reproducibility, and temporal resolution that have refined our knowledge regarding the relationship between IOP and glaucoma risk and pathogenesis. The goal of this article is to review the published literature pertinent to the following points: 1) the factors that determine IOP in physiologic and pathologic states; 2) technologies for measuring IOP; 3) scientific and clinical rationale for measuring diverse IOP metrics in patients with glaucoma; 4) the impact and shortcomings of current standard-of-care IOP monitoring approaches; 5) recommendations for approaches to IOP monitoring that could improve patient outcomes; and 6) research questions that must be answered to improve our understanding of how IOP contributes to disease progression. Retrospective and prospective data, including that from landmark clinical trials, document greater IOP fluctuations in glaucomatous than healthy eyes, tendencies for maximal daily IOP to occur outside of office hours, and, in addition to mean and maximal IOP, an association between IOP fluctuation and glaucoma progression that is independent of mean in-office IOP. Ambulatory IOP monitoring, measuring IOP outside of office hours and at different times of day and night, provides clinicians with discrete data that could improve patient outcomes. Eye care clinicians treating glaucoma based on isolated in-office IOP measurements may make treatment decisions without fully capturing the entire IOP profile of an individual. Data linking home blood pressure monitors and home glucose sensors to dramatically improved outcomes for patients with systemic hypertension and diabetes and will be reviewed as they pertain to the question of whether ambulatory tonometry is positioned to do the same for glaucoma management. Prospective randomized controlled studies are warranted to determine whether remote tonometry-based glaucoma management might reduce vision loss and improve patient outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Thomas V Johnson reports financial support was provided by National Eye Institute. Thomas V Johnson reports financial support was provided by Research to Prevent Blindness. Barbara Wirostko reports financial support was provided by Research to Prevent Blindness. Thomas V. Johnson reports equipment, drugs, or supplies was provided by ICARE. Sanjay G. Asrani reports equipment, drugs, or supplies was provided by ICARE. Sanjay G. Asrani, Lama A. Al-Aswad, Craig J. Chaya, Shan Lin, David C. Musch, Ian Pitha, Alan L. Robin, Barbara Wirostko, and Thomas V. Johnson reports a relationship with lighthouse Strategy Consulting that includes: consulting or advisory and travel reimbursement. Barbara Wirosko reports a relationship with MyEyes.com that includes: board membership, employment, and equity or stocks. The Max IOP Consensus Meeting was held in New Orleans, LA on April 22nd, 2023, and chaired by BW and TVJ. The meeting was organized by Lighthouse Strategy Consulting, which was contracted by iCare USA. SGA, BW, LAA, SL, DCM, IP, AR, and TVJ received effort and travel payments from Lighthouse Strategy Consulting for participation in the meeting. Subsequently, the authors drafted the entirety of this manuscript without input, support, or review from either Lighthouse Strategy Consulting or iCare USA. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: In Medicare Advantage (MA), step therapy for physician-administered drugs is an approach to lowering drug spending. The impact of step therapy in MA on prescribing behavior and the magnitude of any changes has not been analyzed., Objective: To evaluate the impact of step therapy on macular degeneration drug prescribing patterns for 3 large MA insurers., Design, Setting, and Participants: This was a retrospective encounter-based analysis using 20% nationally representative MA outpatient and carrier encounter records for 2017 to 2019. Participants were MA beneficiaries who were 65 years or older and had received a macular degeneration drug administration. Macular degeneration drug administrations for beneficiaries of MA Aetna, Humana, and UnitedHealthcare (UHC) insurers were assessed. Humana implemented macular degeneration step therapy in 2019, setting bevacizumab as the plan-preferred drug, and aflibercept and ranibizumab as the plan-nonpreferred drugs. Aetna and UHC, which did not implement macular degeneration step therapy, served as the control group. Data analyses were performed from May 2024 to December 2024., Exposures: A macular degeneration drug administration subject to a step therapy policy., Main Outcome and Measures: A binary indicator of whether the drug administered was bevacizumab. Linear probability models and a difference-in-differences framework were used to quantify changes in prescribing patterns before and after the introduction of step therapy for MA insurers that did and did not implement step therapy. To empirically measure the impact of step therapy, the first administration of a treatment episode was assessed, followed by switching patterns., Results: A total of 18 331 MA beneficiaries, 21 683 treatment episodes, and 171 985 drug administrations were included across the control and treatment groups. The difference-in-differences regressions found a 7.8% (95% CI, 4.9%-10.7%; P < .001) greater probability of being prescribed bevacizumab for the first administration due to step therapy. The predicted probabilities of preferred-drug administration in the treatment group increased from 0.61 to 0.70 between the periods before and after step therapy implementation for the first administration. Step therapy was not significantly associated with an increased rate of medication switching (hazard ratio, 0.86; 95% CI, 0.71-1.06; P = .15)., Conclusions and Relevance: The findings of this retrospective encounter-based analysis indicate that step therapy is associated with a greater probability of prescribing the plan-preferred drug for the first administration. The analysis failed to find a statistically significant greater rate of medication switching within a treatment episode. Step therapy changed macular degeneration prescribing patterns, but step therapy alone did not transition all administrations to the plan-preferred drug.

Purpose: To determine early endophthalmitis incidence and risk factors after glaucoma surgeries in the Medicare population., Design: Retrospective, longitudinal study., Participants: Medicare Fee-for-Service (FFS) and Medicare Advantage beneficiaries in the United States aged 65 years or older undergoing glaucoma surgery., Methods: Medicare claims were used to identify all patients who underwent glaucoma, cataract, or combined cataract/glaucoma surgery from 2016 to 2019. Endophthalmitis cases within 42 days of the index surgery were identified using the diagnostic codes. Multivariable logistic regression models were used to evaluate factors associated with postoperative endophthalmitis., Main Outcome Measures: The 42-day postoperative endophthalmitis incidence and risk factors associated with endophthalmitis after glaucoma surgery., Results: There were 466 928 glaucoma surgeries, of which 310 823 (66.6%) were combined with cataract surgery. Cataract surgeries alone (n = 8 460 360) served as a reference group. Microinvasive glaucoma surgeries constituted most glaucoma procedures performed (67.8%), followed by trabeculectomy (14.0%), tube shunt (10.9%), and other procedures (7.3%). There were 572 cases of endophthalmitis identified after all glaucoma surgeries. Endophthalmitis incidence after glaucoma, combined cataract/glaucoma, and cataract surgeries alone was 1.5 (95% confidence interval [CI], 1.3-1.7), 1.1 (95% CI, 1.0-1.2), and 0.8 (95% CI, 0.8-0.8) per 1000 procedures, respectively. The median day of diagnosis of endophthalmitis was later for glaucoma surgeries (16.5 days) compared with combined cataract/glaucoma or cataract surgeries alone (8 and 6 days, respectively). Compared with microinvasive glaucoma surgery (MIGS), tube shunts were the only surgery type to be a significant risk factor for endophthalmitis for both stand-alone (adjusted odds ratio [aOR], 1.8, P = 0.002) and combined surgery (aOR 1.8, P = 0.047). The other risk factor for both stand-alone (aOR 1.1, P = 0.001) and combined (aOR 1.06, P = 0.049) surgeries was the Charlson Comorbidity Index (CCI). Age (aOR 1.03, P = 0.004) and male gender (1.46, P = 0.001) were significant risk factors for combined cataract and glaucoma surgeries., Conclusions: Compared with cataract surgery, early endophthalmitis incidence was higher for both glaucoma and combined cataract/glaucoma surgeries, with the highest incidence among tube shunts., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The Consortium of Student-Led Eye Clinics (CSLEC), founded in 2021, administered a comprehensive survey to document the types of services, most common diagnoses, and follow-up care protocols offered by student-led free vision screening programs (SLFVSP) in the United States., Methods: An 81-question institutional review board (IRB)-approved survey was administered to student-led vision screening eye clinics from October 1, 2022 to February 24, 2023., Results: Sixteen SLFVSPs were included in the final analysis, of which 81% (n = 13) conducted variations of fundoscopic examinations and 75% (n = 12) measured intraocular pressure. Cataracts and diabetic retinopathy were reported as the most frequent diagnoses by the majority of SLFVSPs (n = 9, 56%); non-mobile SLFVSPs more commonly reported cataract as a frequent diagnosis (P < 0.05). Most patients screened at participating programs were uninsured or met federal poverty guidelines. Prescription glasses were offered by 56% of the programs (n = 9). SLFVSPs that directly scheduled follow-up appointments reported higher attendance rates (66.5%) than those that only sent referrals (20%). Transportation was the most cited barrier for follow-up appointment attendance., Conclusions: SLFVSPs, one community vision screening initiative subtype, vary significantly in scope and capabilities of identifying vision threatening disease. The follow-up infrastructure is not uniformly robust and represents a key target for improving care delivery to at-risk populations., Translational Relevance: The CSLEC aims to develop a consensus-based standardization for the scope of screening services, offer guidelines for diagnostic criteria, promote real-time data stewardship, and identify means to improve follow-up care mechanisms in member communities.

