Solving STODS-Surgical Temporary Ocular Discomfort Syndrome.

The term STODS (Surgical Temporary Ocular Discomfort Syndrome) has been coined to describe the ocular surface perturbations induced by surgery. As one of the most important refractive elements of the eye, Guided Ocular Surface and Lid Disease (GOLD) optimization is fundamental to success in achieving refractive outcomes and mitigating STODS. Effective GOLD optimization and the prevention/treatment of STODS requires an understanding of the molecular, cellular, and anatomic factors that influence ocular surface microenvironment and the associated perturbations induced by surgical intervention. By reviewing the current understanding of STODS etiologies, we will attempt to outline a rationale for a tailored GOLD optimization depending on the ocular surgical insult. With a bench-to-bedside approach, we will highlight clinical examples of effective GOLD perioperative optimization that can mitigate STODS' deleterious effect on preoperative imaging and postoperative healing.

FOCUSED (Femtosecond Optimized Continuous Uncorrected Sight with EDOF and Diffractive Multifocal IOLs) - A Review.

PURPOSE OF REVIEW: The aim of this article is to review techniques to maximize all-distance uncorrected visual acuity and minimize photic phenomena after the implantation of multifocal and extended-depth of focus (EDOF) intraocular lenses (IOLs). This review examines the role of femtosecond laser-assisted cataract surgery (FLACS) in postoperative minimization of astigmatism and optimization of outcomes with multifocal and EDOF lenses. RECENT FINDINGS: By incorporating intraoperative and preoperative imaging, femtosecond platforms such as those that utilize iris or conjunctival vessel registration, can enable a precision of corneal incisions and toric IOL markings that enable the lowest possible postoperative levels of astigmatism. Current studies suggest that with increasing IOL complexity, that is, trifocal versus bifocal, image degradation with even low levels of postoperative astigmatism are increased. To this end, current data support the utility of femtosecond laser arcuate incisions to enable the achievement of 0.5 D or less postoperative astigmatism for best outcomes with multifocal lenses. SUMMARY: The synergistic combination of multifocal/EDOF IOLs with FLACS is an extremely promising route in achieving postoperative spectacle independence for patients. The marriage of the precision of FLACS with the increasing complexity of multifocal/EDOF IOLs will fuel nomogram adjustment and systematic improvements, such as the Wörtz-Gupta formula. Such strategies provide an unprecedented precision to cataract surgery that makes FOCUSED (Femtosecond Optimized Continuous Uncorrected Sight with EDOF and Diffractive Multifocal IOLs) a reality.

Potential of Ocular Transmission of SARS-CoV-2: A Review.

PURPOSE OF REVIEW: to provide a prospective on the current mechanisms by which SARS-CoV-2 enters cells and replicates, and its implications for ocular transmission. The literature was analyzed to understand ocular transmission as well as molecular mechanisms by which SARS-CoV-2 enters cells and replicates. Analysis of gene expression profiles from available datasets, published immunohistochemistry, as well as current literature was reviewed, to assess the likelihood that ocular inoculation of SARS-CoV-2 results in systemic infection. RECENT FINDINGS: The ocular surface and retina have the necessary proteins, Transmembrane Serine Protease 2 (TMPRSS2), CD147, Angiotensin-Converting Enzyme 2 (ACE2) and Cathepsin L (CTSL) necessary to be infected with SARS-CoV-2. In addition to direct ocular infection, virus carried by tears through the nasolacrimal duct to nasal epithelium represent a means of ocular inoculation. SUMMARY: There is evidence that SARS-CoV-2 may either directly infect cells on the ocular surface, or virus can be carried by tears through the nasolacrimal duct to infect the nasal or gastrointestinal epithelium.

Dupilumab-Associated Mucin Deficiency (DAMD).

