October 2019

Intravitreal injections and implants are used to deliver drugs to the retina because therapeutic levels of these medications cannot be provided by topical administration (i.e. eye drops). In order to reach the retina, a topically applied drug encounters tear dilution, reflex blinking, and rapid fluid drainage that collectively reduce the drug's residence time on the ocular surface. Residing under the tears, the cornea is the primary gateway into the eye for many topical ophthalmic drugs. We hypothesized that a drug-eluting contact lens that rests on the cornea would therefore be well-suited for delivering drugs to the eye including the retina. We developed a contact lens based dexamethasone delivery system (Dex-DS) that achieved sustained drug delivery to the retina at therapeutic levels. Dex-DS consists of a dexamethasone-polymer film encapsulated inside a contact lens. Rabbits wearing Dex-DS achieved retinal drug concentrations that were 200 times greater than those from intensive (hourly) dexamethasone drops. Conversely, Dex-DS demonstrated lower systemic (blood serum) dexamethasone concentrations. In an efficacy study in rabbits, Dex-DS successfully inhibited retinal vascular leakage induced by intravitreal injection of vascular endothelial growth factor (VEGF). Dex-DS was found to be safe in a four-week repeated dose biocompatibility study in healthy rabbits.

The somatotopic motor-neuron projections onto their cognate target muscles are essential for coordinated movement, but how that occurs for facial motor circuits, which have critical roles in respiratory and interactive behaviors, is poorly understood. We report extensive molecular heterogeneity in developing facial motor neurons in the mouse and identify markers of subnuclei and the motor pools innervating specific facial muscles. Facial subnuclei differentiate during migration to the ventral hindbrain, where neurons with progressively later birth dates-and evolutionarily more recent functions-settle in more-lateral positions. One subpopulation marker, ETV1, determines both positional and target muscle identity for neurons of the dorsolateral (DL) subnucleus. In Etv1 mutants, many markers of DL differentiation are lost, and individual motor pools project indifferently to their own and neighboring muscle targets. The resulting aberrant activation patterns are reminiscent of the facial synkinesis observed in humans after facial nerve injury.

Retinopathy of prematurity treatment modalities have expanded over the years, from cryotherapy to laser therapy and now, anti-vascular endothelial factor (VEGF) therapy by intravitreal injection. Use of anti-VEGF treatment varies regionally and depends on multiple factors including severity and progression of ROP, availability of alternative treatments, experience of the local ophthalmologists, medical status of the infant, and expectations for long-term follow-up. While the advantages and disadvantages of anti-VEGF intravitreal treatment on the eye are relatively well-described, few studies provide information about potential long-term systemic effects of this treatment, which is known to transiently reduce systemic VEGF concentrations.

We sought to refine understanding about associations identified in prior studies between angiotensin-II receptor blockers, metformin, selective serotonin reuptake inhibitors, fibric-acid derivatives, or calcium channel blockers and progression to glaucoma filtration surgery for open-angle glaucoma (OAG). We used new-initiator, active-comparator cohort designs to investigate these drugs in two data sources. We adjusted for confounders using stabilized inverse-probability-of-treatment weights and evaluated results using "intention-to-treat" and "as-treated" follow-up approaches. In both data sources, Kaplan-Meier curves showed trends for more rapid progression to glaucoma filtration surgery in patients taking calcium channel blockers compared with thiazides with as-treated (MarketScan P = 0.15; Medicare P = 0.03) and intention-to-treat follow-up (MarketScan P < 0.01; Medicare P = 0.10). There was suggestion of delayed progression for selective serotonin reuptake inhibitor compared with tricyclic antidepressants in Medicare, which was not observed in MarketScan. Our study provided support for a relationship between calcium channel blockers and OAG progression but not for other investigated drugs.

