Emotional face recognition is impaired in bipolar disorder, but it is not clear whether this is specific for the illness. Here, we investigated how aging and bipolar disorder influence dynamic emotional face recognition. Twenty older adults, 16 bipolar patients, and 20 control subjects performed a dynamic affective facial recognition task and a subsequent rating task. Participants pressed a key as soon as they were able to discriminate whether the neutral face was assuming a happy or angry facial expression and then rated the intensity of each facial expression. Results showed that older adults recognized happy expressions faster, whereas bipolar patients recognized angry expressions faster. Furthermore, both groups rated emotional faces more intensely than did the control subjects. This study is one of the first to compare how aging and clinical conditions influence emotional facial recognition and underlines the need to consider the role of specific and common factors in emotional face recognition.

PURPOSE: Identify a reproducible measure of axial globe position (AGP) for multicenter studies on patients with thyroid eye disease (TED). METHODS: This is a prospective, international, multicenter, observational study in which 3 types of AGP evaluation were examined: radiologic, clinical, and photographic. In this study, CT was the modality to which all other methods were compared. CT AGP was measured from an orthogonal line between the anterior lateral orbital rims to the cornea. All CT measurements were made at a single institution by 3 individual clinicians. Clinical evaluation was performed with exophthalmometry. Three clinicians from each clinical site assessed AGP with 3 different exophthalmometers and horizontal palpebral width using a ruler. Each physician made 3 separate measurements with each type of exophthalmometer not in succession. All photographic measurements were made at a single institution. AGP was measured from lateral photographs in which a standard marker was placed at the anterior lateral orbital rim. Horizontal and vertical palpebral fissure were measured from frontal photographs. Three trained readers measured 3 separate times not in succession. Exophthalmometry and photography method validity was assessed by agreement with CT (mean differences calculation, intraclass correlation coefficients [ICCs], Bland-Altman figures). Correlation between palpebral fissure and CT AGP was assessed with Pearson correlation. Intraclinician and interclinician reliability was evaluated using ICCs. RESULTS: Sixty-eight patients from 7 centers participated. CT mean AGP was 21.37 mm (15.96-28.90 mm) right and 21.22 mm (15.87-28.70 mm) left (ICC 0.996 and 0.995). Exophthalmometry AGP fell between 18 mm and 25 mm. Intraclinician agreement across exophthalmometers was ideal (ICC 0.948-0.983). Agreement between clinicians was greater than 0.85 for all upright exophthalmometry measurements. Photographic mean AGP was 20.47 mm (10.92-30.88 mm) right and 20.30 mm (8.61-28.72 mm) left. Intrareader and interreader agreement was ideal (ICC 0.991-0.989). All exophthalmometers' mean differences from CT ranged between -0.06 mm (±1.36 mm) and 0.54 mm (±1.61 mm); 95% confidence interval fell within 1 mm. Magnitude of AGP did not affect exophthalmometry validity. Oculus best estimated CT AGP but differences from other exophthalmometers were not clinically meaningful in upright measurements. Photographic AGP (right ICC = 0.575, left ICC = 0.355) and palpebral fissure do not agree with CT. CONCLUSIONS: Upright clinical exophthalmometry accurately estimates CT AGP in TED. AGP measurement was reliably reproduced by the same clinician and between clinicians at multiple institutions using the protocol in this study. These findings allow reliable measurement of AGP that will be of considerable value in future outcome studies.

PURPOSE: To compare diabetic retinopathy (DR) identification and ungradable image rates between nonmydriatic ultrawide field (UWF) imaging and nonmydriatic multifield fundus photography (NMFP) in a large multistate population-based DR teleophthalmology program. DESIGN: Multiple-site, nonrandomized, consecutive, cross-sectional, retrospective, uncontrolled imaging device evaluation. PARTICIPANTS: Thirty-five thousand fifty-two eyes (17 526 patients) imaged using NMFP and 16 218 eyes (8109 patients) imaged using UWF imaging. METHODS: All patients undergoing Joslin Vision Network (JVN) imaging with either NMFP or UWF imaging from May 1, 2014, through August 30, 2015, within the Indian Health Service-JVN program, which serves American Indian and Alaska Native communities at 97 sites across 25 states, were evaluated. All retinal images were graded using a standardized validated protocol in a centralized reading center. MAIN OUTCOME MEASURES: Ungradable rate for DR and diabetic macular edema (DME). RESULTS: The ungradable rate per patient for DR and DME was significantly lower with UWF imaging compared with NMFP (DR, 2.8% vs. 26.9% [P < 0.0001]; DME, 3.8% vs. 26.2% [P < 0.0001]). Identification of eyes with either DR or referable DR (moderate nonproliferative DR or DME or worse) was increased using UWF imaging from 11.7% to 24.2% (P < 0.0001) and from 6.2% to 13.6% (P < 0.0001), respectively. In eyes with DR imaged with UWF imaging (n = 3926 eyes of 2402 patients), the presence of predominantly peripheral lesions suggested a more severe level of DR in 7.2% of eyes (9.6% of patients). CONCLUSIONS: In a large, widely distributed DR ocular telehealth program, as compared with NMFP, nonmydriatic UWF imaging reduced the number of ungradable eyes by 81%, increased the identification of DR nearly 2-fold, and identified peripheral lesions suggesting more severe DR in almost 10% of patients, thus demonstrating significant benefits of this imaging method for large DR teleophthalmology programs.

