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Hennein L, Robbins SL. Thyroid-Associated Orbitopathy: Management and Treatment. J Binocul Vis Ocul Motil 2021;:1-15.Abstract
Thyroid-associated orbitopathy (TAO) is a leading cause of orbital and strabismus symptoms in adults. Over the last decade, new treatments have greatly changed available options to alleviate symptoms and improve outcomes. This article discusses the pathophysiology and natural disease course of TAO, including when to pursue urgent treatment and when to consider other diagnoses. This article highlights the interventions that may alter the disease course and offers a comprehensive review on evidence-based interventions for both supportive therapy and systemic agents. The surgical strategies and principles for the treatment of TAO are discussed, including indications for combined surgical interventions and varying surgical techniques.
Habib LA, Yoon MK. Patient specific implants in orbital reconstruction: A pilot study. Am J Ophthalmol Case Rep 2021;24:101222.Abstract
Purpose: Successful repair of the orbital skeleton restores function and cosmesis by normalizing globe position and allowing full motility of the extraocular muscles. Routine repairs are successful with standard implants. However, defects that are irregular or cause volume deficiency can be challenging to repair. The development of patient specific implants (PSI) offers an additional tool in complex cases. Herein, we report our experience using PSI for orbital reconstruction. Methods: An IRB-approved review was conducted of consecutive patients who received PSI from 8/2016-9/2018. Demographic and examination findings were recorded. PSI was designed using high-density porous polyethylene or polyetheretherketone (PEEK) and implanted for repair. The postoperative course was reviewed for outcomes and complications. Results: Eight patients were identified. Two had silent sinus syndrome, 3 were complex facial fracture revisions, and 3 were post-oncologic reconstruction. Seven received porous polyethylene implants, and 1 had a PEEK implant. Mean follow up time was 10.2 months (3.3-28.3). All had an improved functional and aesthetic result. Diplopia and enophthalmos completely resolved in 60% of fracture and silent sinus patients. All fracture and silent sinus patients were orthotropic without diplopia in primary gaze at last follow up. Tumor patients had improvement in symmetry and functionality. There were no complications. Conclusion and importance: Complex orbital skeleton derangements can be difficult to repair and standard implants may incompletely resolve the anatomic problem. In challenging cases, PSI may better achieve an aesthetically and anatomically successful outcome and improve functionality.
Sobel RK, Aakalu VK, Vagefi RM, Foster JA, Tao JP, Freitag SK, Wladis EJ, McCulley TJ, Yen MT. Orbital Radiation for Thyroid Eye Disease: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;Abstract
PURPOSE: To review the current literature on the safety and efficacy of orbital radiation for the management of thyroid eye disease (TED). METHODS: A literature search was conducted last in February 2021 of the PubMed database to identify all articles published in the English language on original research that assessed the effect of orbital radiation on TED. The search identified 55 articles, and 18 met the inclusion criteria for this assessment. A panel methodologist then assigned a level of evidence rating for each study, and all of them were rated level III. RESULTS: Two large retrospective studies demonstrated the efficacy of radiation treatment, with or without corticosteroid use, in preventing or treating compressive optic neuropathy (CON). Three studies highlighted the role of orbital radiation therapy (RT) to facilitate the tapering of corticosteroids. Several other studies showed a possible role for RT to improve diplopia and soft tissue signs. CONCLUSIONS: Although no level I or level II evidence exists, the best available evidence suggests that orbital radiation, used with or without corticosteroids, is efficacious in preventing CON, improving motility restriction, and decreasing clinical activity in TED. Orbital radiation also may facilitate a corticosteroid taper. Together, these studies show that RT seems to modify the active phase of TED. Short-term risks of orbital radiation are minor, but long-term outcome data are lacking.