Importance: Gun violence represents a substantial public health issue, and firearm-related injuries rank second among the causes of injury-related deaths in children aged 0 to 17 years in the United States. Ocular trauma from firearm-related injuries can lead to devastating vision loss, but little is known to date about the specific demographics and characteristics of such injuries in children. Objective: To evaluate the epidemiologic pattern of pediatric firearm-related ocular injuries. Design, Setting, and Participants: This retrospective analysis used deidentified data from the National Trauma Data Bank, the largest national registry of hospitalized trauma cases in the United States. The firearm-related ocular injuries (n = 1972) of pediatric patients (defined as those younger than 21 years) hospitalized between January 1, 2008, and December 31, 2014, were analyzed. Statistical analyses were conducted from July 15, 2017, to June 15, 2019. Exposure: Firearm-related ocular trauma. Main Outcomes and Measures: Pediatric patients with firearm-related ocular injuries were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes and external causes of injury codes. Patient demographics (age, sex, and race/ethnicity), type of ocular injury, injury intent, geographic location, length of hospital admission, health insurance status, disposition at discharge, Injury Severity Score (ISS), and Glasgow Coma Scale (GCS) score were collected. Results: A total of 8715 firearm-related ocular injuries were identified. Of these injuries, 1972 (22.6%) occurred in pediatric patients, most of whom were male (1678 [85.1%]) and adolescents (1037 [52.6%]), with a mean (SD) age of 15.2 (5) years. Common locations of injury were home (761 [38.6%]) and street (490 [24.8%]). Mean (SD) hospital length of stay was 7.6 (12) days, ISS was 16 (13.1), and GCS score was 11 (5.1). The most common types of firearm-related ocular injuries were open wound of the eyeball (820 [41.6%]) and ocular adnexa (502 [25.5%]), orbital injuries or fractures (591 [30.0%]), and contusion of the eye or adnexa (417 [21.1%]). Patients aged 0 to 3 years had greater odds of unintentional injuries (odds ratio [OR], 4.41; 95% CI, 2.51-7.75; P < .001) and injuries occurring at home (OR, 5.39; 95% CI, 2.81-10.38; P < .001), and those aged 19 to 21 years had greater odds of assault injuries (OR, 2.17; 95% CI, 1.77-2.66; P < .001) and injuries occurring on the street (OR, 1.61; 95% CI, 1.3-1.98; P < .001). Black patients had the greatest odds of having injuries with assault intention (OR, 4.53; 95% CI, 3.68-5.59; P < .001), and white patients had the greatest likelihood for self-inflicted injury (OR, 7.1; 95% CI, 5.92-9.51; P < .001). Traumatic brain injury resulted mostly from self-inflicted trauma (OR, 5.99; 95% CI, 4.16-8.63; P < .001), as did visual pathway injuries (OR, 2.86; 95% CI, 1.95-4.20; P < .001). The inpatient mortality rate was 12.2%. Conclusions and Relevance: This study found that pediatric firearm-related ocular injuries from 2008 through 2014 were predominantly sight-threatening and associated with traumatic brain injury. If the possible risk factors, including sex, age, race/ethnicity, and injury intention, can be confirmed for 2015 through 2019, these findings may be useful in developing strategies to prevent pediatric firearm-related ocular injuries.

Purpose: Clinical manifestations of photoreceptor degeneration include gradual thinning of the outer nuclear layer (ONL) and progressive reduction of electroretinogram (ERG) amplitudes and vision loss. Although preclinical evaluations of treatment strategies greatly depend on rodent models, the courses of these changes in mice remain unclear. We thus sought to investigate the temporal correlations in changes of spatial vision, ERG response, and ONL thickness in mice with progressive photoreceptor degeneration. Methods: Adult wild-type (WT) mice and mice carrying rhodopsin deficiency (Rho-/-), a frequently used mouse model of human retinitis pigmentosa, were selected for investigation. Mouse spatial vision, including visual acuity (VA) and contrast sensitivity (CS), was determined using optomotor response (OMR) assays; ONL thickness was quantified by spectral-domain optical coherence tomography (SD-OCT), and ERG was performed to evaluate retinal functions. The mice were killed when they were 14 weeks old, and the cone photoreceptors in retinal sections were counted. Results: Spatial vision, ONL thickness, and ERG amplitudes remained stable in WT mice at all examined time points. While 6-week-old Rho-/- mice had VA, CS, as well as ERG responses similar to those of WT mice, progressive reductions in the spatial vision and retinal functions were recorded thereafter. Most tested 12-week-old Rho-/- mice had no visual-evoked OMR and ERG responses. Moreover, CS, but not VA, displayed a linear decline that was closely associated with ONL thinning, reduction of ERG amplitudes, and loss of cones. Conclusions: We presented a comprehensive study of the relation between the changes of spatial vision, retinal function, and ONL thickness in postnatal week (PW)6 to PW12 Rho-/- mice. CS is a more sensitive indicator of spatial vision compared to VA, although both are required as separate parameters for monitoring the visual changes in retina undergoing photoreceptor degeneration.

The optic nerve conveys information about the outside world from the retina to multiple subcortical relay centers. Until recently, the optic nerve was widely believed to be incapable of re-growing if injured, with dire consequences for victims of traumatic, ischemic, or neurodegenerative diseases of this pathway. Over the past 10-20 years, research from our lab and others has made considerable progress in defining factors that normally suppress axon regeneration and the ability of retinal ganglion cells, the projection neurons of the retina, to survive after nerve injury. Here we describe research from our lab on the role of inflammation-derived growth factors, suppression of inter-cellular signals among diverse retinal cell types, and combinatorial therapies, along with related studies from other labs, that enable animals with optic nerve injury to regenerate damaged retinal axons back to the brain. These studies raise the possibility that vision might one day be restored to people with optic nerve damage.