Leading causes of blindness worldwide include neurodegenerative diseases of the retina, which cause irreversible loss of retinal pigment epithelium (RPE) and photoreceptors, and optic neuropathies, which result in retinal ganglion cell (RGC) death. Because photoreceptor and RGCs do not spontaneously regenerate in mammals, including humans, vision loss from these conditions is, at present, permanent. Recent advances in gene and cell-based therapies have provided new hope to patients affected by these conditions. This chapter reviews the current state and future of these approaches to treating ocular neurodegenerative disease. Gene therapies for retinal degeneration and optic neuropathies primarily focus on correcting known pathogenic mutations that cause inherited conditions to halt progression. There are multiple retinal and optic neuropathy gene therapies in clinical trials, and one retinal gene therapy is approved in the United States, Canada, Europe, and Australia. Cell-based therapies are mutation agnostic and have the potential to repopulate neurons regardless of the underlying etiology of degeneration. While photoreceptor cell replacement is nearing a human clinical trial, RPE transplantation is currently in phase I/II clinical trials. RGC replacement faces numerous logistical challenges, but preclinical research has laid the foundation for functional repair of optic neuropathies to be feasible., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: The strain response of the mouse astrocytic lamina (AL) to an ex vivo mechanical test was compared between two protocols: eyes that underwent sustained intraocular pressure (IOP) increase and eyes after optic nerve crush., Methods: Chronic IOP elevation was induced by microbead injection or the optic nerve was crushed in mice with widespread green fluorescence. After 3 days or 6 weeks, eyes were inflation tested by a published method of two-photon fluorescence to image the AL. Digital volume correlation was used to calculate strains. Optic nerve axon damage was also evaluated., Results: In the central AL but not the peripheral AL, four strains were greater in eyes at the 3-day glaucoma time point than control (P from 0.029 to 0.049, n = 8 eyes per group). Also, at this time point, five strains were greater in the central AL compared to the peripheral AL (P from 0.041 to 0.00003). At the 6-week glaucoma time point, the strains averaged across the specimen, in the central AL, and the peripheral AL were indistinguishable from the respective controls. Strains were not significantly different between controls and eyes 3 days or 6 weeks after crush (n = 8 and 16)., Conclusions: We found alterations in the ex vivo mechanical behavior in eyes from mice with experimental glaucoma but not in those with crushed optic nerves. The results of this study demonstrate that significant axon injury does not directly affect mechanical behavior of the astrocytic lamina.

To evaluate how well outcomes following cataract extraction and microinvasive glaucoma surgery in one eye predict outcomes in sequential second eye. Retrospective study of 78 patients who underwent cataract extraction and microinvasive glaucoma surgery in both eyes. Linear regressions using Pearson correlation coefficients were used to evaluate correlations in intraocular pressure and glaucoma medication change between eyes. Multivariable logistic regression models were used to evaluate the associations between first-eye variables and the likelihood of second-eye surgical success at 6 months. Surgical success was defined as meeting target intraocular pressure without additional medications compared to baseline or secondary surgical interventions. Baseline ocular characteristics were comparable between fellow eyes, with the majority having mild glaucoma. Intraocular pressure changes between fellow eyes at 6 months were modestly correlated between eyes (R = 0.48; P < .001). Changes in glaucoma medications were strongly correlated between eyes at all time points, and month 6 demonstrated the most significant correlation (R = 0.80; P < .001). First and second eye cohorts achieved 82% and 83% surgical success. Multivariate analysis for predictive factors of successful second eye surgery showed patients with successful first eye surgery at 6 months were significantly more likely to have successful second eye surgery (odds ratio, 20.67; P < .001). Reductions in intraocular pressure and glaucoma medications at 6 months following surgery in first eyes are correlated to second eye reductions. Successful surgical outcomes at 6 months following first eye surgeries are strongly associated with successful sequential second eye outcomes., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Intercellular cytoplasmic material transfer (MT) occurs between transplanted and developing photoreceptors and ambiguates cell origin identification in developmental, transdifferentiation, and transplantation experiments. Whether MT is a photoreceptor-specific phenomenon is unclear. Retinal ganglion cell (RGC) replacement, through transdifferentiation or transplantation, holds potential for restoring vision in optic neuropathies. During careful assessment for MT following human stem cell-derived RGC transplantation into mice, we identified RGC xenografts occasionally giving rise to labeling of donor-derived cytoplasmic, nuclear, and mitochondrial proteins within recipient Müller glia. Critically, nuclear organization is distinct between human and murine retinal neurons, which enables unequivocal discrimination of donor from host cells. MT was greatly facilitated by internal limiting membrane disruption, which also augments retinal engraftment following transplantation. Our findings demonstrate that retinal MT is not unique to photoreceptors and challenge the isolated use of species-specific immunofluorescent markers for xenotransplant identification. Assessment for MT is critical when analyzing neuronal replacement interventions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This document discusses preprocedural planning for transcatheter aortic valve replacement, evaluating the imaging modalities used in initial imaging for preprocedure planning under two variants 1) Preintervention planning for transcatheter aortic valve replacement: assessment of aortic root; and 2) Preintervention planning for transcatheter aortic valve replacement: assessment of supravalvular aorta and vascular access. US echocardiography transesophageal, MRI heart function and morphology without and with IV contrast, MRI heart function and morphology without IV contrast and CT heart function and morphology with IV contrast are usually appropriate for assessment of aortic root. CTA chest with IV contrast, CTA abdomen and pelvis with IV contrast, CTA chest abdomen pelvis with IV contrast are usually appropriate for assessment of supravalvular aorta and vascular access. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies., (© 2023. Editorial Group and BioMed Central Ltd., part of Springer Nature.)

