Safety and efficacy of topical vs intracanalicular corticosteroids for the prevention of postoperative inflammation after cataract surgery.

PURPOSE: To compare the safety and efficacy of topical prednisolone and intracanalicular dexamethasone ophthalmic insert for the prevention of postoperative inflammation after cataract surgery. SETTING: Penn State College of Medicine, Hershey, Pennsylvania. DESIGN: Retrospective consecutive case series. METHODS: Patients scheduled for elective phacoemulsification cataract surgery with a plan to receive inflammation prophylaxis with topical prednisolone (prednisolone acetate 1 mg/1 mL) between January 2018 and November 2019 or intracanalicular dexamethasone (Dextenza, 0.4 mg) between December 2019 and March 2021 were screened. Patients were seen 1 day, 1 week, and 4 to 16 weeks postoperatively. Medical records were also reviewed for any urgent messages between visits. Primary end points were proportion of eyes with (1) breakthrough inflammation requiring escalation of anti-inflammatory therapy and (2) intraocular pressure (IOP) increase ≥10 mm Hg at 4 to 16 weeks of follow-up. Secondary end points included incidence of intraoperative complications, cystoid macular edema, and infectious sequelae. RESULTS: 358 patient charts (358 eyes) were screened. Of these, 262 eyes of 262 patients met the criteria for inclusion in the study; 131 eyes received topical drops, and 131 eyes received the intracanalicular insert. Among eyes that completed follow-up, 9 eyes (6.9%) in the drops group and 12 eyes (9.2%) in the insert group experienced breakthrough inflammation necessitating treatment ( P = .50). 2 eyes in the drops group and 1 eye in the insert group had elevated IOP. CONCLUSIONS: Postoperative inflammation prophylaxis with the intracanalicular insert may be associated with similar rates of breakthrough inflammation and IOP elevation as topical drops.

Repeatability and comparability of keratometry measurements obtained with swept-source optical coherence and combined dual Scheimpflug-Placido disk-based tomography.

PURPOSE: To assess the repeatability of keratometric measurements obtained using a reflectance and swept-source optical coherence tomography (SS-OCT) based biometer and to compare these values with those obtained with a dual Scheimpflug-Placido (S-P) disk-based tomographer/topographer. SETTING: Department of Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania, USA. DESIGN: Prospective consecutive case series. METHODS: Patients undergoing cataract evaluation were prospectively enrolled. Surgery-naive eyes without corneal pathology were measured 3 times with the reflectance/SS-OCT biometer and once with the dual S-P disk tomographer/topographer. Intradevice repeatability for anterior (K), posterior (PK), and total corneal keratometry (TK) readings were evaluated using within-eye SDs, test-retest repeatability (TRT), coefficients of variance, and intraclass correlation coefficients (ICCs). Bland-Altman analysis was used to assess agreement between devices. RESULTS: Eighty-two eyes from 48 patients met inclusion criteria. The TRT for the anterior, posterior, and total corneal powers were 0.33, 0.08, and 0.36 diopter (D), respectively. TRT for the anterior, posterior, and total keratometric astigmatism were 0.58, 0.14, and 0.64 D, respectively. Anterior keratometric indices had higher ICCs than posterior indices. Bland-Altman analysis revealed that the SS-OCT consistently reported flatter posterior corneal curvatures than the S-P. CONCLUSIONS: The SS-OCT posterior keratometric measurements contain more noise (lower ICCs), but still have lower within-eye SDs and TRTs than that of anterior measurements. This may be due to the small index of refraction change at the cornea-aqueous interface. Although keratometric indices from the 2 devices are highly correlated, measurements taken using SS-OCT and S-P devices were not interchangeable.

Combination Antivascular Endothelial Growth Factor and Modified Panretinal Photocoagulation in Management of Proliferative Diabetic Retinopathy.

Purpose: This work evaluates the effects of combined intravitreal antivascular endothelial growth factor (anti-VEGF) and modified panretinal photocoagulation (PRP) for management of proliferative diabetic retinopathy (PDR). Methods: This retrospective case series included 37 eyes of 33 patients with high-risk PDR. Anti-VEGF injections (≥ 2) were followed by modified, midperipheral PRP performed in 2 or more sessions. Visual and anatomic outcomes were tracked for 1 year after treatment. Regression analysis was performed for factors predictive of final outcomes. Results: Mean visual acuity (VA) at initial and final visit were 20/50 and 20/40 (P = .22), respectively, over a mean follow-up duration of 341.4 days. Central foveal thickness decreased from 321.8 µm to 258.6 µm (P = .01). Resolution of PDR was achieved in 94.6% of eyes, with 5.4% of eyes requiring additional anti-VEGF for persistent neovascularization. Final VA was significantly associated with baseline VA, VA at 1 month, and any adverse anatomical events. Treatment noncompliance was present in 24.3%; compliance decreased with increasing medical comorbidities, but was not significantly associated with final VA. Conclusions: Combination of anti-VEGF and modified PRP preserved VA and yielded PDR regression in the majority of eyes. This combination provides rapid PDR regression with anti-VEGF while achieving durable disease suppression in this real-world cohort without traditional PRP.

Pluripotent Stem Cells as Models of Retina Development.