Marsiglia M, Chwalisz BK, Maher M. Neuroradiologic Imaging of Neurologic and Neuro-Ophthalmic Complications of Coronavirus-19 Infection. J Neuroophthalmol 2021;41(4):452-460.Abstract
BACKGROUND: To review the literature and provide a summary of COVID-19-related neurologic and neuro-ophthalmic complications. METHODS: The currently available literature was reviewed on PubMed and Google Scholar using the following keywords for searches: CNS, Neuro-Ophthalmology, COVID-19, SARS-CoV-2, coronavirus, optic neuritis, pseudotumor cerebri, Acute Disseminated Encephalomyelitis, posterior reversible encephalopathy syndrome (PRES), meningitis, encephalitis, acute necrotizing hemorrhagic encephalopathy, and Guillain-Barré and Miller Fisher syndromes. RESULTS: Neuroradiologic findings of neurologic and neuro-ophthalmologic complications in relationship to COVID-19 infection were reviewed. Afferent visual pathway-related disorders with relevant imaging manifestations included fundus nodules on MRI, papilledema and pseudotumor cerebri syndrome, optic neuritis, Acute Disseminated Encephalomyelitis, vascular injury with thromboembolism and infarct, leukoencephalopathy, gray matter hypoxic injury, hemorrhage, infectious meningitis/encephalitis, acute necrotizing hemorrhagic encephalopathy, and PRES. Efferent visual pathway-related complications with relevant imaging manifestations were also reviewed, including orbital abnormalities, cranial neuropathy, Guillain-Barré and Miller Fisher syndromes, and nystagmus and other eye movement abnormalities related to rhombencephalitis. CONCLUSION: COVID-19 can cause central and peripheral nervous system disease, including along both the afferent and efferent components of visual axis. Manifestations of disease and long-term sequela continue to be studied and described. Familiarity with the wide variety of neurologic, ophthalmic, and neuroradiologic presentations can promote prompt and appropriate treatment and continue building a framework to understand the underlying mechanism of disease.
Inomata T, Nakamura M, Sung J, Midorikawa-Inomata A, Iwagami M, Fujio K, Akasaki Y, Okumura Y, Fujimoto K, Eguchi A, Miura M, Nagino K, Shokirova H, Zhu J, Kuwahara M, Hirosawa K, Dana R, Murakami A. Smartphone-based digital phenotyping for dry eye toward P4 medicine: a crowdsourced cross-sectional study. NPJ Digit Med 2021;4(1):171.Abstract
Multidimensional integrative data analysis of digital phenotyping is crucial for elucidating the pathologies of multifactorial and heterogeneous diseases, such as the dry eye (DE). This crowdsourced cross-sectional study explored a novel smartphone-based digital phenotyping strategy to stratify and visualize the heterogenous DE symptoms into distinct subgroups. Multidimensional integrative data were collected from 3,593 participants between November 2016 and September 2019. Dimension reduction via Uniform Manifold Approximation and Projection stratified the collected data into seven clusters of symptomatic DE. Symptom profiles and risk factors in each cluster were identified by hierarchical heatmaps and multivariate logistic regressions. Stratified DE subgroups were visualized by chord diagrams, co-occurrence networks, and Circos plot analyses to improve interpretability. Maximum blink interval was reduced in clusters 1, 2, and 5 compared to non-symptomatic DE. Clusters 1 and 5 had severe DE symptoms. A data-driven multidimensional analysis with digital phenotyping may establish predictive, preventive, personalized, and participatory medicine.
Finkelstein JB, Tremblay ES, Van Cain M, Farber-Chen A, Schumann C, Brown C, Shah AS, Rhodes ET. Pediatric Clinicians' Use of Telemedicine: Qualitative Interview Study. JMIR Hum Factors 2021;8(4):e29941.Abstract
BACKGROUND: Bedside manner describes how clinicians relate to patients in person. Telemedicine allows clinicians to connect virtually with patients using digital tools. Effective virtual communication or webside manner may require modifications to traditional bedside manner. OBJECTIVE: This study aims to understand the experiences of telemedicine providers with patient-to-provider virtual visits and communication with families at a single large-volume children's hospital to inform program development and training for future clinicians. METHODS: A total of 2 focus groups of pediatric clinicians (N=11) performing virtual visits before the COVID-19 pandemic, with a range of experiences and specialties, were engaged to discuss experiential, implementation, and practice-related issues. Focus groups were facilitated using a semistructured guide covering general experience, preparedness, rapport strategies, and suggestions. Sessions were digitally recorded, and the corresponding transcripts were reviewed for data analysis. The transcripts were coded based on the identified main themes and subthemes. On the basis of a higher-level analysis of these codes, the study authors generated a final set of key themes to describe the collected data. RESULTS: Theme consistency was identified across diverse participants, although individual clinician experiences were influenced by their specialties and practices. A total of 3 key themes emerged regarding the development of best practices, barriers to scalability, and establishing patient rapport. Issues and concerns related to privacy were salient across all themes. Clinicians felt that telemedicine required new skills for patient interaction, and not all were comfortable with their training. CONCLUSIONS: Telemedicine provides benefits as well as challenges to health care delivery. In interprofessional focus groups, pediatric clinicians emphasized the importance of considering safety and privacy to promote rapport and webside manner when conducting virtual visits. The inclusion of webside manner instructions within training curricula is crucial as telemedicine becomes an established modality for providing health care.
