July 2021

PURPOSE: To study acquired vitelliform-like lesions (AVLL) and their diagnostic and prognostic values in uveitis. PATIENTS AND METHODS: This was a retrospective case series. The clinical course, diagnostic value, and prognostic significance of AVLL were compared between uveitic patients with AVLL and uveitic patients without AVLL. RESULTS: Twelve patients (21 eyes) with both uveitis and AVLL (study group) and thirteen patients (24 eyes) without AVLL (control group) were included in the study. Macular leakage (p = .005), the presence of vasculitis (p = .01), the presence of active choroiditis (p = .01), and the presence of CME on OCT (p = .008) were significantly higher in the AVLL group compared to the control group. Best-corrected visual acuity was significantly lower at presentation (p < .001) and the last follow-up visit (p = .014) in the AVLL group. CONCLUSION: The presence of acquired vitelliform-like lesion can have both a diagnostic (uveitis as a differential diagnosis) and prognostic value in patients with different types of uveitis.

Importance: Big data studies may allow for the aggregation of patients with rare diseases such as uveitis to answer important clinical questions. Standardization of uveitis-related variables will be necessary, including the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes used to identify patients of interest. There are currently limited data on the uniformity of diagnosis mapping to ICD-10 codes for uveitis diagnoses among different health systems. Objective: To assess the degree of uniformity in mapping of uveitis clinical concepts to ICD-10 codes across health care systems using the same electronic health record (EHR) system. Design, Setting, and Participants: This multicenter survey study was conducted between September 14 and October 9, 2020, at 5 academic health care systems that use the Epic EHR. Researchers from the University of Washington, Harvard University, Stanford University, Yale University, and the University of California, San Francisco queried 54 uveitis-related diagnostic terms and recorded the associated ICD-10 codes. Main Outcomes and Measures: The degree of uniformity for uveitis clinical concepts and associated ICD-10 codes. Results: Fifty-four uveitis-related diagnostic terms were queried within the Epic EHR at 5 different health care systems. There was perfect agreement among all 5 centers for 52 of the 54 diagnostic terms. Two diagnostic terms had differences in ICD-10 coding: juvenile idiopathic arthritis associated chronic uveitis and intermediate uveitis. Intermediate uveitis was associated with codes H20.1x (ICD-10 description: chronic iridocyclitis) or H20.9 (ICD-10 description: unspecified iridocyclitis) in 3 centers while being associated with code H30.2x (ICD-10 description: posterior cyclitis) at the 2 remaining centers. The discrepancies appear to be related to a recent update in diagnostic mapping in the Epic EHR. Conclusions and Relevance: This study suggests that ICD-10 code mapping to uveitis diagnostic terminology appears to be highly uniform at different centers with the Epic EHR. However, temporal changes in diagnosis mapping to ICD-10 codes and a lack of 1-to-1 mapping of diagnosis to ICD-10 code add additional sources of complexity to the interpretation of big data studies in uveitis.

Our previous studies found that the C-X-C motif chemokine receptor 5 (CXCR5) loss leads to retinal pigment epithelium (RPE) dysfunction and AMD pathogenesis. The current study aimed to characterize the G protein-coupled receptor (GPCR) structure of CXCR5 and analyze its interactions with AMD-related risk genes. The sequence alignments, homology model of CXCR5 and structural assessment analysis were performed. Data and text mining were then performed to identify AMD-related risk genes and their interaction with CXCR5 using statistical and mathematical algorithms. Sequence alignment and phylogenetic tree analysis revealed that human CXCR5 was highly similar (85.4839%) to the rabbit. The least similarity (33.871%) was found to be in zebrafish compared to the other species. The CXCR5 model structural assessment and secondary structure analysis exhibited an excellent model. Network analysis revealed that IL10, TNF, ICAM1, CXCL1, CXCL8, APP, TLR4, SELL, C3, IL17A and CCR2 were the most connected genes CXCR5. These findings suggest that CXCR5 signaling may regulate the biological function of RPE and modulate AMD pathophysiology via GPCR signaling and interacting with identified AMD risk genes. In summary, the data presented here provide novel and crucial insights into the molecular mechanisms of CXCR5 involvement in AMD.Communicated by Ramaswamy H. Sarma.

