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Yang M, Lippestad M, Hodges RR, Fjærvoll HK, Fjærvoll KA, Bair JA, Utheim TP, Serhan CN, Dartt DA. RvE1 uses the LTB receptor BLT1 to increase [Ca] and stimulate mucin secretion in cultured rat and human conjunctival goblet cells. Ocul Surf 2020;18(3):470-482.Abstract
PURPOSE: Specialized pro-resolving lipid mediator resolvin (Rv) E1 stimulates secretion including mucins from conjunctival goblet cells. RvE1 can use both its ChemR23 receptor and the LTB receptor BLT1 to increase [Ca]. The purpose of this study was to determine the expression of ChemR23 and BLT1 and receptors on conjunctival goblet cells and the respective roles these two receptors play in goblet cell responses to RvE1. METHODS: Goblet cells were cultured from male rat or human conjunctiva from both sexes. Western blotting analysis, reverse transcription PCR and immunofluorescence microscopy were used to demonstrate the expression of ChemR23 and BLT1 in conjunctival goblet cells. High molecular weight glycoprotein secretion was determined using an enzyme-linked lectin assay. Signaling pathways were studied by measuring the increase in [Ca] using fura 2/AM. RESULTS: ChemR23 and BLT1 and receptors were present on both rat and human conjunctival goblet cells. The BLT1 inhibitors LY293111 and U75302 significantly blocked RvE1-and LTB-stimulated [Ca] increase. RvE1-and LTB-stimulated [Ca] and secretion increases were blocked by BLT1-targeted siRNA. RvE1-stimulated [Ca] and secretion increases were also blocked by ChemR23-targeted siRNA. Addition of RvE1 2 min before or simultaneously with LTB desensitized the LTB [Ca] response. Addition of RvE1 and LTB simultaneously caused secretion that was decreased compared to either response alone. CONCLUSION: RvE1, in addition to the ChemR23 receptor, uses the BLT1 receptor to increase [Ca] and stimulate secretion in both rat and human cultured conjunctival goblet cells.
Chen EM, Armstrong GW, Cox JT, Wu DM, Hoover DR, Del Priore LV, Parikh R. Association of the Affordable Care Act Medicaid Expansion with Dilated Eye Examinations among the United States Population with Diabetes. Ophthalmology 2020;127(7):920-928.Abstract
PURPOSE: To evaluate the association between Medicaid expansion and diabetic dilated eye examinations. DESIGN: A retrospective difference in differences (DiD) analysis using individual-level survey response data from January 1, 2009, to December 31, 2017. PARTICIPANTS: A total of 52 392 survey responses from 50 states and the District of Columbia between 2009 and 2017. Responders were adults aged 18 to 64 years reporting a previous diagnosis of diabetes and a household income below 138% of the US federal poverty line (FPL). METHODS: The Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System data were used to identify survey responders who were asked about the presence of dilated eye examinations from years before and after Medicaid expansion implementation. MAIN OUTCOME MEASURES: The DiD in proportion of dilated eye examinations among diabetic persons aged 18 to 64 years with household incomes below 138% of the FPL between states that did and did not implement Medicaid expansion. RESULTS: Implementation of Medicaid expansion policies was associated with a 1.3% (95% confidence interval [CI], -3.8 to 6.4; P = 0.61), 6.3% (95% CI, 1.3-11.3; P = 0.016), 4.1% (95% CI, -0.8 to 9.0; P = 0.11), and 2.3% (95% CI, -1.6 to 6.2; P = 0.23) increase in the proportion of diabetic persons aged 18 to 64 years with incomes below 138% of the FPL receiving a dilated eye examination within the past year due to Medicaid expansion 1, 2, 3, and 4 cumulative years after expansion, respectively. CONCLUSIONS: Medicaid expansion policies were significantly associated with an increase in dilated eye examination rates within the first 2 years after implementation. However, this increase did not persist beyond this period, with nonsignificant increases 3 and 4 cumulative years after implementation. Healthcare policymakers should be aware that additional measures beyond expanding insurance coverage may be necessary to increase and sustain the rate of dilated eye examinations among diabetic populations.
