January 2023

The coronavirus disease 2019 (COVID-19) is now known to be associated with several ocular manifestations. The literature thoroughly discussed those that affect adults, with a lesser focus in the pediatric age group. We aim to outline the various pediatric ocular manifestations described in the literature. The manifestations may be divided into isolated events attributed to COVID-19 or occurring in the new multisystem inflammatory syndrome in children (MIS-C), a novel entity associated by COVID-19 infection. Ocular manifestations have virtually affected all ages. They manifested in neonates, infants, children, and adolescents. Episcleritis, conjunctivitis, optic neuritis, cranial nerve palsies, retinal vein occlusion, retinal vasculitis, retinal changes, orbital myositis, orbital cellulitis were reported in the literature with this emerging viral illness. Conjunctivitis was the most common ocular manifestation in MIS-C in nearly half of the patients. Other ocular manifestations in MIS-C were anterior uveitis, corneal epitheliopathy, optic neuritis, idiopathic intracranial hypertension, and retinitis. The clinical outcome was favorable, and children regain their visual ability with minimal or no deficits in most of the cases. Further follow-up may be warranted to better understand the long-term effects and visual prognosis.

OBJECTIVE: To determine the effectiveness of trabeculectomy and glaucoma drainage device (GDD) surgery performed with concurrent phacoemulsification compared with stand-alone procedures. DESIGN: Multicenter retrospective cohort study. PARTICIPANTS: Patients in the Intelligent Research in Sight Registry who underwent trabeculectomy or GDD from 2013 through 2019. METHODS: The Kaplan-Meier survival analysis was used to determine reoperation rates. Reoperation was defined as any subsequent glaucoma surgery occurring 1 month to 3 years after the initial procedure. Multivariable Cox proportional hazard models were used to determine reoperation risk factors. MAIN OUTCOME MEASURES: Reoperation rate, intraocular pressure (IOP), visual acuity, reoperation procedure type, postoperative complications, and predictors of surgical failure. RESULTS: A total of 117 697 eyes undergoing glaucoma surgery alone and 35 657 eyes undergoing surgery with phacoemulsification were included. The cumulative reoperation rates at postoperative years 1 and 3 were 4.9% and 11.5%, respectively, for trabeculectomy alone and 3.0% and 7.3%, respectively, for trabeculectomy combined with phacoemulsification (P < 0.001). The reoperation rates at postoperative 1 and 3 years were 3.8% and 7.8%, respectively, for GDD alone and 2.1% and 5.4%, respectively, for GDD with phacoemulsification (P < 0.001). Stand-alone procedures achieved greater IOP reduction by percentage change from baseline (trabeculectomy alone, 35.3% vs. trabeculectomy with phacoemulsification, 23.1%, P < 0.001; and GDD alone, 36.0% vs. GDD with phacoemulsification, 29.3%; P < 0.001). Visual acuity improved by 0.12 logarithm of the minimum angle of resolution (logMAR) (95% confidence interval [CI], 0.11-0.12) and 0.10 logMAR (95% CI, 0.08-0.11) after trabeculectomy and GDD with phacoemulsification and declined by 0.15 logMAR (95% CI, 0.14-0.15) and 0.12 logMAR (95% CI, 0.11-0.12) after stand-alone trabeculectomy and GDD. The overall documented complication rate was 2.9% for GDD and 1.4% for trabeculectomy. Age, sex, race, ethnicity, baseline IOP, and glaucoma diagnosis and severity were associated with surgical failure risk. The most common reoperation procedure was GDD. CONCLUSIONS: Reoperation rates within the first 3 years after trabeculectomy and GDD with and without phacoemulsification were low. Trabeculectomy and GDD with phacoemulsification had lower reoperation rates than those with stand-alone procedures. However, stand-alone procedures resulted in greater IOP reduction compared with combined procedures. Postoperative complications were uncommon overall. Patient age, sex, race, ethnicity, baseline IOP, and glaucoma diagnosis and severity were associated with surgical success.