PURPOSE: To evaluate the risk of and risk factors for retinal neovascularization (NV) in cases of uveitis. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with uveitis at 4 US academic ocular inflammation subspecialty practices. METHODS: Data were ascertained by standardized chart review. Prevalence data analysis used logistic regression. Incidence data analysis used survival analysis with time-updated covariates where appropriate. MAIN OUTCOME MEASURES: Prevalence and incidence of NV. RESULTS: Among uveitic eyes of 8931 patients presenting for initial evaluation, 106 of 13 810 eyes had NV (prevalence = 0.77%, 95% confidence interval [CI], 0.60-0.90). Eighty-eight more eyes developed NV over 26 465 eye-years (incidence, 0.33%/eye-year; 95% CI, 0.27-0.41). Factors associated with incident NV include age <35 years compared with >35 years (adjusted hazard ratio [aHR], 2.4; 95% CI, 1.5-3.9), current cigarette smoking (aHR, 1.9; 95% CI, 1.1-3.4), and systemic lupus erythematosus (aHR, 3.5, 95% CI, 1.1-11). Recent diagnosis of uveitis was associated with an increased incidence of NV (compared with patients diagnosed >5 years ago, aHR, 2.4 [95% CI, 1.1-5.0] and aHR, 2.6 [95% CI, 1.2-6.0] for diagnosis within <1 year vs. 1-5 years, respectively). Compared with anterior uveitis, intermediate uveitis (aHR, 3.1; 95% CI, 1.5-6.6), posterior uveitis (aHR, 5.2; 95% CI, 2.5-11), and panuveitis (aHR, 4.3; 95% CI, 2.0-9.3) were associated with a similar degree of increased NV incidence. Active (aHR, 2.1, 95% CI, 1.2-3.7) and slightly active (aHR, 2.4, 95% CI, 1.3-4.4) inflammation were associated with an increased incidence of NV compared with inactive inflammation. Neovascularization incidence also was increased with retinal vascular occlusions (aHR, 10, 95% CI, 3.0-33), retinal vascular sheathing (aHR, 2.6, 95% CI, 1.4-4.9), and exudative retinal detachment (aHR, 4.1, 95% CI, 1.3-13). Diabetes mellitus was associated with a somewhat increased incidence of retinal NV (aHR, 2.3, 95% CI, 1.1-4.9), and systemic hypertension (aHR 1.5, 95% CI, 0.89-2.4) was associated with nonsignificantly increased NV incidence. Results were similar in sensitivity analyses excluding the small minority of patients with diabetes mellitus. CONCLUSIONS: Retinal NV is a rare complication of uveitis, which occurs more frequently in younger patients, smokers, and those with intermediate/posterior/panuveitis, systemic vasculopathy, retinal vascular disease, or active inflammation. Inflammation and retinal NV likely are linked; additional studies are needed to further elucidate this connection.