BACKGROUND AND PURPOSE: Age-related macular degeneration is associated with reduced perfusion of the eye; however, the role of altered blood flow in the upstream ophthalmic or internal carotid arteries is unclear. We used ultra-high-field MR imaging to investigate whether the diameter of and blood flow in the ophthalmic artery and/or the ICA are altered in age-related macular degeneration and whether any blood flow changes are associated with disease progression. MATERIALS AND METHODS: Twenty-four patients with age-related macular degeneration and 13 similarly-aged healthy controls participated. TOF and high-resolution dynamic 2D phase-contrast MRA (0.26 × 0.26 × 2mm3, 100-ms effective sampling rate) was acquired at 7T. Vessel diameters were calculated from cross-sectional areas in phase-contrast acquisitions. Blood flow time-series were measured across the cardiac cycle. RESULTS: The ophthalmic artery vessel diameter was found to be significantly smaller in patients with age-related macular degeneration than in controls. Volumetric flow through the ophthalmic artery was significantly lower in patients with late age-related macular degeneration, with a significant trend of decreasing volumetric ophthalmic artery flow rates with increasing disease severity. The resistance index was significantly greater in patients with age-related macular degeneration than in controls in the ophthalmic artery. Flow velocity through the ophthalmic artery and ICA was significantly higher in patients with age-related macular degeneration. Ophthalmic artery blood flow as a percentage of ipsilateral ICA blood flow was nearly double in controls than in patients with age-related macular degeneration. CONCLUSIONS: These findings support the hypothesis that vascular changes upstream to the eye are associated with the severity of age-related macular degeneration. Additional investigation into the potential causality of this relationship and whether treatments that improve ocular circulation slow disease progression is warranted.

Graft-versus-host disease is a common complication following allogeneic hematopoetic stem cell transplantation that can affect multiple organ systems, including the eyes. Ocular GVHD (oGVHD) is characterized by a T cell-mediated immune response that leads to immune cell infiltration and inflammation of ocular structures, including the lacrimal glands, eyelids, cornea and conjunctiva. oGVHD has a significant negative impact on visual function and quality of life and successful management requires a multi-disciplinary approach with frequent monitoring. Here, we review the pathophysiology and clinical presentation of oGVHD, along with current therapeutic strategies based on our clinical experience and the reported literature.

Post-keratoplasty infectious keratitis (PKIK) represents a unique clinical entity that often poses significant diagnostic and therapeutic challenges. It carries a high risk of serious complications such as graft rejection and failure, and less commonly endophthalmitis. Topical corticosteroids are often required to reduce the risk of graft rejection but their use in PKIK may act as a double-edged sword, particularly in fungal infection. The increased uptake in lamellar keratoplasty in the recent years has also led to complications such as graft-host interface infectious keratitis (IIK), which is particularly difficult to manage. The reported incidence of PKIK differs considerably across different countries, with a higher incidence observed in developing countries (9.2-11.9%) than developed countries (0.02-7.9%). Common risk factors for PKIK include the use of topical corticosteroids, suture-related problems, ocular surface diseases and previous corneal infection. PKIK after penetrating keratoplasty or (deep) anterior lamellar keratoplasty is most commonly caused by ocular surface commensals, particularly Gramme-positive bacteria, whereas PKIK after endothelial keratoplasty is usually caused by Candida spp. Empirical broad-spectrum antimicrobial treatment is the mainstay of treatment for both PKIK, though surgical interventions are required in medically refractory cases (during the acute phase) and those affected by visually significant scarring (during the late phase). In this paper, we aim to provide a comprehensive overview on PKIK, encompassing the epidemiology, risk factors, causes, management and outcomes, and to propose a treatment algorithm for systematically managing this challenging condition.