A major risk factor for glaucomatous optic neuropathy is the level of intraocular pressure (IOP), which can lead to retinal ganglion cell axon injury and cell death. The optic nerve has a rostral unmyelinated portion at the optic nerve head followed by a caudal myelinated region. The unmyelinated region is differentially susceptible to IOP-induced damage in rodent models and human glaucoma. While several studies have analyzed gene expression changes in the mouse optic nerve following optic nerve injury, few were designed to consider the regional gene expression differences that exist between these distinct areas. We performed bulk RNA-sequencing on the retina and separately micro-dissected unmyelinated and myelinated optic nerve regions from naïve C57BL/6 mice, mice after optic nerve crush, and mice with microbead-induced experimental glaucoma (total = 36). Gene expression patterns in the naïve unmyelinated optic nerve showed significant enrichment of the Wnt, Hippo, PI3K-Akt, and transforming growth factor β pathways, as well as extracellular matrix-receptor and cell membrane signaling pathways, compared to the myelinated optic nerve and retina. Gene expression changes induced by both injuries were more extensive in the myelinated optic nerve than the unmyelinated region, and greater after nerve crush than glaucoma. Changes present three and fourteen days after injury largely subsided by six weeks. Gene markers of reactive astrocytes did not consistently differ between injury states. Overall, the transcriptomic phenotype of the mouse unmyelinated optic nerve was significantly different from immediately adjacent tissues, likely dominated by expression in astrocytes, whose junctional complexes are inherently important in responding to IOP elevation.

Prcis: Compared with phacoemulsification and microstent alone, we observed that phacoemulsification with combined microstent and canaloplasty resulted in a significantly greater reduction in glaucoma medications while maintaining similar rates of intraocular pressure reduction and low complications., Purpose: The purpose of this study was to compare the outcomes of phacoemulsification combined with Hydrus Microstent (Alcon Inc.) implantation alone or in combination with canaloplasty (OMNI Surgical System, Sight Sciences Inc.)., Materials and Methods: Retrospective study of mild-to-moderate primary open angle glaucoma patients who underwent phacoemulsification with microstent alone (42 eyes of 42 patients) or in combination with canaloplasty (canaloplasty-microstent, 32 eyes of 32 patients). The mean number of ocular hypotensive medications and intraocular pressure were assessed preoperatively and postoperatively at 1 week and at 1, 3, and 6 months. Complications and secondary surgical interventions were recorded. Outcomes measures included the percentage of unmedicated eyes and surgical success at 6 months. Surgical success was defined as reaching the target intraocular pressure without medications or secondary surgical interventions., Results: Mean intraocular pressure at 6 months was 14.1±3.5 mm Hg (13% reduction) after microstent alone and 13.6±3.1 mm Hg (17% reduction) after canaloplasty-microstent. Mean medications at 6 months were 0.57±0.9 (67% reduction) after microstent alone and 0.16±0.4 (88% reduction) after canaloplasty-microstent ( P< 0.05). At 6 months, 64.3% of microstent alone and 87.3% of canaloplasty-microstent were off all medications ( P =0.02). Success probabilities at 6 months were 44.5% for microstent alone and 70.0% for canaloplasty-microstent ( P =0.04). No secondary surgical interventions occurred in either group., Conclusions: Microstent combined with canaloplasty resulted in a significantly higher rate of medication-free status compared with microstent alone through 6 months., Competing Interests: Disclosure: J.A. reports consulting fees from Alcon and Sight Sciences. J.Y. and P.R. report consulting fees from Alcon. T.V.J. reports research support from Alcon. M.K. reports consulting fees from Sight Sciences. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The Retinal Ganglion Cell (RGC) Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) consortium was founded in 2021 to help address the numerous scientific and clinical obstacles that impede development of vision-restorative treatments for patients with optic neuropathies. The goals of the RReSTORe consortium are: (1) to define and prioritize the most critical challenges and questions related to RGC regeneration; (2) to brainstorm innovative tools and experimental approaches to meet these challenges; and (3) to foster opportunities for collaborative scientific research among diverse investigators., Design and Participants: The RReSTORe consortium currently includes > 220 members spanning all career stages worldwide and is directed by an organizing committee comprised of 15 leading scientists and physician-scientists of diverse backgrounds., Methods: Herein, we describe the structure and organization of the RReSTORe consortium, its activities to date, and the perceived impact that the consortium has had on the field based on a survey of participants., Results: In addition to helping propel the field of regenerative medicine as applied to optic neuropathies, the RReSTORe consortium serves as a framework for developing large collaborative groups aimed at tackling audacious goals that may be expanded beyond ophthalmology and vision science., Conclusions: The development of innovative interventions capable of restoring vision for patients suffering from optic neuropathy would be transformative for the ophthalmology field, and may set the stage for functional restoration in other central nervous system disorders. By coordinating large-scale, international collaborations among scientists with diverse and complementary expertise, we are confident that the RReSTORe consortium will help to accelerate the field toward clinical translation., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.)