Singh RB, Sinha S, Saini C, Elbasiony E, Thakur S, Agarwal A. Recent advances in the management of non-infectious posterior uveitis. Int Ophthalmol 2020;40(11):3187-3207.Abstract
PURPOSE: To review the current regimens and novel therapeutic modalities in various stages of research and development for the management of non-infectious posterior uveitis (NIPU). METHODS: We performed a thorough review of current literature using PubMed, Google Scholar and Clinicaltrials.gov to identify the published literature about the available therapeutics and novel drugs/therapies in different stages of clinical trials. RESULTS: The current management regimen for non-infectious posterior uveitis includes corticosteroids, immunomodulatory therapies and anti-metabolites. However, NIPU requires long-term management for efficacious remission of the disease and to prevent disease relapse. Long-term safety issues associated with steroids have led to efforts to develop novel therapeutic agents including biological response modulators and immunosuppressants. The current therapeutic agents in various stages of development include calcineurin inhibitors, biologic response modifiers and a more a comprehensive modalities like ocular gene therapy as well as novel drug delivery mechanisms for higher bioavailability to the target tissues, with minimal systemic effects. CONCLUSION: Novel efficacious therapeutic modalities under development will help overcome the challenges associated with the traditional therapeutic agents.
Hernandez-Llamas S, Paz-Ramos AK, Marcos-Gonzalez P, Amparo F, Garza-Leon M. Symptoms of ocular surface disease in construction workers: comparative study with office workers. BMC Ophthalmol 2020;20(1):272.Abstract
BACKGROUND: To investigate and contrast the prevalence of dry eye symptoms in construction workers and office workers using the OSDI questionnaire. METHODS: A cross-sectional, observational study was conducted using the OSDI questionnaire to evaluate dry eye symptoms and associated risk factors. Sampled size calculation with a power of 80% and a 95% degree of confidence suggested the inclusion of 298 participants. RESULTS: We studied 304 subjects (149 construction workers and 155 office workers). More than half (55%) of the participants presented dry eye symptoms (OSDI > 12). The average OSDI score was 21.30 ± 22.20 points, being lower in the group of construction workers (12.45 ± 17.50) than in-office workers (28.51 ± 22.99) (p <  0.001). Considering participants who had moderate and severe symptoms (23 to 100 points in OSDI), office workers presented dry eye symptoms 4.15 times more frequently than construction workers (OR 4.15, 95% CI 2.52, 6.85). Women presented statistical evidence of higher OSDI scores than men (32.47 ± 23.72 vs. 14.87 ± 18.48, respectively). CONCLUSIONS: construction workers have four times less risk of presenting dry eye symptoms than people working in the average office space. This highlights the pernicious effects on the ocular surface of the office environment, which poses a significant risk for the development or worsening of dry eye symptoms.
Wolkow N, Jakobiec FA, Gragoudas ES. LONG-TERM OBSERVATION OF MULTIFOCAL METASTATIC INTRAOCULAR CARCINOID WITH ACQUIRED IRIS HETEROCHROMIA. Retin Cases Brief Rep 2020;14(3):265-267.Abstract
BACKGROUND/PURPOSE: To report a unique case of a pulmonary carcinoid tumor unilaterally metastatic to the iris and ciliary body and bilaterally to the choroid that was conservatively followed. METHODS: A 46-year-old woman presented with bilateral choroidal lesions and a left iris tumor. Ultrasound biomicroscopy disclosed a ciliary body component. A diagnosis of metastatic carcinoid tumor was made based on the clinical features. Rather than an excision, photodynamic therapy, or radiation treatment, as has been reported in all previous cases of carcinoid tumor metastatic to the iris, the patient was observed. RESULTS: Excellent vision was maintained for 8 years. The iris tumor gradually enlarged, but the choroidal lesions remained unchanged. The iris with the carcinoid tumor gradually acquired a brown pigmentation; this is the first reported case of acquired iris heterochromia in the setting of carcinoid tumor. CONCLUSION: We conclude, in cases of metastatic carcinoid in which visual acuity is excellent and the patient is asymptomatic, that observation of the ocular lesions is an acceptable course of action. The iris heterochromia is believed to have been caused by secretory factors produced by the tumor.