Defining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8+ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.

Purpose: A larger display at the same viewing distance provides relative-size magnification for individuals with central vision loss (CVL). However, the resulting large visible area of the display is expected to result in more head rotation, which may cause discomfort. We created a zoom magnification technique that placed the center of interest (COI) in the center of the display to reduce the need for head rotation. Methods: In a 2 × 2 within-subject study design, 23 participants with CVL viewed video clips from 1.5 m (4.9 feet) shown with or without zoom magnification, and with a large (208 cm/82" diagonal, 69°) or a typical (84 cm/33", 31°) screen. Head position was tracked and a custom questionnaire was used to measure discomfort. Results: Video comprehension was better with the large screen (P < 0.001) and slightly worse with zoom magnification (P = 0.03). Oddly, head movements did not vary with screen size (P = 0.63), yet were greater with zoom magnification (P = 0.001). This finding was unexpected, because the COI remains in the center with zoom magnification, but moves widely with a large screen and no magnification. Conclusions: This initial attempt to implement the zoom magnification method had flaws that may have decreased its effectiveness. In the future, we propose alternative implementations for zoom magnification, such as variable magnification. Translational Relevance: We present the first explicit demonstration that relative-size magnification improves the video comprehension of people with CVL when viewing video.

PURPOSE: To evaluate the best-corrected visual acuity and stereoacuity gains in children >7 years of age and adults with unilateral amblyopia treated with a prototype virtual reality-based binocular amblyopia therapy. METHODS: In this randomized, double masked, cross-in clinical trial, patients at Boston Children's Hospital with unilateral anisometropic and/or strabismic amblyopia and history of prior amblyopia treatment failure were randomized to either a full-treatment group (8 weeks of binocular treatment using therapeutic software application in virtual reality headset) or a sham-crossover group (4 weeks of sham treatment followed by 4 weeks of binocular treatment). Amblyopic eye visual acuity and stereoacuity were evaluated at 4, 8, and 16 weeks' follow-up. RESULTS: The study cohort included 20 participants (10 females), with a median age of 9 years (range, 7-38 years). In the full-treatment group (11 patients), the mean amblyopic eye logMAR visual acuity at 16 weeks was 0.49 ± 0.26, compared with 0.47 ± 0.20 at baseline. In the sham-crossover group, it was 0.51 ± 0.18 at 16 weeks, compared with 0.53 ± 0.21 at baseline. Stereoacuity (log arcsec) was significantly improved, from 7.3 ± 2 at baseline to 6.6 ± 2.3 at 8 weeks (P < 0.001) and 6.7 ± 2.6 at 16 weeks (P < 0.001). No significant adverse events (diplopia, asthenopia, or worsening strabismus) were noted in either group. CONCLUSIONS: Although the virtual reality-based prototype for binocular amblyopia therapy did not significantly improve visual acuity in the amblyopic eyes of older children and adults, stereoacuity did significantly improve compared with baseline; improvements were clinically minute. However, larger studies are required to confirm the results.

Objective: Gastric adenocarcinoma originates from the glands in the superficial layer or mucosa of the stomach. It is prone to metastases, of which ocular metastasis (OM) is rare, but once it occurs the disease is considered more serious. The aim of this study was to investigate the risk factors for OM in gastric adenocarcinoma. Methods: Patients with gastric adenocarcinoma were recruited to this study between June 2003 and July 2019. Demographic data and serological indicators (SI) were compared between patients with and without OM, and binary logistic regression was used to explore whether the relevant SI may be risk factors for OM of gastric adenocarcinoma. Receiver operating characteristic (ROC) curves were used to analyze different SIs for OM in gastric cancer patients. Results: Chi-square tests showed significant between-groups difference in gender composition (P < 0.05), but not in age or histological grade (P > 0.05). t-test results showed that low-density lipoprotein (LDL) and carbohydrate antigen-724 (CA724) were significantly higher in patients with than without OM (P < 0.05). Binary logistic regression analysis showed that LDL was an independent risk factor for OM (P < 0.001). ROC curve analysis showed that the areas under the curves (AUC) for LDL and CA724 were 0.903 and 0.913 respectively, with higher AUC for combined LDL and CA724 (0.934; P < 0.001). Conclusion: LDL and CA724 have value as predictors for OM in patients with gastric adenocarcinoma, with higher predictive value when these factors are combined.