EFEMP1 R345W is a dominant mutation causing Doyne honeycomb retinal dystrophy/malattia leventinese (DHRD/ML), a rare blinding disease with clinical pathology similar to age-related macular degeneration (AMD). Aged Efemp1  R345W/R345W knock-in mice (Efemp1ki/ki) develop microscopic deposits on the basal side of retinal pigment epithelial cells (RPE), an early feature in DHRD/ML and AMD. Here, we assessed the role of alternative complement pathway component factor B (FB) in the formation of these deposits. RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response, decreased mitochondrial function in the neural retina (by 3 months of age) and increased inflammatory pathways in both neural retina and posterior eyecups (at 17 months of age) of Efemp1ki/ki mice compared with wild-type littermate controls. Proteomics analysis of eye lysates confirmed similar dysregulated pathways as detected by RNA-seq. Complement activation was increased in aged Efemp1ki/ki eyes with an approximately 2-fold elevation of complement breakdown products iC3b and Ba (P < 0.05). Deletion of the Cfb gene in female Efemp1ki/ki mice partially normalized the above dysregulated biological pathway changes and oral dosing of a small molecule FB inhibitor from 10 to 12 months of age reduced sub-RPE deposits by 65% (P = 0.029). In contrast, male Efemp1ki/ki mice had fewer sub-RPE deposits than age-matched females, no elevation of ocular complement activation and no effect of FB inhibition on sub-RPE deposits. The effects of FB deletion or inhibition on Efemp1ki/ki mice supports systemic inhibition of the alternative complement pathway as a potential treatment of dry AMD and DHRD/ML.

Strabismus, the condition of misaligned eyes, can result in severe, long-lasting functional and psychosocial sequelae. This review examines existing literature that has described and quantified the psychosocial consequences of strabismus. In particular, the role of strabismus in creating social, psychological, and vocational disparities, and how these intersect with race, ethnicity, and gender, is described. The reviewed data suggest that negative perceptions of strabismus are formed early in life. Overall, exotropia is more easily noticed than esotropia. Esotropia is perceived more negatively than exotropia, and there is significant variation with respect to gender, racial, and ethnic groups. The data demonstrate that the presence of strabismus affects self-esteem, interpersonal relationships, and access to vocational opportunities. Surgical correction of strabismus has been shown to provide significant and long-lasting improvements in psychosocial well-being.

PURPOSE OF REVIEW: We discuss the preoperative, intraoperative, and postoperative considerations for cataract surgery in eyes with high myopia. We also reviewed the recent literature on refractive outcomes and complications of cataract surgery in myopic eyes. RECENT FINDINGS: Several novel intraocular lens (IOL) power calculation formulas have recently been developed to optimize refractive outcomes. Haigis formula is the most accurate among the third-generation IOL formulas. Novel formulas such as Barrett Universal II, Kane, and modified Wang-Koch adjustment for Holladay I formula provide a better refractive prediction compared with old formulas. Intraoperatively, the chopping technique is preferred to minimize pressure on weak zonules and reduce the incidence of posterior capsule rupture. Anterior capsular polishing is recommended to reduce the risk of postoperative capsular contraction syndrome (CCS). Postoperatively, complications such as refractive surprises, intraocular pressure spikes, and CCS remain higher in myopic eyes. Only 63% of myopic patients with axial length more than 26 mm achieve a visual acuity at least 20/40 after cataract surgery, mainly because of coexisting ocular comorbidities. SUMMARY: There are multiple preoperative, intraoperative, and postoperative considerations when performing cataract surgery in myopic eyes. Further research is needed to optimize the refractive outcomes in these eyes and determine the best IOL formula. Surgeons should be adept and knowledgeable with different techniques to manage intraoperative complications.