Purpose: Dupilumab, a monoclonal antibody directed against the interleukin-4 receptor subunit α (IL-4Rα) of IL-4 and IL-13, is increasingly being used to control atopic disease. Dupilumab use has been associated with a poorly understood conjunctivitis. In this study, we sought to investigate the hypothesis that dupilumab use and the associated IL-13 blockade causes a relative ocular mucin deficiency. Methods: Tear levels of mucin 5ac (Muc5AC) and total tear protein levels were evaluated from 28 eyes of 14 patients. Bilateral tear samples were acquired from seven patients on dupilumab and seven patients with no exposure to dupilumab. Study subjects were age and gender matched. In addition to tear samples, photographic documentation of ocular surface findings and a questionnaire of ocular surface symptoms were obtained. Between-group mean differences were calculated. Results: Compared with control, ocular Muc5AC levels normalized to total tear protein was statistically significantly lower. The average Muc5AC levels for persons on dupilumab was 1.54 ± 0.58 ng/mg and that of controls was 7.99 ± 1.16 ng/ mg. Persons on dupilumab reported a statistically increased occurrence of ocular fatigue/eye strain, uncomfortable sensation, pain, red eye, and itching. Conclusions: This study demonstrates for the first time, a relative deficiency of Muc5AC in patients on dupilumab. Translational Relevance: The results of this study support the previously reported role of IL-13 in increasing goblet cell density and associated Muc5AC production. Further efforts are underway to better understand the relative contribution of Muc5AC deficiency in the overall presentation of conjunctivitis associated with dupilumab use.

Rationale for American Society of Retina Specialists Best Practice Recommendations for Conducting Vitreoretinal Surgery during the COVID-19 Era.

PURPOSE: To detail the rationale behind recommendations recently published by the American Society of Retina Specialists (ASRS) outlining best practices for safety of vitreoretinal surgeons and staff while performing vitreoretinal surgery during the coronavirus disease (COVID)-19 pandemic. METHODS: The committee for ASRS Best Practices for Retinal Surgery during the COVID-19 Pandemic reviewed existing evidence and information on SARS-CoV-2 transmission, and risk factors during vitreoretinal surgery. Recommendations were based on best available published data, cumulative clinical experiences, and recommendations and policies from other organizations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the strength of recommendations and confidence in the evidence. These serve as interim recommendations which are routinely updated given gaps of knowledge and lack of high-quality data on this evolving subject. RESULTS: Relevant existing literature related to methods of transmission, and ocular manifestations of SARS-CoV-2 are summarized. The data and clinical experiences driving recommendations for pre-operative, intraoperative and post-operative surgical considerations, anesthesia choice, as well as considerations for intravitreal injections are provided. CONCLUSION: Recommendations are provided with the goal of protecting vitreoretinal surgeons and associated personnel from exposure to SARS-CoV-2 during interventional vitreoretinal procedures. This is a rapidly evolving topic with numerous remaining gaps in our current knowledge. As such, recommendations will evolve and the current manuscript is intended to serve as a foundation for continued dialogue on best practices.

Evolution of Leukemic Retinal Hemorrhages Documented by Spectral-Domain OCT and Color Fundus Photography.

PURPOSE: Retinal hemorrhages are observed frequently in patients with leukemia. However, little is known about the impact and natural history of these hemorrhages. The purpose of this study was to describe leukemic retinal hemorrhages using multimodal imaging and to monitor their evolution longitudinally. DESIGN: Retrospective case series. PARTICIPANTS: A total of 11 eyes of 7 symptomatic leukemic patients with posterior segment hemorrhages. METHODS: Single-center study performed at the Johns Hopkins Hospital. Symptomatic leukemic patients with posterior segment hemorrhages underwent serial dilated fundus examinations. The hemorrhages were documented longitudinally with color fundus photographs and spectral-domain (SD) OCT. MAIN OUTCOMES MEASURES: Microanatomic locations of leukemic retinal hemorrhages and their impact on vision and evolution over time. RESULTS: A total of 7 patients (71.4% men; 57.1% white, 28.6% black, and 14.3% Hispanic) were included, with 11 eyes showing posterior segment hemorrhages. The median age at presentation was 49.8 years. All patients had intraretinal hemorrhages; these involved the vitreous and sub-internal limiting membrane (ILM) space in 1 and 3 patients, respectively. The median total follow-up duration was 4.0 months. At the final follow-up visits, 4 of 6 patients showed complete resolution of hemorrhages on examination and color fundus photographs. The final SD-OCT images of all patients did not show any retinal thinning, disruption of the ellipsoid zone, disorganization of the retinal layers, intraretinal fluid, or subretinal fluid. CONCLUSIONS: Symptomatic leukemic retinal hemorrhages are associated with anemia and thrombocytopenia. These hemorrhages, including visually significant central sub-ILM hemorrhages, tend to be self-limiting and resolve within a few months with treatment of the underlying disease.

Noninvasive Tracking of Alginate-Microencapsulated Cells.

This chapter presents a description of standardized techniques used routinely in our laboratory to encapsulate different cell types using the alginate-PLL-alginate immunoisolation system. Given the importance of noninvasive tracking of encapsulated cell transplants, we present a detailed guidance to achieve maximum efficiency and functionality of the capsule preparations for optimal tracking posttransplantation. The provided protocols cover tracking of encapsulated cells using magnetic resonance (MR), X-ray, computed tomography (CT), and ultrasound (US) imaging. Practical suggestions to optimize each method with specific references to recommended suppliers are included.