Objective: To compare outcomes following Ahmed-FP7 (AGI-FP7), Baerveldt-250mm 2 (BGI-250), or Baerveldt-350mm 2 (BGI-350) implantation., Methods and Analysis: Retrospective cohort study comprising 800 eyes from 800 individuals who underwent surgery 1 January 2016-31 December 2020 at a tertiary-care institution. Data were extracted from standardised fields in the electronic health record. Primary outcome was failure (defined as intraocular pressure (IOP) ≤5 mm Hg or >18 mm Hg or reduction <20% at two consecutive visits from month 3 onwards; or visual acuity (VA) loss ≥3 lines; or return to the operating room (OR)). Secondary outcomes were IOP, VA, number of follow-up visits and return to the OR., Results: A total of 523 AGI-FP7, 133 BGI-250 and 144 BGI-350 cases were analysed. The AGI-FP7 group was more likely to be younger and diagnosed with secondary glaucoma, with a higher mean baseline IOP (28.5±12.2 vs 22.0±7.7 mm Hg in BGI-250 and 23.4±9.0 in BGI-350, p<0.001). Cumulative failure rate at month 12 was 30% (AGI-FP7) vs 39% (BGI-250) vs 33% (BGI-350, p=0.159). Mean IOP at month 12 was lower in the BGI-350 group compared with AGI-FP7 (12.4±4.4 vs 14.8±5.6 mm Hg, p=0.003) but not BGI-250 (vs 13.1±4.6, p=0.710). Target IOP was achieved in 71% of AGI-FP7, 66% BGI-250, and 76% BGI-350. VA loss and rates of return to the OR did not differ between groups. Both BGI-250 and BGI-350 had more follow-up visits than AGI-FP7 (p<0.001)., Conclusion: These three glaucoma drainage devices performed similarly within 1 year, with no difference in failure rates despite differing baseline patient characteristics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neuronal repopulation achieved through transplantation or transdifferentiation from endogenous sources holds tremendous potential for restoring function in chronic neurodegenerative disease or acute injury. Key to the evaluation of neuronal engraftment is the definitive discrimination of new or donor neurons from preexisting cells within the host tissue. Recent work has identified mechanisms by which genetically encoded donor cell reporters can be transferred to host neurons through intercellular material transfer. In addition, labeling transplanted and endogenously transdifferentiated neurons through viral vector transduction can yield misexpression in host cells in some circumstances. These issues can confound the tracking and evaluation of repopulated neurons in regenerative experimental paradigms. Using the retina as an example, we discuss common reasons for artifactual labeling of endogenous host neurons with donor cell reporters and suggest strategies to prevent erroneous conclusions based on misidentification of cell origin., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Tight glycemic control (TGC), the cornerstone of diabetic management, reduces the incidence and progression of diabetic microvascular disease. However, TGC can also lead to transient episodes of hypoglycemia, which have been associated with adverse outcomes in patients with diabetes. Here, we demonstrate that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, in retinal cells. Enhanced nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization but instead dependent on stimulation of its translation and nuclear localization. In the presence of hypoxia, this physiologic response to low glucose resulted in a marked increase in the secretion of the HIF-dependent vasoactive mediators that promote diabetic retinopathy. Our results provide a molecular explanation for how early glucose control, as well as glycemic variability (i.e., oscillating serum glucose levels), contributes to diabetic eye disease. These observations have important implications for optimizing glucose management in patients with diabetes., Competing Interests: Declaration of interests A.S. is co-founder of and holds equity in HIF Therapeutics, Inc. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

To identify changes in response to experimental intraocular pressure (IOP) elevation associated with the laminin α1 nmf223 mutation in mice. Laminin mutant (LM) mice (Lama1 nmf223 ) and C57BL/6J (B6) mice in two age groups each (4-5 months and >1 year) underwent intracameral microbead injections to produce unilaterally elevated IOP. We assessed axonal transport block of immunofluorescently labeled amyloid precursor protein (APP) after 3 days and retinal ganglion cell (RGC) axon loss after 6 weeks. Light, electron and fluorescent microscopy was used to study baseline anatomic differences and effects of 3-day IOP elevation in younger LM mice. In younger mice of both LM and B6 strains, elevated IOP led to increased APP block in the retina, prelaminar optic nerve head (preONH), unmyelinated optic nerve (UON), and myelinated optic nerve (MON). APP blockade not significantly different between younger B6 and LM mouse strains. Older LM mice had greater APP accumulation in both control and glaucoma eyes compared to older B6, however, accumulation was not significantly greater in LM glaucoma eyes compared to LM controls. Axon loss at 6 weeks was 12.2% in younger LM and 18.7% in younger B6 mice (difference between strains, p = 0.22, Mann Whitney test). Untreated LM optic nerve area was lower compared to B6 (nerve area, p < 0.0001, t-test). Aberrant axon bundles, as well as defects, thickening and reduplication of pia mater, were seen in the optic nerves of younger LM mice. Axonal transport blockade significantly differed between old B6 and old LM mice in control and glaucoma eyes, and younger LM mice had abnormal axon paths and lower optic nerve area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The advent of the first-ever retinal gene therapy product, involving subretinal administration of a virus-based gene delivery platform, has garnered hope that this state-of-the-art therapeutic modality may benefit a broad spectrum of patients with diverse retinal disorders. On the other hand, clinical studies have revealed limitations of the applied delivery strategy that may restrict its universal use. To this end, intravitreal administration of synthetic gene-delivery platforms, such as polymer-based nanoparticles (PNPs), has emerged as an attractive alternative to the current mainstay. To achieve success, however, it is imperative that synthetic platforms overcome key biological barriers in human eyes encountered following intravitreal administration, including the vitreous gel and inner limiting membrane (ILM). Here, we introduce a series of experiments, from the fabrication of PNPs to a comprehensive evaluation in relevant experimental models, to determine whether PNPs overcome these barriers and efficiently deliver therapeutic gene payloads to retinal cells. We conclude the article by discussing a few important considerations for successful implementation of the strategy. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation and characterization of PNPs Basic Protocol 2: Evaluation of in vitro transfection efficacy Basic Protocol 3: Evaluation of PNP diffusion in vitreous gel Basic Protocol 4: Ex vivo assessment of PNP penetration within vitreoretinal explant culture Basic Protocol 5: Assessment of in vivo transgene expression mediated by intravitreally administered PNPs., (© 2022 Wiley Periodicals LLC.)

Purpose: To measure quantitatively changes in lamina cribrosa (LC) cell and connective tissue structure in human glaucoma eyes., Methods: We studied 27 glaucoma and 19 age-matched non-glaucoma postmortem eyes. In 25 eyes, LC cross-sections were examined by confocal and multiphoton microscopy to quantify structures identified by anti-glial fibrillary acidic protein (GFAP), phalloidin-labeled F-actin, nuclear 4',6-diamidino-2-phenylindole (DAPI), and by second harmonic generation imaging of LC beams. Additional light and transmission electron microscopy were performed in 21 eyes to confirm features of LC remodeling, including immunolabeling by anti-SOX9 and anti-collagen IV. All glaucoma eyes had detailed clinical histories of open-angle glaucoma status, and degree of axon loss was quantified in retrolaminar optic nerve cross-sections., Results: Within LC pores, the proportionate area of both GFAP and F-actin processes was significantly lower in glaucoma eyes than in controls (P = 0.01). Nuclei were rounder (lower median aspect ratio) in glaucoma specimens (P = 0.02). In models assessing degree of glaucoma damage, F-actin process width was significantly wider in glaucoma eyes with more damage (P = 0.024), average LC beam width decreased with worse glaucoma damage (P = 0.042), and nuclear count per square millimeter rose with worse damage (P = 0.019). The greater cell count in LC pores represented 92.3% astrocytes by SOX9 labeling. The results are consistent with replacement of axons in LC pores by basement membrane labeled by anti-collagen IV and in-migrating astrocytes., Conclusions: Alteration in LC structure in glaucoma involves migration of astrocytes into axonal bundles, change in astrocyte orientation and processes, production of basement membrane material, and thinning of connective tissue beams.