Mutations in PDE6D impair the function of its cognate protein, phosphodiesterase 6D (PDE6D), in prenylated protein trafficking towards the ciliary membrane, causing the human ciliopathy Joubert Syndrome (JBTS22) and retinal degeneration in mice. In this study, we purified the prenylated cargo of PDE6D by affinity proteomics to gain insight into PDE6D-associated disease mechanisms. By this approach, we have identified a specific set of PDE6D-interacting proteins that are involved in photoreceptor integrity, GTPase activity, nuclear import, or ubiquitination. Among these interacting proteins, we identified novel ciliary cargo proteins of PDE6D, including FAM219A, serine/threonine-protein kinase NIM1 (NIM1K), and ubiquitin-like protein 3 (UBL3). We show that NIM1K and UBL3 localize inside the cilium in a prenylation-dependent manner. Furthermore, UBL3 also localizes in vesicle-like structures around the base of the cilium. Through affinity proteomics of UBL3, we confirmed its strong interaction with PDE6D and its association with proteins that regulate small extracellular vesicles (sEVs) and ciliogenesis. Moreover, we show that UBL3 localizes in specific photoreceptor cilium compartments in a prenylation-dependent manner. Therefore, we propose that UBL3 may play a role in the sorting of proteins towards the photoreceptor outer segment, further explaining the development of PDE6D-associated retinal degeneration.

Salt stress is of the most detrimental abiotic stress factors on either crop or non-crop species. Of the strategies employed to boost the performance of the plants against harmful impacts of salt stress; application of novel nano-engineered particles have recently gained great attention as a promising tool. Octa-aminopropyl polyhedral oligomeric silsesquioxanes nanoparticles (OA-POSS NPs) were synthesized and then a foliar-application of OA-POSS NPs were carried out on sweet basil plants subjected to the salt stress. In that context, interactive effects of OA-POSS NPs (25, 50 and 100 mg L-1) and salinity stress (50 and 100 mM NaCl) were assayed by estimating a series of agronomic, physiological, biochemical and analytical parameters. OA-POSS NPs decreased the harmful effects of salinity by increasing photosynthetic pigment content, adjusting chlorophyll fluorescence, and triggering non-enzymatic (phenolic content) and enzymatic antioxidant components. The findings suggested that 25 mg L-1 OA-POSS NPs is the optimum concentration for sweet basil grown under salt stress. Considering the essential oil profile, estragole was the predominant compound with a percentage higher than 50% depending on the treatment. In comparison to the control group, 50 mM NaCl did not significantly affect estragole content, whilst 100 mM NaCl caused a substantial increase in estragole content. Regarding OA-POSS NPs treatments, increments by 16.8%, 11.8% and 17.5% were observed following application with 25, 50 and 100 mg L-1, respectively. Taken together, the current study provides evidence that POSS NPs can be employed as novel, 'green' growth promoting agents in combating salt stress in sweet basil.

An underlying diagnosis of keratoconus (KC) can complicate cataract surgery. In this study, the results of a focused review of the literature pertaining to cataract surgery in patients with KC are detailed. Topics essential for the appropriate management of this patient population are discussed. First, the individual and shared epidemiology and pathophysiology of cataract and KC are reviewed. Then, the theory and approach to intraocular lens power calculation are discussed, highlighting particularities and pitfalls of this exercise when performed in patients with KC. Finally, several special-although not uncommon-management scenarios and questions are addressed, such as surgical planning in cases where corneal stabilization or tissue replacement interventions are also necessitated.

PURPOSE: To quantitatively evaluate safety profile for botulinum toxin A (BTX-A) injections among patients undergoing treatment for cosmetic indications is produced, with special attention to clinically relevant covariates and their relative impact on safety. METHODS: A systematic literature search was performed using PubMed (1996-January 2020) and Embase (1947-January 2020) to identify all randomized controlled trials (RCTs) that reported safety data for patients receiving BTX-A for cosmetic indications compared to placebo. A meta-analysis was performed to determine pooled risk ratios (RR) for treatment-related adverse events (TRAEs) and for specific adverse events. Meta-regression and additional analyses were performed for significant and/or clinically relevant covariates. RESULTS: Following the review of 8,690 studies, 32 RCTs involving 9,669 patients were included. The pooled RR of any TRAE occurring after BTX-A injection compared to placebo injection was 1.53 (95% CI, 1.33-1.77; p < 0.001). Statistically significant covariates included individual injection volume and total injection volume. The type of BTX-A formulation, treatment site, total BTX-A units, and BTX-A units per injection were not significant. Specific adverse events more likely to occur following BTX-A injection rather than placebo injection included eyelid/eyebrow malposition (RR 3.55; p < 0.001), facial paresis (RR 2.42; p = 0.316), and headache (RR 1.45; p = 0.003). Injection site reactions and injection site bruising occurred at similar rates in both groups. CONCLUSIONS: The overall safety profile of BTX-A is acceptable and consistent with previous publications. The authors' additional analyses provide a relative comparison of the impact of various treatment parameters on safety.