Siddiqui N, Chen EM, Parikh R, Douglas VP, Douglas KA, Feng PW, Armstrong GW. Epidemiology of United States Inpatient Open Globe Injuries from 2009-2015. Ophthalmic Epidemiol 2021;28(6):469-478.Abstract
PURPOSE: To study the epidemiology of inpatient open globe injuries (OGI) in the United States (US). METHODS: This was a retrospective cohort study of patients with a primary diagnosis of OGI in the National Inpatient Sample (NIS) from 2009 to 2015. Sociodemographic characteristics, including age, gender, race, ethnicity, insurance, and income were stratified for comparison. Annual prevalence rates were calculated using 2010 US Census data. Statistical analysis included Chi-square tests, ANCOVA, and Tukey tests. RESULTS: A total of 6,821 US inpatient hospital discharge records met inclusion/exclusion criteria. The estimated national prevalence of OGI during the 5-year period from 2009 to 2015 was 34,061 (95% confidence interval [CI] 31,445-36,677). The overall annual prevalence rate was 1.58 per 100,000 per year (CI 1.56-1.59). Overall, average annual prevalence rates were highest among patients 85 years or older (7.72, CI 6.95-8.49), on Medicare (3.92, CI 3.84-4.00), males (2.28, CI 2.25-2.30), African Americans (2.38, CI 2.32-2.44), and Native Americans (1.80, CI 1.62-2.00). OGI rates were lowest among Whites (1.21, CI 1.19-1.22), females (0.89, CI 0.87-0.91), those with private insurance (0.84, CI 0.82-0.86), and Asians (0.69, CI 0.64-0.74). Being in the lowest income quartile was a risk factor for OGI (p < .05). CONCLUSIONS: Inpatient OGIs disproportionately affected those over 85, young males, elderly females, patients of African-American descent, on Medicare, and in the lowest income quartile. Additionally, children and young children had lower rates of OGI compared to adolescents. Further studies should delineate causes for socioeconomic differences in OGI rates to guide future public health measures.
Sharifi S, Sharifi H, Akbari A, Chodosh J. Systematic optimization of visible light-induced crosslinking conditions of gelatin methacryloyl (GelMA). Sci Rep 2021;11(1):23276.Abstract
Gelatin methacryloyl (GelMA) is one of the most widely used photo-crosslinkable biopolymers in tissue engineering. In in presence of an appropriate photoinitiator, the light activation triggers the crosslinking process, which provides shape fidelity and stability at physiological temperature. Although ultraviolet (UV) has been extensively explored for photo-crosslinking, its application has been linked to numerous biosafety concerns, originated from UV phototoxicity. Eosin Y, in combination with TEOA and VC, is a biosafe photoinitiation system that can be activated via visible light instead of UV and bypasses those biosafety concerns; however, the crosslinking system needs fine-tuning and optimization. In order to systematically optimize the crosslinking conditions, we herein independently varied the concentrations of Eosin Y [(EY)], triethanolamine (TEOA), vinyl caprolactam (VC), GelMA precursor, and crosslinking times and assessed the effect of those parameters on the properties the hydrogel. Our data showed that except EY, which exhibited an optimal concentration (~ 0.05 mM), increasing [TEOA], [VA], [GelMA], or crosslinking time improved mechanical (tensile strength/modulus and compressive modulus), adhesion (lap shear strength), swelling, biodegradation properties of the hydrogel. However, increasing the concentrations of crosslinking reagents ([TEOA], [VA], [GelMA]) reduced cell viability in 3-dimensional (3D) cell culture. This study enabled us to optimize the crosslinking conditions to improve the properties of the GelMA hydrogel and to generate a library of hydrogels with defined properties essential for different biomedical applications.