Hellström A, Hellström W, Hellgren G, Smith LEH, Puttonen H, Fyhr I-M, Sävman K, Nilsson AK, Klevebro S. Docosahexaenoic Acid and Arachidonic Acid Levels Are Associated with Early Systemic Inflammation in Extremely Preterm Infants. Nutrients 2020;12(7)Abstract
Fetal and early postnatal inflammation have been associated with increased morbidity in extremely preterm infants. This study aimed to demonstrate if postpartum levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) were associated with early inflammation. In a cohort of 90 extremely preterm infants, DHA and AA in cord blood, on the first postnatal day and on postnatal day 7 were examined in relation to early systemic inflammation, defined as elevated C-reactive protein (CRP) and/or interleukin-6 (IL-6) within 72 h from birth, with or without positive blood culture. Median serum level of DHA was 0.5 mol% (95% CI (confidence interval) 0.2-0.9, = 0.006) lower than the first postnatal day in infants with early systemic inflammation, compared to infants without signs of inflammation, whereas levels of AA were not statistically different between infants with and without signs of inflammation. In cord blood, lower serum levels of both DHA (correlation coefficient -0.40; = 0.010) and AA (correlation coefficient -0.54; < 0.001) correlated with higher levels of IL-6. Levels of DHA or AA did not differ between infants with and without histological signs of chorioamnionitis or fetal inflammation. In conclusion, serum levels of DHA at birth were associated with the inflammatory response during the early postnatal period in extremely preterm infants.
Sinha S, Singh RB, Dohlman TH, Wang M, Taketani Y, Yin J, Dana R. Prevalence of Persistent Corneal Epithelial Defects in Chronic Ocular Graft-Versus-Host Disease. Am J Ophthalmol 2020;218:296-303.Abstract
PURPOSE: To establish the prevalence, clinical characteristics, and risk factors for persistent corneal epithelial defects (PED) in patients with chronic ocular graft-versus-host disease (oGVHD) and to determine visual outcomes after healing. DESIGN: Retrospective cohort study. METHODS: A chart review was conducted of patients in whom chronic oGVHD was diagnosed between January 2011 and December 2018 and their demographic and clinical characteristics were collected. Data were analyzed to determine prevalence of PED, and multivariate logistic regression was performed to determine the risk factors associated with it. RESULTS: A total of 405 patients at a mean age of 60 ± 13 years in whom chronic oGVHD was diagnosed; 58% were men. The prevalence of PED was 8.1%. The median time for PED development after hematopoietic stem cell transplantation was approximately 24 months. Median time to PED resolution was 4.5 weeks after starting therapy. The mean best-corrected visual acuity declined by 2 lines post-PED resolution. The prevalence rates of corneal ulcer and perforation were 6.2% and 4.0%, respectively, over 8 years. Logistic regression analysis, used to determine factors associated with PED, showed diabetes (P = .006), limbal stem cell deficiency (LSCD) (P = .02), filamentary keratitis (P = .02), subconjunctival fibrosis (P = .02), and a higher National Institutes of Health (NIH) oGVHD score (P = .01) were significant risk factors for PED development. CONCLUSIONS: The study found the prevalence rate of PED, corneal ulceration, and corneal perforation in chronic oGVHD to be 8.1%, 6.2%, and 4%, respectively. Analysis showed that oGVHD patients with diabetes, LSCD, filamentary keratitis, subconjunctival fibrosis, and a high NIH score were at higher risk of developing severe corneal disease.
Chan CSY, Lonfat N, Zhao R, Davis AE, Li L, Wu M-R, Lin C-H, Ji Z, Cepko CL, Wang S. Cell type- and stage-specific expression of Otx2 is regulated by multiple transcription factors and -regulatory modules in the retina. Development 2020;147(14)Abstract
Transcription factors (TFs) are often used repeatedly during development and homeostasis to control distinct processes in the same and/or different cellular contexts. Considering the limited number of TFs in the genome and the tremendous number of events that need to be regulated, re-use of TFs is necessary. We analyzed how the expression of the homeobox TF, orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during development in the mouse retina. We identified seven -regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. We discovered that Otx2, Crx and Sox2, which are well-known TFs regulating retinal development, bind to and activate the O5, O7 or O9 CRMs, respectively. The chromatin status of these three CRMs was found to be distinct in different retinal cell types and at different stages. We conclude that retinal cells use a cohort of TFs with different expression patterns and multiple CRMs with different chromatin configurations to regulate the expression of Otx2 precisely.