PURPOSE: To determine the relationships of (1) tear osmolarity (TO) levels with the severity of signs and symptoms of dry eye disease (DED) and (2) changes in TO with changes in signs and symptoms. METHODS: Patients (N = 405) with moderate to severe DED in the Dry Eye Assessment and Management (DREAM) Study were evaluated at baseline and at six and 12 months. Associations of TO with signs and symptoms were evaluated using Pearson correlation coefficient (r) and regression models. RESULTS: The mean (standard deviation [SD]) TO was 303 (16) mOsm/L at baseline and 303 (18) mOsm/L at both six and 12 months. TO was higher in older patients (306 mOsm/L for ≥70 years vs. 300 mOsm/L for <50 years; P = 0.01) and those with Sjögren's disease (311 vs. 302 mOsm/L; P < 0.0001). TO did not differ between patients randomized to placebo and omega-3 fatty acid supplementation. TO was weakly correlated with conjunctival (r = 0.18; P < 0.001) and corneal staining scores (r = 0.17; P < 0.001), tear film break-up time (r = 0.06; P = 0.03), and Schirmer test score (r = -0.07; P = 0.02) but not with Ocular Surface Disease Index scores (r = 0.03; P = 0.40). Changes in signs and were not significantly correlated with change in TO at six or 12 months. CONCLUSIONS: Within DREAM, TO was weakly correlated with DED signs, explaining <5% variability in signs. Changes in tear osmolarity were not associated with changes in signs and symptoms of DED, indicating that the association may not be causal.

Epithelial mesenchymal transition (EMT) plays a vital role in a variety of human diseases including proliferative vitreoretinopathy (PVR), in which retinal pigment epithelial (RPE) cells play a key part. Transcriptomic analysis showed that the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway was up-regulated in human RPE cells upon treatment with transforming growth factor (TGF)-β2, a multifunctional cytokine associated with clinical PVR. Stimulation of human RPE cells with TGF-β2 induced expression of p110δ (the catalytic subunit of PI3Kδ) and activation of NFκB/p65. CRISPR-Cas9-mediated depletion of p110δ or NFκB/p65 suppressed TGF-β2-induced fibronectin expression and activation of Akt as well as migration of these cells. Intriguingly, abrogating expression of NFκB/p65 also blocked TGF-β2-induced expression of p110δ, and luciferase reporter assay indicated that TGF-β2 induced NFκB/p65 binding to the promoter of the PIK3CD that encodes p110δ. These data reveal that NFκB/p65-mediated expression of PI3Kδ is essential in human RPE cells for TGF-β2-induced EMT, uncovering hindrance of TGF-β2-induced expression of p110δ as a novel approach to inhibit PVR.

Although tissue culture is the gold standard for diagnosing infection, histologic examination of surgically resected tissue can be a critical component in the diagnosis of tissue infection. The goal of this brief report is to alert surgical pathologists that Pseudomonas species can appear strikingly filamentous histologically and may somewhat mimic the appearance of filamentous bacteria, such Actinomyces or Nocardia, or thin fungal hyphae. A secondary aim is to raise awareness that Pseudomonas can sometimes only be identified histologically through the use of a modified silver impregnation method (Steiner stain). Five cases of filamentous Pseudomonas were encountered in three different surgical pathology subspecialities (ophthalmic pathology, cardiovascular pathology, and dermatopathology) over a 1-year period. All cases were of formalin-fixed, paraffin-embedded tissue, stained using hematoxylin & eosin (H&E) and multiple histochemical stains. Four cases grew Pseudomonas aeruginosa in culture and, in the fifth case, a nonaeruginosa species was detected using polymerase chain reaction-based methods. The markedly filamentous-appearing Pseudomonas organisms were identified in five different tissue sites: vascular graft, enucleation (whole eye) specimen, scleral biopsy, soft-tissue excision, and skin punch biopsy. In one of the five cases the organisms were seen on H&E, and in only two of the five were the organisms seen on Brown-Hopps stain. In all five cases, the organisms were identified on Steiner stain. It is therefore important to recognize that Pseudomonas can appear markedly filamentous, Pseudomonas or other bacterial infection is suspected, the surgical pathologist would be advised to employ the Steiner stain to most consistently detect the organisms.

