Substance P (SP) is a tachykinin neuropeptide, implicated in the pathogenesis of various inflammatory conditions and a critical mediator in pain transmission. Recently, the role of SP was described in the pathogenesis of dry eye disease (DED) through its role in the maturation of antigen-presenting cells at the ocular surface after exposure to desiccating stress. However, the effect of SP on regulatory T cells (Tregs), which are functionally impaired in DED, remains unclear. This study examined the phenotypic and functional changes in Tregs in response to SP in DED. The in vitro cultures of normal Tregs in the presence of SP led to a significant reduction in both Treg frequencies and their suppressive function, which was prevented by the addition of an SP receptor (neurokinin-1 receptor) antagonist. Furthermore, in vivo treatment with the neurokinin-1 receptor antagonist in DED mice effectively restored Treg function, suppressed pathogenic T helper 17 response, and significantly ameliorated the disease. Our results show that a significant increase in SP levels promotes Treg dysfunction in DED, and blockade of SP effectively restores Treg function and suppresses DED severity.
PURPOSE: To report outcomes of secondary intraocular lens (IOL) implantation in the Infant Aphakia Treatment Study (IATS) SETTING:: Multicenter clinical practice DESIGN:: Secondary analysis of patients enrolled in a randomized clinical trial METHODS:: Details regarding all secondary IOL surgeries conducted in children enrolled in the IATS were compiled. We evaluated visual outcomes, refractive outcomes, and adverse events at age 10 ½ years. Comparisons were made to eyes that remained aphakic and to eyes randomized to primary IOL placement. RESULTS: 55/57 patients randomized to aphakia with contact lens correction were seen for the 10 ½ year study visit; 24/55 eyes (44%) had secondary IOL surgery. Median age at IOL surgery was 5.4 years (range 1.7 to 10.3 years). Mean absolute prediction error was 1.0 ± 0.7D. At age 10 ½ years, the median log MAR VA was 0.9 (range 0.2 to 1.7), similar to VA in the 31 eyes still aphakic (0.8, range 0.1 to 2.9); the number of eyes with stable or improved VA scores between the 4 ½ and 10 ½ year study visits was also similar (78% secondary IOL eyes, 84% aphakic eyes). For eyes undergoing IOL implantation after the 4.5 year study visit (n=22), the mean refraction at age 10 ½ years was -3.2 ±2.7D (range -9.9D to 1.1D), compared to -5.5 ±6.6 D (n=53, range -26.5 to 3.0D) in eyes with primary IOL (p=0.03). CONCLUSIONS: Delayed IOL implantation allows a more predictable refractive outcome at age 10 ½ years, though the range of refractive error is still large.
The damage or loss of retinal ganglion cells (RGCs) and their axons accounts for the visual functional defects observed after traumatic injury, in degenerative diseases such as glaucoma, or in compressive optic neuropathies such as from optic glioma. By using optic nerve crush injury models, recent studies have revealed the cellular and molecular logic behind the regenerative failure of injured RGC axons in adult mammals and suggested several strategies with translational potential. This review summarizes these findings and discusses challenges for developing clinically applicable neural repair strategies.
PURPOSE: The purpose of this assessment is to evaluate the accuracy of autorefraction compared with cycloplegic retinoscopy in children. METHODS: Literature searches were last conducted in October 2019 in the PubMed and the Cochrane Library databases for studies published in English. The combined searches yielded 118 citations, of which 53 were reviewed in full text. Of these, 31 articles were deemed appropriate for inclusion in this assessment and subsequently assigned a level of evidence rating by the panel methodologists. Four articles were rated level I, 11 were rated level II, and 16 were rated level III articles. The 16 level III articles were excluded from this review. RESULTS: Thirteen of the 15 studies comparing cycloplegic autorefraction with cycloplegic retinoscopy found a mean difference in spherical equivalent or sphere of less than 0.5 diopters (D); most were less than 0.25 D. Even lower mean differences were found when evaluating the cylindrical component of cycloplegic autorefraction versus cycloplegic retinoscopy. Despite low mean variability, there was significant individual measurement variability; the 95% limits of agreement were wide and included clinically relevant differences. Comparisons of noncycloplegic with cycloplegic autorefractions found that noncyloplegic refraction tends to over minus by 1 to 2 D. CONCLUSIONS: Cycloplegic autorefraction is appropriate to use in pediatric population-based studies. Cycloplegic retinoscopy can be valuable in individual clinical cases to confirm the accuracy of cycloplegic autorefraction, particularly when corrected visual acuity is worse than expected or the autorefraction results are not consistent with expected findings.