Importance: Reported transfers of value (TOV) from pharmaceutical companies have been associated with greater use of branded anti-vascular endothelial growth factor agents by ophthalmologists, but payment under the Medicare Part B buy-and-bill model includes a financial incentive to choose costlier agents, potentially confounding analyses of pharmaceutical TOV and prescribing patterns. How these reported TOV are associated with prescribing patterns for prescription eye drops, not subject to the incentives created by Part B payments, should be considered., Objective: To assess the association between prostaglandin analog (PGA) eye drop prescribing and reported nonresearch TOV by makers of branded PGAs to US vision care professionals., Design, Setting, and Participants: This retrospective cohort analysis used a 20% nationally representative sample of 2018 Medicare Part D claims and industry TOV reported to the Open Payments program. Optometrists and ophthalmologists who had more than 10 claims for PGA drops in the 20% sample were analyzed. Analysis took place from June 2021 to February 2022., Main Outcomes and Measures: Multivariable logistic regression assessing the association between membership in strata of reported TOV and branded PGA prescribing rate, controlling for prescriber demographic factors, local area practices, total PGA prescribing volume, and plan formularies involved., Results: A total of 20 612 ophthalmologists and 5426 optometrists (7449 [29%] female and 18 589 [71%] male) prescribed PGA eye drops. Of these, 9685 (37%) were reported to have received TOV from manufacturers of branded PGAs in 2018, totaling $5 060 346. The median (IQR) reported TOV was $65 ($24-$147). Multivariable logistic regression showed that the predicted probability of primarily prescribing branded PGAs among prescribers who reported receiving no TOV was 12.9% (95% CI, 12.4%-13.4%). This figure increased to 19.6% (95% CI, 18.8%-20.4%) among prescribers receiving TOV, a 50% increase. There was a dose-response association, such that the top 10% of TOV recipients had a 29.2% probability (95% CI, 26.4%-31.9%) of preferential branded use., Conclusions and Relevance: While the median reported TOV to a PGA prescriber was relatively low in this study, there was a positive association between amount of reported nonresearch TOV received from PGA makers and the frequency of branded PGA use. This shows that small reported TOV were associated with differences in prescribing. High rates of branded PGA prescribing may pose a cost burden to patients that affects adherence. Clinicians and policy makers should be aware of these associations.

Prcis: Of 611 individuals seen at referral clinic visits following community screenings, 76% were diagnosed with ≤1 eye condition needing treatment, generating a total of $213,110 in collections for the institution over 2.5 years., Purpose: The purpose of this study was to examine the outcomes and revenue generation of community-based eye screenings., Materials and Methods: Individuals aged 50 years and above screened at community sites in Baltimore, MD, with abnormal ophthalmic findings were referred for one free-of-charge definitive eye examination at the Wilmer Eye Institute. Diagnoses, treatment, and billing information were abstracted from electronic medical records of patients subsequently seen at Wilmer from January 1, 2016, to July 31, 2018., Results: A total of 611 individuals attended 3696 encounters at Wilmer during this time period. Most patients were female (60.3%) and African American (83.7%). At the screening event, 82.9% reported difficulty seeing when not wearing corrective eyewear, although only 49.8% reported having visited an eye doctor within the last 2 years. The majority (60.2%) reported having Medicare/Medicaid coverage, and 8.1% reported being uninsured. At the definitive eye examination after the screening, 75.5% of patients were diagnosed with ≥1 eye condition, most commonly cataract (30.3%), suspicion of glaucoma (24.9%), manifest glaucoma (11.9%), diabetic retinopathy (5.4%), and ocular hypertension (2.6%). Overall, 430 (70.4%) individuals required treatment including surgery (n=106), intravitreal injections (n=14), laser procedures (n=9), and medications (n=48). A total of $213,110 was collected for visits and procedures after the initial referral visit during the study period., Conclusions: A large community-based vision screening program in Baltimore was able to identify ocular conditions requiring treatment in underserved older adults and connect them to eyecare. Our findings also highlight that this model simultaneously generates new revenue streams for the institution organizing the community screenings., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To compare electronically measured adherence with topical corticosteroid (CS) drops with outcomes of glaucoma surgery., Design: This prospective cohort study included eyes undergoing surgery from August 2019 to January 2021 and followed for up to 1 year., Participants: All patients were recruited from the Glaucoma Center of Excellence at the Wilmer Eye Institute, Johns Hopkins. Eligible patients had primary open-angle or angle-closure glaucoma, were aged ≥18 years, and underwent trabeculectomy (with or without cataract surgery) or tube-shunt implantation., Methods: Patients were instructed on the use of an eye drop monitoring device (Kali Drop), with the knowledge that it would be used to record postoperative CS instillation in real time., Main Outcome Measures: Adherence to a regimen of CS eye drops during the first 5 postoperative weeks; achievement of target intraocular pressure (IOP) at 6 weeks and 6 months to 1 year after surgery; and bleb morphology at 1 year., Results: Among 90 patients, adherence was 89.7% ± 13.7% overall and 80.9% ± 15.8% during dosing every 2 hours. Target IOP was achieved at the final visit (6 months or 1 year) in 81% (59/73) without reoperation. Eyes with a higher ratio of drops taken versus prescribed were significantly more likely to achieve target IOP at 6 months/1 year (P = 0.05). Total adherence was better in younger persons, eyes with less field loss, and patients of one particular surgeon (P < 0.03). Percent adherence during dosing every 2 hours was higher in eyes with higher target IOP (P = 0.01). No adherence outcome was significantly related to race, sex, bleb morphology, postoperative pain, or postoperative anterior chamber inflammation. Adherence values did not significantly correlate with adherence questionnaire data (predicted mean = 78% ± 17%, actual mean = 91% ± 13% adherent, P < 0.001)., Conclusions: Adherence to frequent postoperative eye drops was high and can be successfully monitored remotely. Surgical success was greater among eyes with nearly ideal adherence and was poorer in older persons and those with more advanced glaucoma., (Published by Elsevier Inc.)

This paper reports an important breakthrough in partially restoring sight to a man who had lost his vision due to retinitis pigmentosa (RP), a heritable retinal degenerative disease that affects approximately 1 in 4000 people. Long considered an insurmountable challenge, a stellar team of vision scientists, engineers, basic biologists, and others, working together for many years, has enabled a man who had been legally blind for decades to begin distinguishing objects and navigating his environment 1 ., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2022 Faculty Opinions Ltd.)

Aquaporin 4 is absent from astrocytes in the rodent optic nerve head, despite high expression in the retina and myelinated optic nerve. The purpose of this study was to quantify regional aquaporin channel expression in astrocytes of the porcine and human mouse optic nerve (ON). Ocular tissue sections were immunolabeled for aquaporins 1(AQP1), 4(AQP4), and 9(AQP9), myelin basic protein (MBP), glial fibrillary acidic protein (GFAP) and alpha-dystroglycan (αDG) for their presence in retina, lamina, myelin transition zone (MTZ, region just posterior to lamina) and myelinated ON (MON). Semi- quantification of AQP4 labeling & real-time quantitative PCR (qPCR) data were analyzed in retina and ON tissue. Porcine and control human eyes had abundant AQP4 in Müller cells, retinal astrocytes, and myelinated ON (MON), but minimal expression in the lamina cribrosa. AQP1 and AQP9 were present in retina, but not in the lamina. Immunolabeling of GFAP and αDG was similar in lamina, myelin transition zone (MTZ) and MON regions. Semi-quantitative AQP4 labeling was at background level in lamina, increasing in the MTZ, and highest in the MON (lamina vs MTZ, MON; p≤0.05, p≤0.01, respectively). Expression of AQP4 mRNA was minimal in lamina and substantial in MTZ and MON, while GFAP mRNA expression was uniform among the lamina, MTZ, and MON regions. Western blot assay showed AQP4 protein expression in the MON samples, but none was detected in the lamina tissue. The minimal presence of AQP4 in the lamina is a specific regional phenotype of astrocytes in the mammalian optic nerve head., Competing Interests: The authors have declared that no competing interests exist.