Yemanyi F, Bora K, Blomfield AK, Wang Z, Chen J. Wnt Signaling in Inner Blood-Retinal Barrier Maintenance. Int J Mol Sci 2021;22(21)Abstract
The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood-retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological balance is fundamental to visual function by facilitating the delivery of nutrients and oxygen and for protection from blood-borne toxins. The inner BRB (iBRB), composed mostly of inner retinal vasculature, controls substance exchange mainly via transportation processes between (paracellular) and through (transcellular) the retinal microvascular endothelium. Disruption of iBRB, characterized by retinal edema, is observed in many eye diseases and disturbs the physiological quiescence in the retina's extracellular space, resulting in vision loss. Consequently, understanding the mechanisms of iBRB formation, maintenance, and breakdown is pivotal to discovering potential targets to restore function to compromised physiological barriers. These unraveled targets can also inform potential drug delivery strategies across the BRB and the blood-brain barrier into retinas and brain tissues, respectively. This review summarizes mechanistic insights into the development and maintenance of iBRB in health and disease, with a specific focus on the Wnt signaling pathway and its regulatory role in both paracellular and transcellular transport across the retinal vascular endothelium.
Woodward AM, Feeley MN, Rinaldi J, Argüeso P. CRISPR/Cas9 genome editing reveals an essential role for basigin in maintaining a nonkeratinized squamous epithelium in cornea. FASEB Bioadv 2021;3(11):897-908.Abstract
One of the primary functions of nonkeratinized stratified squamous epithelia is to protect underlying tissues against chemical, microbial, and mechanical insult. Basigin is a transmembrane matrix metalloproteinase inducer commonly overexpressed during epithelial wound repair and cancer but whose physiological significance in normal epithelial tissue has not been fully explored. Here we used a CRISPR/Cas9 system to study the effect of basigin loss in a human cornea model of squamous epithelial differentiation. We find that epithelial cell cultures lacking basigin change shape and fail to produce a flattened squamous layer on the apical surface. This process is associated with the abnormal expression of the transcription factor SPDEF and the decreased biosynthesis of MUC16 and involucrin necessary for maintaining apical barrier function and structural integrity, respectively. Expression analysis of genes encoding tight junction proteins identified a role for basigin in promoting physiological expression of occludin and members of the claudin family. Functionally, disruption of basigin expression led to increased epithelial cell permeability as evidenced by the decrease in transepithelial electrical resistance and increase in rose bengal flux. Overall, these results suggest that basigin plays a distinct role in maintaining the normal differentiation of stratified squamous human corneal epithelium and could have potential implications to therapies targeting basigin function.
Gárriz A, Aubry S, Wattiaux Q, Bair J, Mariano M, Hatzipetrou G, Bowman M, Morokuma J, Ortiz G, Hamrah P, Dartt DA, Zoukhri D. Role of the Phospholipase C Pathway and Calcium Mobilization in Oxytocin-Induced Contraction of Lacrimal Gland Myoepithelial Cells. Invest Ophthalmol Vis Sci 2021;62(14):25.Abstract
Purpose: We reported that oxytocin (OXT), added to freshly prepared lacrimal gland lobules, induced myoepithelial cell (MEC) contraction. In other systems, OXT activates phospholipase C (PLC) generating Inositol 1,4,5-trisphosphate (IP3) which increases intracellular calcium concentration ([Ca2+]i) causing contraction. The aim of the current study was to investigate the role of this pathway in OXT-induced contraction of MEC. Methods: Tear volume was measured using the cotton thread method. Lacrimal gland MEC were isolated and propagated from α-smooth muscle actin (SMA)-green fluorescent protein (GFP) mice, in which MEC express GFP making them easily identifiable. RNA and protein samples were prepared for RT-PCR and Western blotting for G protein expression. Changes in [Ca2+]i were measured in Fura-2 loaded MEC using a ratio imaging system. MEC contraction was monitored in real time and changes in cell size were quantified using ImageJ software. Results: OXT applied either topically to surgically exposed lacrimal glands or delivered subcutaneously resulted in increased tear volume. OXT stimulated lacrimal gland MEC contraction in a dose-dependent manner, with a maximum response at 10-7 M. MEC express the PLC coupling G proteins, Gαq and Gα11, and their activation by OXT resulted in a concentration-dependent increase in [Ca2+]i with a maximum response at 10-6 M. Furthermore, the activation of the IP3 receptor to increase [Ca2+]i is crucial for OXT-induced MEC contraction since blocking the IP3 receptor with 2-APB completely abrogated this response. Conclusions: We conclude that OXT uses the PLC/Ca2+ pathway to stimulate MEC contraction and increase lacrimal gland secretion.