PURPOSE: To review the literature on the efficacy of intense pulsed light (IPL) on the eyelids in the management of meibomian gland disease (MGD) and meibomian gland-related ocular surface disease. METHODS: A literature search was last conducted on May 15, 2019, in the PubMed and Cochrane Library databases for English-language original research that assessed the effect of IPL on MGD in adult patients. Thirty-three articles were identified, and 12 studies were determined to be relevant to the criteria outlined for assessment. The panel methodologist (V.K.A.) assigned a level of evidence rating to each study; 4 studies were rated level II, and 8 studies were rated level III. Five studies had potential conflicts of interest and design limitations that affected interpretation of results. RESULTS: All studies documented improvement in clinically meaningful metrics, including tear breakup time (TBUT), corneal staining and eyelid margin measurements, meibum quality, meibomian gland expressability, ocular surface disease index (OSDI), and standard patient evaluation of eye dryness (SPEED) questionnaire scores. Side effects were relatively uncommon but included discomfort, cutaneous erythema, blistering, eyelash loss, and floaters; these were uniformly self-limited. CONCLUSIONS: Although methodological limitations and potential conflicts of interest in some studies raised concern, the existing body of literature demonstrates improvements in the signs and symptoms of MGD after IPL therapy.
In visual search tasks, observers look for targets among distractors. In the lab, this often takes the form of multiple searches for a simple shape that may or may not be present among other items scattered at random on a computer screen (e.g., Find a red T among other letters that are either black or red.). In the real world, observers may search for multiple classes of target in complex scenes that occur only once (e.g., As I emerge from the subway, can I find lunch, my friend, and a street sign in the scene before me?). This article reviews work on how search is guided intelligently. I ask how serial and parallel processes collaborate in visual search, describe the distinction between search templates in working memory and target templates in long-term memory, and consider how searches are terminated.
PURPOSE: To determine if there is a biologic rationale for using checkpoint inhibitor drugs targeting programmed cell death ligand 1 (PD-L1) and PD-L2 in the treatment of adenoid cystic carcinoma of the orbit. METHODS: Twenty-three cases of adenoid cystic carcinoma involving the orbit (13 primary lacrimal gland, 5 secondarily extending into the orbit, and 5 unspecified) were examined histopathologically. Immunohistochemistry for PD-L1, PD-L2, and CD8 was performed. Charts were reviewed for clinical correlations. RESULTS: Expression of PD-L1 and of PD-L2 was overall low in adenoid cystic carcinoma (mean expression 1.4 ± 0.9 of 5 for PD-L1, mean 0.83 ± 1.1 of 5 for PD-L2), and tumor-infiltrating CD8-positive T-lymphocytes were sparse (mean 1.1 ± 0.51 of 3). Only 13 of the 23 (57%) cases expressed PD-L1 as a combined positive score ≥1 of cells. No associations were found between expression levels of these markers and patient sex, tumor site of origin, Tumor, Node, Metastasis stage, or patient outcome. A significant association was observed between stromal PD-L1 expression and tumor histopathologic subtype (p = 0.05), and between tumor PD-L1 expression and prior exposure to radiation (p = 0.03). CONCLUSIONS: Checkpoint inhibitor drugs may have limited impact in the treatment and clinical course of orbital adenoid cystic carcinoma based on the low frequency of CD8 infiltrate and low expression of PD-L1 and PD-L2. Pretreatment with radiation, however, may improve tumor response to checkpoint inhibitor drugs.