The ability of pluripotent stem cells (PSCs) to differentiate into retinal tissue has led to many attempts to direct this process to yield specific retinal cell types. The ability to do so would greatly impact both the study of normal retina development in model systems that can be precisely controlled and the generation of a homogeneous population of cells optimized for transplantation in cell replacement therapy. Thus far, many reviews have focused on the translational potential of PSC retinal studies. Here, we focus on the former by summarizing the advances and reflecting on the current limitations to using in vitro differentiation of PSCs into retinal cells and organoids to model in vivo retinal development, with a specific emphasis on photoreceptors. We discuss the versatility of PSC retinal differentiation systems in investigating specific developmental time points that are difficult to assess with classic developmental model systems as well as the potential for efficient screening of factors involved in regulating photoreceptor differentiation. PSCs can be used in conjunction with existing model systems to contribute to the understanding of retina and photoreceptor development, which in turn can enhance the success of using stem cells in translational studies.

Generation of Photoreceptor Precursors from Mouse Embryonic Stem Cells.

Embryonic stem cell (ESC) differentiation can be used to model development and to produce transplantable cells of the desired phenotype. ESCs can reproducibly generate retinal cells but the derivation of photoreceptor precursors is variable and depends on an array of exogenous factors and intrinsic cell-cell interactions. In this work, we have defined the use of exogenous signaling factors, dissociation, and adherent versus 3-dimensional (3D) conditions on the derivation of retinal cells from pluripotent mouse ESCs. Differentiation protocols were chosen based on the developmental stage and cell population of interest and evaluated by expression of developmental stage- and lineage-specific marker genes. We present a relatively simple protocol that guides differentiating ESCs through stages that correspond to the sequence of in vivo developmental events and is optimized for studying the time frame between eye field formation and photoreceptor precursor development in the equivalent of embryonic retina. Step-wise exposure of adherent cultures to exogenous factors facilitated expression of eye field transcription factors and limited non-specific differentiation. Dissociation after the establishment of eye field and retinal progenitor cell gene expression did not cause substantial loss in expression of markers of mature photoreceptors. Finally, 3D organoids improved expression of photoreceptor genes and region-specific architecture but required more technical manipulation. We demonstrate the usefulness of this ESC-retinal induction protocol in screening for factors that improve photoreceptor precursor yield by evaluating response to alterations in Activin signaling.

Activin Signals through SMAD2/3 to Increase Photoreceptor Precursor Yield during Embryonic Stem Cell Differentiation.

In vitro differentiation of mouse embryonic stem cells (ESCs) into retinal fates can be used to study the roles of exogenous factors acting through multiple signaling pathways during retina development. Application of activin A during a specific time frame that corresponds to early embryonic retinogenesis caused increased generation of CRX+ photoreceptor precursors and decreased PAX6+ retinal progenitor cells (RPCs). Following activin A treatment, SMAD2/3 was activated in RPCs and bound to promoter regions of key RPC and photoreceptor genes. The effect of activin on CRX expression was repressed by pharmacological inhibition of SMAD2/3 phosphorylation. Activin signaling through SMAD2/3 in RPCs regulates expression of transcription factors involved in cell type determination and promotes photoreceptor lineage specification. Our findings can contribute to the production of photoreceptors for cell replacement therapy.

Carcinogen-specific mutations in preferred Ras-Raf pathway oncogenes directed by strand bias.

Carcinogen exposures inscribe mutation patterns on cancer genomes and sometimes bias the acquisition of driver mutations toward preferred oncogenes, potentially dictating sensitivity to targeted agents. Whether and how carcinogen-specific mutation patterns direct activation of preferred oncogenes remains poorly understood. Here, mouse models of breast cancer were exploited to uncover a mechanistic link between strand-biased mutagenesis and oncogene preference. When chemical carcinogens were employed during Wnt1-initiated mammary tumorigenesis, exposure to either 7,12-dimethylbenz(a)anthracene (DMBA) or N-ethyl-N-nitrosourea (ENU) dramatically accelerated tumor onset. Mammary tumors that followed DMBA exposure nearly always activated the Ras pathway via somatic Hras(CAA61CTA) mutations. Surprisingly, mammary tumors that followed ENU exposure typically lacked Hras mutations, and instead activated the Ras pathway downstream via Braf(GTG636GAG) mutations. Hras(CAA61CTA) mutations involve an A-to-T change on the sense strand, whereas Braf(GTG636GAG) mutations involve an inverse T-to-A change, suggesting that strand-biased mutagenesis may determine oncogene preference. To examine this possibility further, we turned to an alternative Wnt-driven tumor model in which carcinogen exposures augment a latent mammary tumor predisposition in Apc(min) mice. DMBA and ENU each accelerated mammary tumor onset in Apc(min) mice by introducing somatic, "second-hit" Apc mutations. Consistent with our strand bias model, DMBA and ENU generated strikingly distinct Apc mutation patterns, including stringently strand-inverse mutation signatures at A:T sites. Crucially, these contrasting signatures precisely match those proposed to confer bias toward Hras(CAA61CTA) versus Braf(GTG636GAG) mutations in the original tumor sets. Our findings highlight a novel mechanism whereby exposure history acts through strand-biased mutagenesis to specify activation of preferred oncogenes.