Vision concerns after mild traumatic brain injury.

OPINION STATEMENT: Mild traumatic brain injury (mTBI) can manifest with visual dysfunction including deficits in accommodation, vergence movements, versions, and field of vision as well increased photosensitivity and a decline in ocular and overall health. Patients with incomitant strabismus should be referred to an ophthalmologist for intervention. Patients with mTBI who experience photosensitivity, or deficits in accommodation, versions, vergences, or field of vision may benefit from vision rehabilitation. These therapies may include spectacles with tinting and a variety of prism combinations. Patients with chronic visual dysfunction following mTBI may benefit from occupational, vestibular, cognitive, and other forms of physical therapy.

Retinal microenvironment imbalance in dry age-related macular degeneration: a mini-review.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. To prevent what will certainly be a tremendous health and economic burden, effective therapeutics for AMD are urgently needed. To develop these agents in a timely fashion, the molecular pathways that cause disease progression must be elucidated. OBJECTIVE: To briefly describe the clinical features of AMD, and review the current understanding of the molecular basis of AMD. METHODS: A literature review. RESULTS: The discussion will primarily focus on the interplay of oxidative stress and complement dysregulation and the resulting chronic proinflammatory state thought to be central in AMD pathogenesis. CONCLUSIONS: Oxidative stress and complement dysregulation play a substantive role in the development of AMD.

X-ray-visible microcapsules containing mesenchymal stem cells improve hind limb perfusion in a rabbit model of peripheral arterial disease.

The therapeutic goal in peripheral arterial disease (PAD) patients is to restore blood flow to ischemic tissue. Stem cell transplantation offers a new avenue to enhance arteriogenesis and angiogenesis. Two major problems with cell therapies are poor cell survival and the lack of visualization of cell delivery and distribution. To address these therapeutic barriers, allogeneic bone marrow-derived mesenchymal stem cells (MSCs) were encapsulated in alginate impregnated with a radiopaque contrast agent (MSC-Xcaps). In vitro MSC-Xcap viability by a fluorometric assay was high (96.9% ± 2.7% at 30 days postencapsulation) and as few as 10 Xcaps were visible on clinical x-ray fluoroscopic systems. Using an endovascular PAD model, rabbits (n = 21) were randomized to receive MSC-Xcaps (n = 6), empty Xcaps (n = 5), unencapsulated MSCs (n = 5), or sham intramuscular injections (n = 5) in the ischemic thigh 24 hours postocclusion. Immediately after MSC transplantation and 14 days later, digital radiographs acquired on a clinical angiographic system demonstrated persistent visualization of the Xcap injection sites with retained contrast-to-noise. Using a modified TIMI frame count, quantitative angiography demonstrated a 65% improvement in hind limb perfusion or arteriogenesis in MSC-Xcap-treated animals versus empty Xcaps. Post-mortem immunohistopathology of vessel density by anti-CD31 staining demonstrated an 87% enhancement in angiogenesis in Xcap-MSC-treated animals versus empty Xcaps. MSC-Xcaps represent the first x-ray-visible cellular therapeutic with enhanced efficacy for PAD treatment.

Use of perfluorocarbon nanoparticles for non-invasive multimodal cell tracking of human pancreatic islets.

In vivo imaging of engraftment and immunorejection of transplanted islets is critical for further clinical development, with (1)H MR imaging of superparamagnetic iron oxide-labeled cells being the current premier modality. Using perfluorocarbon nanoparticles, we present here a strategy for non-invasive imaging of cells using other modalities. To this end, human cadaveric islets were labeled with rhodamine-perfluorooctylbromide (PFOB) nanoparticles, rhodamine-perfluoropolyether (PFPE) nanoparticles or Feridex as control and tested in vitro for cell viability and c-peptide secretion for 1 week. (19)F MRI, computed tomography (CT) and ultrasound (US) imaging was performed on labeled cell phantoms and on cells following transplantation beneath the kidney capsule of mice and rabbits. PFOB and PFPE-labeling did not reduce human islet viability or glucose responsiveness as compared with unlabeled cells or SPIO-labeled cells. PFOB- and PFPE-labeled islets were effectively fluorinated for visualization by (19)F MRI. PFOB-labeled islets were acoustically reflective for detection by US imaging and became sufficiently brominated to become radiopaque allowing visualization with CT. Thus, perfluorocarbon nanoparticles are multimodal cellular contrast agents that may find applications in real-time targeted delivery and imaging of transplanted human islets or other cells in a clinically applicable manner using MRI, US or CT imaging.