Retinal ganglion cell (RGC) transplantation has the potential to restore vision in optic neuropathy, but donor neuron survival and retinal integration remain challenging. Here, we present a protocol for ex vivo human RGC transplantation on flatmounted murine organotypic retinal explants, providing a robust platform for studying donor RGC survival, dendritic stratification, topographic distribution, donor-host interactions, and pro-engraftment strategies. The protocol includes microscopy-based analyses to evaluate donor cell engraftment and can be adapted to various donor cell types or culture systems. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021a, 2021b)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Background: Medical school curricular hours dedicated to ophthalmology are low and declining. Extracurricular ophthalmology activities, such as participation in community vision screenings, may serve an important adjunctive role in medical school curricula. The Johns Hopkins University (JHU) Vision Screening In Our Neighborhoods (ViSION) Program is an example of a voluntary medical student-directed community service-learning program., Methods: We used a mixed-methods cross-sectional approach, including an online survey and semi-structured interviews. JHU School of Medicine students enrolled in MD or MD/PhD programs during the 2019-2020 academic year were surveyed regarding demographics, career and service interests, involvement in ophthalmology-related activities, and confidence in their ophthalmology-related skills. Survey responses were compared between ViSION volunteers and non-volunteers using Fisher's exact chi-square tests. Semi-structured interviews were conducted via webconference with 8 prior or current ViSION volunteers and responses analyzed using inductive thematic analysis. Data were collected when ViSION volunteers were in variable stages of their medical education and involvement with the ViSION program., Results: A total of 118 medical students were included, representing an overall response rate of 24.6% of JHU medical students. ViSION volunteers reported greater involvement in ophthalmology-related research (42% vs. 4%, p < 0.001), intent to apply to ophthalmology residency programs (35% vs. 1%, p = 0.001), and confidence with multiple ophthalmology knowledge and clinical skill domains. In particular, ViSION volunteers were more likely to feel confident estimating cup-to-disc ratio using direct ophthalmoscopy (20% vs. 0%, p < 0.001). In open-ended survey and interview questions, most volunteers attributed at least some degree of their ophthalmology skill development and desire to pursue ophthalmology and public health careers to their ViSION experience., Conclusions: Medical students who volunteered with a student-led community vision screening program were more likely to have a prior interest in ophthalmology than those who did not volunteer, but only 1/3 of volunteers planned to pursue a career in ophthalmology. Overall, volunteers reported higher confidence performing ophthalmology-related clinical skills, suggesting that student-led community vision screening programs may provide an important avenue for medical students to explore public health aspects of ophthalmology, while practicing ophthalmology exam skills and learning about common ophthalmic pathologies, regardless of their career intentions., (© 2022. The Author(s).)

Purpose: To describe trends in the glaucoma fellowship match results, glaucoma applicant characteristics, and applicant characteristics associated with matching., Design: Retrospective study., Participants: Ophthalmology fellowship applicants participating in the San Francisco (SF) Match between 2010 and 2017., Methods: De-identified, individual applicant data provided by the San Francisco (SF) Match were used to describe glaucoma fellowship match trends and applicant characteristics between 2010 and 2017. Publicly available, conglomerate SF Match data were used to determine trends in the number of programs participating in the glaucoma fellowship match, as well as the number of positions offered and filled from 2014 to 2019. All trends analyses were performed using linear regression models on log-transformed response variables. Summary statistics for applicants who matched in glaucoma were compared with those who did not match. A multivariable logistic regression model was used to evaluate factors associated with matching in glaucoma fellowship., Main Outcome Measures: Fellowship match status (matched in glaucoma vs. did not match in any ophthalmology subspecialty)., Results: From 2010 to 2019, the number of matched glaucoma fellowship applicants increased from 54 to 77 (mean 3.3% per year, P = 0.001), and the proportion of applicants to any ophthalmology fellowship who matched in glaucoma increased from 13% to 15.5% (mean, 3% per year; P = 0.041). Compared with applicants who did not match in any specialty between 2010 and 2017, matched glaucoma applicants were more likely to have graduated from a top 10 residency program (10.7% vs. 4.5%, P < 0.001), U.S. medical school (93.1% vs. 39.1%, P < 0.001), or U.S. residency program (95.0% vs. 42.2%, P < 0.001), and complete more interviews (9 vs. 1, P < 0.001). After controlling for potential covariates, factors associated with increased odds of matching in glaucoma included graduating from a U.S. residency program (odds ratio [OR], 9.91; 95% confidence interval [CI], 5.45-18.03), applying to fewer programs (OR, 0.91; 95% CI, 0.88-0.93), and completing a greater number of interviews (OR, 1.49; CI, 1.39-1.60). United States Medical Licensing Examination (USMLE) Step scores were not associated with matching in glaucoma., Conclusions: The number of applicants who matched in glaucoma fellowship increased from 2010 to 2019. Factors associated with matching in glaucoma were graduating from a U.S. residency program and completing more interviews., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: This study examined characteristics of intraocular pressure (IOP) as measured during home tonometry in comparison with in-clinic tonometry in patients with glaucoma., Design: Retrospective cross-sectional study of glaucoma patients who completed 1 week of self-tonometry at a single academic center., Participants: Patients with glaucoma who completed home tonometry trials with the iCare HOME tonometer (iCare USA) for any reason., Methods: Home IOP measurements were compared with in-clinic tonometry performed during the 5 visits preceding home tonometry. Maximum daily IOP was correlated to time of day. Generalized estimating equations were used to evaluate patient characteristics and clinic-derived variables that predicted differences between home and clinic IOP., Main Outcome Measures: IOP mean, maximum, minimum, range, standard deviation and coefficient of variation were compared between clinic and home tonometry. IOP mean daily maximum (MDM) and mean daily range were calculated to describe recurrent IOP spiking., Results: A total of 107 eyes from 61 patients were analyzed. Mean age was 63.2 years (standard deviation [SD], 14.0 years) and 59.0% were women. Mean clinic and home IOPs were 14.5 mmHg (SD, 4.7 mmHg) and 13.6 mmHg (SD, 5.1 mmHg). Home tonometry identified significantly higher maximum IOP, lower minimum IOP, and greater IOP range than clinic tonometry (P < 0.001). Maximum daily IOP occurred outside of clinic hours (8 am-5 pm) on 50% of days assessed and occurred between 4:30 am and 8 am on 24% of days. Mean daily maximum IOP exceeded maximum clinic IOP in 44% of patients and exceeded target IOP by 3 mmHg, 5 mmHg, or 10 mmHg in 31%, 15%, and 6% of patients, respectively. Patient characteristics that predicted significant deviations between MDM and mean clinic IOP or target IOP in multivariate models included younger age, male gender, and absence of prior filtering surgery., Conclusions: Self-tonometry provides IOP data that supplements in-clinic tonometry and would not be detectable over daytime in-clinic diurnal curves. A subset of patients in whom home tonometry was ordered by their glaucoma clinician because of suspicion of occult IOP elevation demonstrated reproducible IOP elevation outside of the clinic setting. Such patients tended to be younger and male and not to have undergone previous filtering surgery., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce endogenous RGC neuroprotection and axon regeneration, obstacles to achieving functional visual recovery through exogenous RGC transplantation remain. Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration.