Sharifi S, Islam MM, Sharifi H, Islam R, Koza D, Reyes-Ortega F, Alba-Molina D, Nilsson PH, Dohlman CH, Mollnes TE, Chodosh J, Gonzalez-Andrades M. Tuning gelatin-based hydrogel towards bioadhesive ocular tissue engineering applications. Bioact Mater 2021;6(11):3947-3961.Abstract
Gelatin based adhesives have been used in the last decades in different biomedical applications due to the excellent biocompatibility, easy processability, transparency, non-toxicity, and reasonable mechanical properties to mimic the extracellular matrix (ECM). Gelatin adhesives can be easily tuned to gain different viscoelastic and mechanical properties that facilitate its ocular application. We herein grafted glycidyl methacrylate on the gelatin backbone with a simple chemical modification of the precursor, utilizing epoxide ring-opening reactions and visible light-crosslinking. This chemical modification allows the obtaining of an elastic protein-based hydrogel (GELGYM) with excellent biomimetic properties, approaching those of the native tissue. GELGYM can be modulated to be stretched up to 4 times its initial length and withstand high tensile stresses up to 1.95 MPa with compressive strains as high as 80% compared to Gelatin-methacryloyl (GeIMA), the most studied derivative of gelatin used as a bioadhesive. GELGYM is also highly biocompatible and supports cellular adhesion, proliferation, and migration in both 2 and 3-dimensional cell-cultures. These characteristics along with its super adhesion to biological tissues such as cornea, aorta, heart, muscle, kidney, liver, and spleen suggest widespread applications of this hydrogel in many biomedical areas such as transplantation, tissue adhesive, wound dressing, bioprinting, and drug and cell delivery.
Yu Z, Efstathiou NE, Correa VSMC, Chen XH, Ishihara K, Iesato Y, Narimatsu T, Ntentakis D, Chen Y, Vavvas DG. Receptor interacting protein 3 kinase, not 1 kinase, through MLKL-mediated necroptosis is involved in UVA-induced corneal endothelium cell death. Cell Death Discov 2021;7(1):366.Abstract
Ultraviolet (UV) is one of the most energetic radiations in the solar spectrum that can result in various tissue injury disorders. Previous studies demonstrated that UVA, which represents 95% of incident photovoltaic radiation, induces corneal endothelial cells (CECs) death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor-interacting protein 3 kinase (RIPK3), a key signaling molecule of PCD, in UVA-induced injury using a short-term corneal endothelium (CE) culture model. UVA irradiation activated RIPK3 and mediated necroptosis both in mouse CE and primary human CECs (pHCECs). UVA irradiation was associated with upregulation of key necroptotic molecules (DAI, TRIF, and MLKL) that lie downstream of RIPK3. Moreover, RIPK3 inhibition or silencing in primary corneal endothelial cells suppresses UVA-induced cell death, along with downregulation of MLKL in pHCECs. In addition, genetic inhibition or knockout of RIPK3 in mice (RIPK3K51A and RIPK3-/- mice) similarly attenuates cell death and the levels of necroptosis in ex vivo UVA irradiation experiments. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced cell death in CE and indicate its potential as a future protective target.

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