Pediatric abusive head trauma (AHT), still colloquially known as shaken baby syndrome, is a leading cause of morbidity and mortality among infants. Controversy has grown surrounding this diagnosis, and the specificity of the clinical findings-subdural hemorrhage, cerebral edema, and retinal hemorrhages-has been challenged. A literature search of peer reviewed publications on PubMed pertaining to the history, clinical, and pathologic features of AHT was conducted using the terms "shaken baby syndrome," "non-accidental trauma," "abusive head trauma," "inflicted traumatic brain injury," "shaken impact syndrome," and "whiplash shaken infant syndrome." Focus was placed on articles discussing ophthalmic findings in AHT. Retinal hemorrhages-particularly those that are too numerous to count, occurring in all layers of the retina (preretinal, intraretinal, subretinal), covering the peripheral pole and extending to the ora serrata, and accompanied by retinoschisis and other ocular/periocular hemorrhages-are highly suggestive of AHT, particularly in the absence of otherwise explained massive accidental trauma. Although the diagnosis has grown in controversy in recent years, AHT has well-documented clinical and pathologic findings across a large number of studies.

Retinal explant cultures provide a valuable system to study retinal function in vitro. This study established a new retinal explant culture method to prolong the survival of retinal ganglion cells (RGCs). Explants were prepared in two different ways: with or without optic nerve. Retinas from newborn mice that had received an injection of MitoTracker Red into the contralateral superior colliculus to label axonal mitochondria were cultured as organotypic culture for 7 days in vitro. At several time points during the culture, viability of RGCs was assessed by multi-electrode array recording, and morphology by immunohistochemical methods. During the culture, the thickness of the retinal tissue in both groups gradually decreased, however, the structure of the layers of the retina could be identified. Massive apoptosis in the retinal ganglion cell layer (GCL) appeared on the first day of culture, thereafter the number of apoptotic cells decreased. Glial activation was observed throughout the culture, and there was no difference in morphology between the two groups. RGCs loss was exacerbated on 3rdday of culture, and RGCs loss in retinal explants with preserved optic nerve was significantly lower than in retinas that did not preserve the optic nerve. More and longer-lasting mitochondrial signals were observed in the injured area of the optic nerve-preserving explants. Retinal explants provide an invaluable tool for studying retinal function and developing treatments for ocular diseases. The optic nerve-preserving culture helps preserve the integrity of RGCs. The higher number of mitochondria in the nerve-preserving cultures may help maintain viability of RGCs.

(1) Background: In recent years, medical institutions across the U.S. have implemented a points system based on the Educational Value Unit (EVU) to assess and reward faculty for their educational efforts. The purpose of this narrative review is to summarize the current literature on EVU systems and to evaluate their utility in the U.S. healthcare system. (2) Methods: We searched the Ovid MEDLINE, Embase, Web of Science, and PubMed databases to identify literature describing the inception of EVU systems and current systems implemented by U.S. academic medical centers and medical schools. In total, a combined 48 studies and abstracts pertaining to EVU systems were reviewed, and a combined 26 published studies and abstracts from 1999 to 2022 pertaining to EVU systems were included. (3) Results: To our knowledge, at least 40 U.S. academic medical centers have used an educational metrics system, of which 21 institutions have published studies describing EVU systems in one or more of their medical departments. The outcomes associated with these self-described EVU systems are the focus of this study. EVU systems increase the number of faculty who meet baseline educational requirements, promote educational productivity, redistribute educational burden and funding among faculty members, and shift physician priorities towards education. The monetary reward associated with EVU systems is unlikely to be a significant factor contributing to these changes; instead, intrinsic motivation and a sense of academic responsibility play a larger role. (4) Conclusions: EVU systems are an effective way to evaluate and reward individual and departmental educational efforts in U.S. academic medical centers and medical schools. The adoption of EVUs will likely become more commonplace as U.S. academic medical centers and medical schools place additional emphasis on medical education.