Freitag SK, Aakalu VK, Tao JP, Wladis EJ, Foster JA, Sobel RK, Yen MT. Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancy: A Report by the American Academy of Ophthalmology. Ophthalmology 2020;127(12):1757-1765.Abstract
PURPOSE: To determine the efficacy and safety of sentinel lymph node biopsy (SLNB) in the management of eyelid and conjunctival malignancy. METHODS: A literature search was performed in August 2019 and January 2020 for articles published in English in the PubMed and Cochrane Library databases. This search yielded 151 articles that were reviewed for relevancy, of which 27 were deemed to have met the inclusion criteria for this assessment. The data from these articles were abstracted and the articles were rated for strength of evidence by the panel methodologist. RESULTS: All 27 studies were rated level III, and a total of 197 SLNBs were reported. Diagnoses included conjunctival and eyelid cutaneous melanoma (85 and 42 patients, respectively), sebaceous gland carcinoma (35 patients), squamous cell carcinoma (26 patients), Merkel cell carcinoma (6 patients), pigmented epithelioid melanocytoid tumor (1 patient), mucoepidermoid carcinoma (1 patient), and signet ring carcinoma (1 patient). Tracer was found in regional lymph nodes in 100% of patients in 21 of 27 articles and in 191 of 197 patients overall. The number of lymph nodes removed ranged from 1 to 16, with most ranging from 1 to 5. Tumor-positive lymph nodes were found in 33 of 197 patients (16.8%), prompting recommendations for adjuvant treatments. Survival data were reported for 16 of these patients, with follow-up periods ranging from 3 to 36 months (average, 12.7 months). Fourteen of 16 patients received adjuvant treatments. Nine were alive and well, 1 was alive with metastases, and 6 had died of metastatic disease (including 2 patients who declined additional treatment). False-negative SLNB results were reported in 5 articles involving 9 of 197 procedures (4.6%). Complications were documented in 7 of 27 articles and included transient facial nerve weakness, persistent blue dye staining of the conjunctiva, neck hematoma, and suture abscess. CONCLUSIONS: Sentinel lymph node biopsy is a promising procedure in patients with eyelid and conjunctival malignancy, and it is useful in identifying sentinel lymph nodes. However, at present, insufficient evidence exists showing that SLNB improves patient outcomes and survival. Recognition of microscopic metastatic disease may prove beneficial in staging and guiding adjuvant therapy.
Bayraktutar BN, Ozmen CM, Muzaaya N, Dieckmann G, Koseoglu DN, Müller RT, Cruzat A, Cavalcanti BM, Hamrah P. Comparison of clinical characteristics of post-refractive surgery-related and post-herpetic neuropathic corneal pain. Ocul Surf 2020;Abstract
PURPOSE: To compare the clinical characteristics and in vivo confocal microscopy (IVCM) findings of patients with neuropathic corneal pain (NCP) due to refractive surgery (RS-NCP) and herpetic eye disease (H-NCP) to controls. METHODS: Sixteen patients with RS-NCP and 7 patients with H-NCP, and 37 healthy reference age- and sex-matched healthy controls were included to the study. The medical records were reviewed for demographic features, detailed disease history, ocular surface disease index (OSDI), ocular pain assessment survey (OPAS) scores. IVCM images of patients were analyzed and compared to reference controls by two masked observers. RESULTS: The mean pain intensity score for the last 24 h (5.1 ± 2.4 vs. 3.9 ± 1.2; p = 0.27), last 2 weeks (6.1 ± 2.5 vs. 4.8 ± 2.3; p = 0.13) for RS-NCP vs. H-NCP respectively, and quality of life scores (p = 0.23) were similar in both groups. Quality of life, especially mood (p = 0.06) and enjoying life/relations to others (p = 0.10) were affected in both groups, but were not statistically significant between groups. The mean total nerve density was lower in RS-NCP (5702.4 ± 4599.0 μm/mm) compared to their respective controls (26,422.8 ± 4491.0; p < 0.001) and in the H-NCP group (2149.5 ± 2985.9) compared to their respective controls (22,948.8 ± 3169.0; p < 0.001). Alterations in DC density were similar between all groups (38.3 ± 48.0 cells/mm in RS-NCP, 61.0 ± 76.9 in H-NCP, p = 0.95). CONCLUSION: Neuropathic corneal pain patients due to refractive surgery show similar clinical characteristics, pain levels, quality of life impact, and IVCM findings as patients with NCP due to herpetic eye disease.
Haque M, Lei F, Xiong X, Ren Y, Kumar A, Das JK, Ren X, Fang D, de Figueiredo P, Yang J-M, Song J. Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HBV Replication through Production of IFN-γ and TNF-⍺. iScience 2020;23(7):101333.Abstract
The viral antigen (Ag)-specific CD8 cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress hepatitis B virus (HBV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the liver to suppress HBV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs provoke the antiviral response remain to be fully elucidated. In this study, we generated the functional HBV surface Ag-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the underlying mechanisms of the CTL-mediated antiviral replication in a murine model. We show that adoptive transfer of HBV surface Ag-specific iPSC-CTLs greatly suppressed HBV replication and prevented HBV surface Ag expression. We further demonstrate that the adoptive transfer significantly increased T cell accumulation and production of antiviral cytokines. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the liver and suppress HBV replication through producing antiviral cytokines.