Basement membranes help to establish, maintain, and separate their associated tissues. They also provide growth and signaling substrates for nearby resident cells. The internal limiting membrane (ILM) is the basement membrane at the ocular vitreoretinal interface. While the ILM is essential for normal retinal development, it is dispensable in adulthood. Moreover, the ILM may constitute a significant barrier to emerging ocular therapeutics, such as viral gene therapy or stem cell transplantation. Here we take a neurodevelopmental perspective in examining how retinal neurons, glia, and vasculature interact with individual extracellular matrix constituents at the ILM. In addition, we review evidence that the ILM may impede novel ocular therapies and discuss approaches for achieving retinal parenchymal targeting of gene vectors and cell transplants delivered into the vitreous cavity by manipulating interactions with the ILM., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Glaucoma is the leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP. A complementary strategy to IOP reduction is the use of neuroprotective agents that interrupt the process of cell death by mechanisms independent of IOP. Here, we describe an ion complexation approach for formulating microcrystals containing ~50% loading of a protein kinase inhibitor, sunitinib, to enhance survival of RGCs with subconjunctival injection. A single subconjunctival injection of sunitinib-pamoate complex (SPC) microcrystals provided 20 weeks of sustained retina drug levels, leading to neuroprotection in a rat model of optic nerve injury. Furthermore, subconjunctival injection of SPC microcrystals also led to therapeutic effects in a rat model of corneal neovascularization. Importantly, therapeutically relevant retina drug concentrations were achieved with subconjunctival injection of SPC microcrystals in pigs. For a chronic disease such as glaucoma, a formulation that provides sustained therapeutic effects to complement IOP lowering therapies could provide improved disease management and promote patient quality of life.

Coronary atherosclerotic disease is a leading cause of mortality and morbidity due to major cardiovascular events in the United States and abroad. Risk stratification and early preventive measures can reduce major cardiovascular events given the long latent asymptomatic period. Imaging tests can detect subclinical coronary atherosclerosis and aid initiation of targeted preventative efforts based on patient risk. A summary of available imaging tests for low-, intermediate-, and high-risk asymptomatic patients is outlined in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2021. Published by Elsevier Inc.)

Syncope and presyncope lead to well over one million emergency room visits in the United States each year. Elucidating the cause of syncope or presyncope, which are grouped together given similar etiologies and outcomes, can be exceedingly difficult given the diverse etiologies. This becomes more challenging as some causes, such as vasovagal syncope, are relatively innocuous while others, such as cardiac-related syncope, carry a significant increased risk of death. While the mainstay of syncope and presyncope assessment is a detailed history and physical examination, imaging can play a role in certain situations. In patients where a cardiovascular etiology is suspected based on the appropriate history, physical examination, and ECG findings, resting transthoracic echocardiography is usually considered appropriate for the initial imaging. While no imaging studies are considered usually appropriate when there is a low probability of cardiac or neurologic pathology, chest radiography may be appropriate in certain clinical situations. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2021 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Purpose : As ophthalmic elective surgeries resume amidst the COVID-19 pandemic, protocols for testing patients for SARS-CoV-2 is important due to the transmissibility of the virus. Here, we describe the protocol our institution has implemented for screening asymptomatic patients before proceeding to elective ophthalmic surgery. Methods: A retrospective chart review analyzed the number of elective surgeries, results of SARS-CoV-2 testing, and the effect of a positive result on surgery scheduling. Results : We display the screening protocol our institution used to test for SARS-CoV-2. Through its implementation, we found 2 asymptomatic patients who were positive for SARS-CoV-2 resulting in cancellation of their surgeries.  Conclusion : Because of the possibility of positive COVID-19 status in asymptomatic patients and the risk this poses to patients and staff, we recommend testing all asymptomatic patients for SARS-CoV-2 prior to elective surgeries.