IMPORTANCE: An ongoing global monkeypox virus outbreak in 2022 includes the US and other nonendemic countries. Monkeypox ophthalmic manifestations may present to the ophthalmologist, or the ophthalmologist may be involved in comanagement. This narrative review creates a primer for the ophthalmologist of clinically relevant information regarding monkeypox, its ophthalmic manifestations, and the 2022 outbreak. OBSERVATIONS: Monkeypox virus is an Orthopoxvirus (genus includes variola [smallpox] and vaccinia [smallpox vaccine]). The 2022 outbreak is of clade II (historically named West African clade), specifically subclade IIb. In addition to historic transmission patterns (skin lesions, bodily fluids, respiratory droplets), sexual transmission has also been theorized in the current outbreak due to disproportionate occurrence in men who have sex with men. Monkeypox causes a characteristic skin eruption and mucosal lesions and may cause ophthalmic disease. Monkeypox-related ophthalmic disease (MPXROD) includes a spectrum of ocular pathologies including eyelid/periorbital skin lesions, blepharoconjunctivitis, and keratitis). Smallpox vaccination may reduce MPXROD occurrence. MPXROD seems to be rarer in the 2022 outbreaks than in historical outbreaks. MPXROD may result in corneal scarring and blindness. Historical management strategies for MPXROD include lubrication and prevention/management of bacterial superinfection in monkeypox keratitis. Case reports and in vitro data for trifluridine suggest a possible role in MPXROD. Tecovirimat, cidofovoir, brincidofovir and vaccinia immune globulin intravenous may be used for systemic infection. There is a theoretical risk for monkeypox transmission by corneal transplantation, and the Eye Bank Association of America has provided guidance. Smallpox vaccines (JYNNEOS [Bavarian Nordic] and ACAM2000 [Emergent Product Development Gaithersburg Inc]) provide immunity against monkeypox. CONCLUSIONS AND RELEVANCE: The ophthalmologist may play an important role in the diagnosis and management of monkeypox. MPXROD may be associated with severe ocular and visual morbidity. As the current outbreak evolves, up-to-date guidance from public health organizations and professional societies are critical.

PURPOSE OF REVIEW: There is now a large body of experience with intraoperative aberrometry. This review aims to synthesize available data regarding intraoperative aberrometry applications and outcomes. RECENT FINDINGS: The Optiwave Refractive Analysis (ORA) System utilizes Talbot-moiré interferometry and is the only commercially available intraoperative aberrometry device. There are few studies that include all-comers undergoing intraoperative aberrometry-assisted cataract surgery, as most studies examine routine patients only or atypical eyes only. In non-post-refractive cases, studies have consistently shown a small but statistically significant benefit in spherical equivalent refractive outcome for intraoperative aberrometry versus preoperative calculations. In studies examining axial length extremes, most studies have shown intraoperative aberrometry to perform similarly to preoperative calculations. Amongst post-refractive cases, post-myopic ablation cases appear to benefit the most from intraoperative aberrometry. For toric intraocular lenses (IOLs), intraoperative aberrometry may be used for refining IOL power (toricity and spherical equivalent) and alignment, and most studies show intraoperative aberrometry to achieve low postoperative residual astigmatism. SUMMARY: Intraoperative aberrometry can be utilized as an adjunct to preoperative planning and surgeon's judgment to optimize cataract surgery refractive outcomes. Non-post-refractive cases, post-myopic ablation eyes, and toric intraocular lenses may have the greatest demonstrated benefit in intraoperative aberrometry studies to date, but other eyes may also benefit from intraoperative aberrometry use.