Conjunctival papillomas are common tumors that exhibit an exophytic growth pattern, comprised of multiple filiform fronds of squamous epithelium that contain fibrovascular cores. The inverted (endophytic) variety of papilloma, often termed "Schneiderian," rarely occurs on the conjunctiva, with only 15 cases reported to date. Endophytic and exophytic papillomas are well described arising in the sinonasal Schneiderian epithelium where a low rate of malignant transformation may occur in the endophytic type; malignant transformation in exophytic sinonasal papillomas is exceedingly rare. The authors describe 2 cases of exophytic conjunctival papillomas with the morphology of a sinonasal or Schneiderian-type papilloma. Both were pink, sessile acquired growths in women in the sixth decade of life involving the inferior conjunctival fornix or nasal limbus. Nonkeratinizing squamous epithelium along with numerous goblet cells, intraepithelial mucinous cysts, and microabscesses were present. Immunohistochemistry showed reactivity for cytokeratin 7 and wild-type staining for p16 and p53, paralleling the findings in common conjunctival papillomas; both were also driven by low-risk human papillomavirus.

Following preterm birth, serum levels of insulin-like growth factor 1 (IGF-1) decrease compared to corresponding in utero levels. A recent clinical trial indicated that supplementation with recombinant human (rh) IGF-1/rhIGF-binding protein 3 (rhIGF-1/rhIGFBP-3) prevents severe intraventricular hemorrhage (IVH) in extremely preterm infants. In a preterm rabbit pup model, we characterized endogenous serum and hepatic IGF-1, along with brain distribution of IGF-1 and IGF-1 receptor (IGF1R). We then evaluated the effects of rhIGF-1/rhIGFBP-3 on gene expression of regulators of cerebrovascular maturation and structure. Similar to preterm infants, serum IGF-1 concentrations decreased rapidly after preterm birth in the rabbit pup. Administration of rhIGF-1/rhIGFBP-3 restored in utero serum levels but was rapidly eliminated. Immunolabeled IGF1R was widely distributed in multiple brain regions, displaying an abundant density in the choroid plexus and sub-ependymal germinal zones. Increased IGF-1 immunoreactivity, distributed as IGF1R, was detected 4 h after rhIGF-1/rhIGFBP-3 administration. The rhIGF-1/rhIGFBP-3 treatment led to upregulation of choroid plexus genes involved in vascular maturation and structure, with corresponding protein translation for most of these genes. The preterm rabbit pup model is well suited for evaluation of IGF-1-based prevention of IVH. Administration of rhIGF-1/rhIGFBP-3 affects cerebrovascular maturation, suggesting a role for it in preventing preterm IVH.

Purpose: Determine the risk of immunomodulatory therapy (IMT) for COVID-19 infection morbidity.Method: A telemedicine survey on patients of a referral uveitis clinic was performed. Signs of infection, habits, and hospitalizations during the 7 months of the COVID-19 pandemic prior to the study date were recorded. Suggestive findings in chest CT scan and/or positive RT-PCR were considered as confirmed COVID-19 infection while those with only suggestive symptoms were considered as suspected cases. Risk factors including sanitary measures and IMT were compared between patients with confirmed cases and patients without infection.Result: 694 patients were included. Eight patients were identified as confirmed cases and 22 patients as suspected cases of COVID-19 infection. Close contact with infected persons was the only significant risk factor for contracting COVID-19.Conclusion: Using IMT did not affect hospitalization and/or ICU admission and can thus be continued during the pandemic, provided that instructions for preventive measures are followed.