Kempen JH, Van Natta ML, Friedman DS, Altaweel MM, Ansari H, Dunn JP, Elner SG, Holbrook JT, Lim LL, Sugar EA, Jabs DA, and Group MUST (MUST) TF-up SR. Incidence and Outcome of Uveitic Glaucoma in Eyes With Intermediate, Posterior, or Panuveitis Followed up to 10 Years After Randomization to Fluocinolone Acetonide Implant or Systemic Therapy. Am J Ophthalmol 2020;219:303-316.Abstract
PURPOSE: To evaluate long-term risk and outcomes of glaucoma in eyes with intermediate, posterior, and panuveitis managed with systemic or fluocinolone acetonide (0.59 mg, "implant") therapy. DESIGN: Prospective Follow-up of the Multicenter Uveitis Steroid Treatment (MUST) Clinical Trial Cohort. METHODS: Patients with intermediate, posterior, or panuveitis randomized to implant or systemic therapy (corticosteroid plus immunosuppression in >90%) were followed prospectively for glaucoma incidence and outcome. RESULTS: Among 405 uveitic at-risk eyes of 232 patients (median follow-up = 6.9 years), 40% (79/196) of eyes assigned and treated with implant and 8% (17/209) of eyes assigned and treated with systemic therapy (censoring eyes receiving an implant on implantation) developed glaucoma (hazard ratio [HR] = 5.9, 95% confidence interval [CI] 3.2, 10.8; P < .001). Adjustment for intraocular pressure (IOP) elevation during follow-up only partially mitigated the association of implant treatment with glaucoma incidence: HR = 3.1 (95% CI 1.6, 6.0); P = .001. Among 112 eyes of 83 patients developing glaucoma, the 5-year cumulative incidence following diagnosis of sustained (2 or more consecutive visits) worsening of mean deviation by ≥6 dB was 20% (95% CI 12%, 33%); 5-year cumulative incidence of sustained worsening of cup-to-disc ratio by ≥0.2 was 26% (95% CI 17%, 39%). CONCLUSIONS: The implant has substantially higher risk of glaucoma than systemic therapy, a difference not entirely explained by posttreatment IOP elevation. Management of IOP elevation was effective in preventing worsening of glaucoma for the large majority of cases, but even under expert clinical management, some glaucoma worsened. Uveitis cases should be monitored carefully for IOP elevation and glaucoma indefinitely.
Jakobiec FA, Hanbazazh M, Barrantes PC, Chodosh J. Adult Primary Capillary Hemangioma of the Sclera: A Previously Undescribed Entity With a Review of Epibulbar Vascular Lesions. Ophthalmic Plast Reconstr Surg 2020;36(4):327-333.Abstract
PURPOSE: The objective of this article is to document a unique case of a primary hemangioma and review epibulbar vascular tumors of the conjunctiva and episclera. METHODS: A case report with detailed histopathologic, histochemical, and immunohistochemical studies coupled with a comprehensive review of the relevant literature with a tabulation of previously reported epibulbar vascular lesions was performed. RESULTS: A vascular tumor developed in a 46-year-old woman over 2-3 months that histopathologically was located in the superficial third of the normally avascular sclera and was composed of capillary caliber vessels. CD31 and CD34 positivity established the vascular nature of the lesion. Despite its adult onset, the tumor was also glut-1 positive, a vascular characteristic of childhood capillary hemangiomas that will ultimately involute. Smooth muscle actin was positive in the endothelial cells and associated pericytes. An ectatic muscular vessel identified in the midst of the lesion was interpreted as an anomalous intrascleral branch of an epibulbar anterior ciliary artery, where it perforated the sclera in the vicinity of the insertion of an extraocular rectus muscle. It was deduced to be the source of the capillary proliferation. A literature review failed to identify any previously reported epibulbar vascular tumor that originated primarily in the sclera or secondarily infiltrated this ocular tunic. CONCLUSION: An adult primary capillary intrascleral neoplasm is described as the rarest of all epibulbar vascular tumors and in keeping with the exceptional status of the ocular endothelium was glut-1 positive. This lesion must be distinguished from an array of other common and esoteric epibulbar vascular conditions.

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