OBJECTIVE: Postoperative diplopia occurs in up to 45% of patients following orbital decompression for exophthalmos associated with Graves' orbitopathy. We sought to describe outcomes of our balanced orbital decompression strategy that includes the preservation of a modified inferomedial orbital strut (mIOS). STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: A total of 115 consecutive orbital decompressions were performed on 73 patients (42 bilateral) with Graves' orbitopathy. All patients underwent (1) a balanced decompression technique incorporating an endoscopic medial and external lateral decompression and (2) a mIOS technique with preservation of the anterior half of the inferomedial orbital strut. A periorbital periosteal (orbital) sling was utilized in patients (n = 54) without threatened vision loss, proptosis >28 mm, or periorbital disruption to prevent prolapse of the medial rectus muscle. RESULTS: Utilization of the mIOS technique with or without a sling did not adversely affect the reduction in proptosis (5.1 mm with sling vs 5.0 mm without sling; P = .85).The incidence of new-onset postoperative diplopia was 17% (n = 6). The sling was not associated with postoperative diplopia (odds ratio = 0.54, 95% confidence interval: 0.08-3.40, P = .51), while it was associated with resolution of preexisting diplopia (odds ratio = 6.67, 95% confidence interval: 1.06-42.06, P = .04). No intraoperative complications occurred, and no patients suffered a decrement in visual acuity. CONCLUSION: Balanced orbital decompression utilizing a mIOS in patients with Graves' orbitopathy provides a safe and effective reduction in proptosis with a low rate of new-onset diplopia as compared with historical values. Utilization of an orbital sling may be beneficial in reducing postoperative diplopia in select patients.

PURPOSE: To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti-TNF-α antibody administration. METHODS: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100-300 μm in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti-TNF-α antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37°C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. RESULTS: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37°C for 1 month had no deleterious effects on antibody affinity. Anti-TNF-α release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. CONCLUSIONS: Sustained local delivery of anti-TNF-α antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. TRANSLATIONAL RELEVANCE: The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy.

PURPOSE: Intraocular vascular diseases are leading causes of adult vision loss, and in the mid-1900s, I. C. Michaelson postulated that the retina releases a soluble, diffusible factor that causes abnormal vascular growth and leakage. What became known as "Factor X" eluded investigators for decades. METHODS: The field of cancer research, where Judah Folkman pioneered the concept of angiogenesis, provided the inspiration for the work honored by the 2014 Champalimaud Vision Award. Recognizing that tumors recruit their own blood supply to achieve critical mass, Dr Folkman proposed that angiogenic factors could be therapeutic targets in cancer. Napoleone Ferrara identified vascular endothelial growth factor (VEGF) as such an angiogenic agent: stimulated by hypoxic tumor tissue, secreted, and able to induce neovascularization. VEGF also was a candidate for Factor X, and the 2014 Champalimaud Laureates and colleagues worked individually and collaboratively to identify the role of VEGF in ocular disease. RESULTS: The Champalimaud Laureates correlated VEGF with ocular neovascularization in animal models and in patients. Moreover, they showed that VEGF not only was sufficient, but it also was required to induce neovascularization in normal animal eyes, as VEGF inhibition abolished ocular neovascularization in key animal models. CONCLUSIONS: The identification of VEGF as Factor X altered the therapeutic paradigms for age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, and other retinal disorders. TRANSLATIONAL RELEVANCE: The translation of VEGF from discovery to therapy resulted in the most successful applications of antiangiogenic therapy to date. Annually, over one million patients with eye disease are treated with anti-VEGF agents.

BACKGROUND: Corneal allograft survival dramatically decreases in hosts with inflamed or vascularized recipient beds. We have previously shown that in rejected corneal allografts regulatory T cells (Treg) demonstrate diminished Foxp3 expression and immunoregulatory function. Treatment with low doses of IL-2 selectively expands Treg and has been proposed for the treatment of autoimmune diseases. In this study, we investigated the effect of low-dose IL-2 administration on Treg function and corneal allograft survival. METHODS: Allogeneic corneal transplantation was performed on inflamed host beds. Low-dose systemic IL-2 was administered starting 3 days before grafting until 6 weeks after transplantation. Frequencies of Treg and their immunosuppressive function and antigen specificity were assessed using flow cytometry, in vitro proliferation assays, and adoptive transfer experiments. Frequencies of effector T cells (Teff) and graft infiltrating immune cells were measured at 2 weeks posttransplantation. Long-term allograft survival was evaluated for up to 9 weeks using Kaplan-Meier survival analysis. RESULTS: Treatment with low-dose IL-2 significantly increased frequencies of CD4CD25Foxp3 Treg and their immunosuppressive function. It also suppressed alloimmune response as shown by the decreased CD4 IFNγ T cell frequencies and graft infiltration of CD45 and CD4 cells. Clinical evaluation of the grafts showed significant improvement in long-term corneal allograft survival in the IL-2 treated group compared with controls. CONCLUSIONS: Our study is the first to report that treatment with low-dose IL-2 increases survival of corneal allografts. We propose that IL-2-mediated Treg expansion can be an effective tool to prevent alloimmunity and to improve long-term allograft survival in transplantation.