Leukotriene B4 (LTB4) is a major proinflammatory mediator important in host defense, whereas resolvins (Rvs) are produced during the resolution phase of inflammation. The authors determined the actions of both RvE1 and RvD1 on LTB4-induced responses of goblet cells cultured from rat conjunctiva. The responses measured were an increase in the intracellular [Ca] ([Ca]) and high-molecular-weight glycoprotein secretion. Treatment with RvE1 or RvD1 for 30 minutes significantly blocked the LTB4-induced [Ca] increase. The actions of RvE1 on LTB4-induced [Ca] increase were reversed by siRNA for the RvE1 receptor, and the actions of RvD1 were reversed by an RvD1 receptor inhibitor. The RvE1 and RvD1 block of LTB4-stimulated increase in [Ca] was also reversed by an inhibitory peptide to β-adrenergic receptor kinase. LTB4 and block of the LTB4-stimulated increase in [Ca] by RvE1 and RvD1 were partially mediated by the depletion of intracellular Ca stores. RvE1, but not RvD1, counterregulated the LTB4-induced high-molecular-weight glycoprotein secretion. Thus, both RvE1 and RvD1 receptors directly inhibit LTB4 by phosphorylating the LTB4 receptor using β adrenergic receptor kinase. RvE1 receptor counterregulates the LTB4-induced increase in [Ca] and secretion, whereas RvD1 receptor only counterregulates LTB4-induced [Ca] increase.
PURPOSE: To develop an artificial intelligence (AI) dashboard for monitoring glaucomatous functional loss. DESIGN: Retrospective, cross-sectional, longitudinal cohort study. PARTICIPANTS: Of 31 591 visual fields (VFs) on 8077 subjects, 13 231 VFs from the most recent visit of each patient were included to develop the AI dashboard. Longitudinal VFs from 287 eyes with glaucoma were used to validate the models. METHOD: We entered VF data from the most recent visit of glaucomatous and nonglaucomatous patients into a "pipeline" that included principal component analysis (PCA), manifold learning, and unsupervised clustering to identify eyes with similar global, hemifield, and local patterns of VF loss. We visualized the results on a map, which we refer to as an "AI-enabled glaucoma dashboard." We used density-based clustering and the VF decomposition method called "archetypal analysis" to annotate the dashboard. Finally, we used 2 separate benchmark datasets-one representing "likely nonprogression" and the other representing "likely progression"-to validate the dashboard and assess its ability to portray functional change over time in glaucoma. MAIN OUTCOME MEASURES: The severity and extent of functional loss and characteristic patterns of VF loss in patients with glaucoma. RESULTS: After building the dashboard, we identified 32 nonoverlapping clusters. Each cluster on the dashboard corresponded to a particular global functional severity, an extent of VF loss into different hemifields, and characteristic local patterns of VF loss. By using 2 independent benchmark datasets and a definition of stability as trajectories not passing through over 2 clusters in a left or downward direction, the specificity for detecting "likely nonprogression" was 94% and the sensitivity for detecting "likely progression" was 77%. CONCLUSIONS: The AI-enabled glaucoma dashboard, developed using a large VF dataset containing a broad spectrum of visual deficit types, has the potential to provide clinicians with a user-friendly tool for determination of the severity of glaucomatous vision deficit, the spatial extent of the damage, and a means for monitoring the disease progression.
PURPOSE: To evaluate the efficacy of combined pneumatic and enzymatic vitreolysis for treatment of severe cases of vitreomacular traction (VMT). METHODS: We analyzed a retrospective, consecutive series of five patients diagnosed with severe VMT refractory to pneumatic vitreolysis (PV) who then received an additional ocriplasmin injection while their gas bubble from PV was still present between February 2015 to February 2019. VMT release was confirmed using spectral domain optical coherence tomography (OCT). RESULTS: Four out of 5 patients treated with combined pneumatic and enzymatic vitreolysis achieved VMT release by day 28, and all cases eventually achieved complete VMT release. In addition to having VMT refractory to PV, patient characteristics included broad adhesion diameter (>1500 μm, n=1), presence of epiretinal membrane (n=2), age > 65 years (n=4), and pseudophakia (n=1). Visual acuity (VA) improved by 3 or more lines at 6 months in both of the patients with initial vision worse than 20/50 on an ETDRS chart but not in those whose vision was already fairly good (i.e. VA > 20/60). None of the patients experienced the following complications after receiving this combined treatment: retinal tears or detachments, vitreous floaters, and ellipsoid zone changes. CONCLUSION: Sequential, combined pneumatic and enzymatic vitreolysis resulted in VMT release in all 5 cases (4 cases by 28 days) and may be a potentially useful alternative to surgical intervention for refractory VMT cases.