Retinal ganglion cell (RGC) replacement holds potential for restoring vision lost to optic neuropathy. Transplanted RGCs must undergo neuroretinal integration to receive afferent visual signals for processing and efferent transmission. To date, retinal integration following RGC transplantation has been limited. We sought to overcome key barriers to transplanted human stem cell-derived RGC integration. Following co-culture ex vivo on organotypic mouse retinal explants, human RGCs cluster and extend bundled neurites that remain superficial to the neuroretina, hindering afferent synaptogenesis. To enhance integration, we increased the cellular permeability of the internal limiting membrane (ILM). Extracellular matrix digestion using proteolytic enzymes achieved ILM disruption while minimizing retinal toxicity and preserving glial reactivity. ILM disruption is associated with dispersion rather than clustering of co-cultured RGC bodies and neurites, and increased parenchymal neurite ingrowth. The ILM represents a significant obstacle to transplanted RGC connectivity and its circumvention may be necessary for functional RGC replacement., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the effectiveness of topical ocular hypotensive medications in patients with open-angle glaucoma and to identify factors associated with postwashout intraocular pressure (IOP) elevation., Design: Secondary analysis of prerandomization data from 2 prospective, multicenter, randomized clinical trials., Methods: Fourteen hundred subjects (1,400 eyes, 781 from the HORIZON study of the Hydrus micro-stent and 619 from the COMPASS study of the Cypass micro-stent) with primary open-angle glaucoma who were using 0-4 classes of topical IOP-lowering medication underwent Goldmann applanation tonometry before and after a protocol-defined washout period., Results: The mean (standard deviation) age was 70.7 (8.0) years and 55.6% were female. The change in IOP following washout for patients using 0 (n = 100), 1 (n = 705), 2 (n = 355), 3 (n = 214), or 4 (n = 26) medications was 0.2 (2.8), 5.7 (3.3), 6.9 (3.7), 8.8 (5.0), and 9.5 (4.1) mm Hg, respectively (P < .001, Kruskal-Wallis test). Postwashout IOP change was similar between the HORIZON and COMPASS cohorts. No difference in postwashout IOP change was detected among individual prostaglandin analogues in patients on monotherapy. A generalized linear model identified the following factors to be associated with greater IOP rise upon medication washout: greater number of glaucoma medications, higher unmedicated IOP, thinner central corneal thickness (CCT), lack of prior selective laser trabeculoplasty (SLT), and male sex., Conclusions: Cessation of glaucoma medications results in a dose-dependent IOP increase in treated open-angle glaucoma patients. Two independent clinical trial cohorts exhibit similar levels of IOP elevation upon washout, using standardized methodology to estimate real-world medication effectiveness. Thicker CCT and history of SLT may predict reduced response to IOP lowering medications., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Axonal transport blockade is an initial step in retinal ganglion cell (RGC) degeneration in glaucoma and targeting maintenance of normal axonal transport could confer neuroprotection. We present an objective, quantitative method for assessing axonal transport blockade in mouse glaucoma models. Intraocular pressure (IOP) was elevated unilaterally in CD1 mice for 3 days using intracameral microbead injection. Longitudinal sections of optic nerve head (ONH) were immunofluorescently labeled for myelin basic protein (MBP) and amyloid precursor protein (APP), which is transported predominantly orthograde by neurons. The beginning of the myelin transition zone, visualized with the MBP label, was more posterior with elevated IOP, 288.8 ± 40.9 μm, compared to normotensive control eyes, 228.7 ± 32.7 μm (p = 0.030, N = 6 pairs). Glaucomatous regional APP accumulations in retina, prelaminar ONH, unmyelinated ONH, and myelinated optic nerve were identified by objective qualification of pixels with fluorescent intensity greater than the 97.5th percentile value of control eyes (suprathreshold pixels). This method segregated images with APP blockade from those with normal transport of APP. The fraction of suprathreshold pixels was significantly higher following IOP elevation than in normotensive controls in the unmyelinated ONH and myelinated nerve regions (paired analyses, p = 0.02 and 0.003, respectively, N = 12), but not in retina or prelaminar ONH (p = 0.91 and 0.08, respectively). The mean intensity of suprathreshold pixels was also significantly greater in glaucoma than in normotensive controls in prelaminar ONH, unmyelinated ONH and myelinated optic nerve (p = 0.01, 0.01, 0.002, respectively). Using this method, subconjunctival glyceraldehyde, which is known to worsen long-term RGC loss with IOP elevation, also produced greater APP blockade, but not statistically significant compared to glaucoma alone. Systemic losartan, which aids RGC axonal survival in glaucoma, reduced APP blockade, but not statistically significant compared to glaucoma alone. The method provides a short-term assessment of axonal injury for use in initial tests of neuroprotective therapies that may beneficially affect RGC transport in animal models of glaucoma., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chest pain is a frequent cause for emergency department visits and inpatient evaluation, with particular concern for acute coronary syndrome as an etiology, since cardiovascular disease is the leading cause of death in the United States. Although history-based, electrocardiographic, and laboratory evaluations have shown promise in identifying coronary artery disease, early accurate diagnosis is paramount and there is an important role for imaging examinations to determine the presence and extent of anatomic coronary abnormality and ischemic physiology, to guide management with regard to optimal medical therapy or revascularization, and ultimately to thereby improve patient outcomes. A summary of the various methods for initial imaging evaluation of suspected acute coronary syndrome is outlined in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2020 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The use of computers has become increasingly relevant to medical decision-making, and artificial intelligence methods have recently demonstrated significant advances in medicine. We therefore provide an overview of current artificial intelligence methods and their applications, to help the practicing ophthalmologist understand their potential impact on glaucoma care., Recent Findings: Techniques used in artificial intelligence can successfully analyze and categorize data from visual fields, optic nerve structure [e.g., optical coherence tomography (OCT) and fundus photography], ocular biomechanical properties, and a combination thereof to identify disease severity, determine disease progression, and/or recommend referral for specialized care. Algorithms have become increasingly complex in recent years, utilizing both supervised and unsupervised methods of artificial intelligence. Impressive performance of these algorithms on previously unseen data has been reported, often outperforming standard global indices and expert observers. However, there remains no clearly defined gold standard for determining the presence and severity of glaucoma, which undermines the training of these algorithms. To improve upon existing methodologies, future work must employ more robust definitions of disease, optimize data inputs for artificial intelligence analysis, and improve methods of extracting knowledge from learned results., Summary: Artificial intelligence has the potential to revolutionize the screening, diagnosis, and classification of glaucoma, both through the automated processing of large data sets, and by earlier detection of new disease patterns. In addition, artificial intelligence holds promise for fundamentally changing research aimed at understanding the development, progression, and treatment of glaucoma, by identifying novel risk factors and by evaluating the importance of existing ones.

Purpose: To evaluate the diagnostic performance characteristics of the Van Herick assessment (VHA) for identifying angle closure compared to gold-standard gonioscopy, as conducted by trained observers of varying expertise., Design: Reliability analysis., Methods: Patients (n = 131) from a glaucoma referral clinic aged ≥50 years without prior ocular surgery or iridotomy underwent unilateral VHA by 1 of 11 trained ophthalmic technicians, followed by VHA and indirect gonioscopy by 1 of 15 ophthalmology residents and 1 of 4 glaucoma specialist attending physicians. Observers were masked to others' gradings. Cohen's kappa (κ) assessed test reproducibility. VHA sensitivity and specificity for identifying gonioscopic angle closure were calculated., Results: Mean patient age was 62.0 ± 8.7 years, 56% of patients were male, and 84% were African American. Angles were gonioscopically closed in 14.5% of eyes. Moderate agreement was observed comparing technician or resident VHA to attending VHA (κ = 0.48 and κ = 0.56, respectively). Resident and attending gonioscopy demonstrated excellent agreement (κ = 0.94). Sensitivities of technician, resident, and attending VHA for detecting angle closure were 57.9% (95% confidence interval: 34.0%-78.9%), 78.9% (53.9%-93.0%), and 68.4% (43.5%-86.4%), respectively. Specificities were 88.5% (80.3%-93.6%), 88.2% (80.3%-93.3%), and 87.5% (79.6%-92.8%), respectively., Conclusions: VHA, even when performed by experienced ophthalmologists, misses a substantial proportion of angle closure while incorrectly identifying roughly 1 in 8 open-angle eyes as closed. These results suggest that clinical assessment of anterior chamber angle configuration is best accomplished with gonioscopy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Retinal hemorrhages are observed frequently in patients with leukemia. However, little is known about the impact and natural history of these hemorrhages. The purpose of this study was to describe leukemic retinal hemorrhages using multimodal imaging and to monitor their evolution longitudinally., Design: Retrospective case series., Participants: A total of 11 eyes of 7 symptomatic leukemic patients with posterior segment hemorrhages., Methods: Single-center study performed at the Johns Hopkins Hospital. Symptomatic leukemic patients with posterior segment hemorrhages underwent serial dilated fundus examinations. The hemorrhages were documented longitudinally with color fundus photographs and spectral-domain (SD) OCT., Main Outcomes Measures: Microanatomic locations of leukemic retinal hemorrhages and their impact on vision and evolution over time., Results: A total of 7 patients (71.4% men; 57.1% white, 28.6% black, and 14.3% Hispanic) were included, with 11 eyes showing posterior segment hemorrhages. The median age at presentation was 49.8 years. All patients had intraretinal hemorrhages; these involved the vitreous and sub-internal limiting membrane (ILM) space in 1 and 3 patients, respectively. The median total follow-up duration was 4.0 months. At the final follow-up visits, 4 of 6 patients showed complete resolution of hemorrhages on examination and color fundus photographs. The final SD-OCT images of all patients did not show any retinal thinning, disruption of the ellipsoid zone, disorganization of the retinal layers, intraretinal fluid, or subretinal fluid., Conclusions: Symptomatic leukemic retinal hemorrhages are associated with anemia and thrombocytopenia. These hemorrhages, including visually significant central sub-ILM hemorrhages, tend to be self-limiting and resolve within a few months with treatment of the underlying disease., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)