Synthesis of magnetic resonance-, X-ray- and ultrasound-visible alginate microcapsules for immunoisolation and noninvasive imaging of cellular therapeutics.

Cell therapy has the potential to treat or cure a wide variety of diseases. Non-invasive cell tracking techniques are, however, necessary to translate this approach to the clinical setting. This protocol details methods to create microcapsules that are visible by X-ray, ultrasound (US) or magnetic resonance (MR) for the encapsulation and immunoisolation of cellular therapeutics. Three steps are generally used to encapsulate cellular therapeutics in an alginate matrix: (i) droplets of cell-containing liquid alginate are extruded, using an electrostatic generator, through a needle tip into a solution containing a dissolved divalent cation salt to form a solid gel; (ii) the resulting gelled spheres are coated with polycations as a cross-linker; and (iii) these complexes are then incubated in a second solution of alginate to form a semipermeable membrane composed of an inner and an outer layer of alginate. The microcapsules can be rendered visible during the first step by adding contrast agents to the primary alginate layer. Such contrast agents include superparamagnetic iron oxide for detection by (1)H MR imaging (MRI); the radiopaque agents barium or bismuth sulfate for detection by X-ray modalities; or perfluorocarbon emulsions for multimodal detection by (19)F MRI, X-ray and US imaging. The entire synthesis can be completed within 2 h.

Assessment of EmboGel--a selectively dissolvable radiopaque hydrogel for embolic applications.

PURPOSE: To evaluate the embolic properties of an alginate-based embolic biomaterial (EmboGel) and its solvent (EmboClear) in treatment of aneurysms. MATERIALS AND METHODS: EmboGel is a mixture of iohexol and alginate that polymerizes into a hydrocoil when delivered through a coaxial catheter with a distal mixing tip, exposing alginate to a calcium chloride solution. In contrast to previously reported embolic agents, EmboGel can be selectively dissolved by EmboClear, a mixture of the enzyme alginate lyase and ethylenediaminetetraacetic acid (EDTA). The embolic and contrast properties of EmboGel were assessed in in vitro models of saccular aneurysm and an aortic aneurysm endoleak. The dissolvability of EmboGel with EmboClear was assessed further after endovascular delivery in the New Zealand white rabbit in the native aortoiliofemoral territory, a created saccular aneurysm, and the native carotid arteries. RESULTS: EmboGel effectively filled aneurysm cavities in the case of stent excluded saccular and fusiform aneurysms. EmboGel was readily dissolved by EmboClear in vitro and after in vivo embolization. When the distal abdominal aorta and pelvic arteries were occluded with EmboGel, within 1 minute of EmboClear infusion, patency of the aorta and most of the pelvic circulation was regained as noted by angiography. Embolization in the subclavian artery and numerous distal branches was rapidly dissolved by EmboClear. Finally, the carotid artery occluded with EmboGel regained patency after administration of EmboClear. CONCLUSIONS: EmboGel is a dissolvable alginate-based biomaterial that can be used for numerous embolic applications. EmboGel can be selectively dissolved with EmboClear, a solution of alginate lyase and EDTA.

Fluorine (19F) MRS and MRI in biomedicine.

Shortly after the introduction of (1)H MRI, fluorinated molecules were tested as MR-detectable tracers or contrast agents. Many fluorinated compounds, which are nontoxic and chemically inert, are now being used in a broad range of biomedical applications, including anesthetics, chemotherapeutic agents, and molecules with high oxygen solubility for respiration and blood substitution. These compounds can be monitored by fluorine ((19)F) MRI and/or MRS, providing a noninvasive means to interrogate associated functions in biological systems. As a result of the lack of endogenous fluorine in living organisms, (19)F MRI of 'hotspots' of targeted fluorinated contrast agents has recently opened up new research avenues in molecular and cellular imaging. This includes the specific targeting and imaging of cellular surface epitopes, as well as MRI cell tracking of endogenous macrophages, injected immune cells and stem cell transplants.

Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging.

PURPOSE: To develop novel immunoprotective alginate microcapsule formulations containing perfluorocarbons (PFCs) that may increase cell function, provide immunoprotection for xenografted cells, and simultaneously enable multimodality imaging. MATERIALS AND METHODS: All animal experiments were approved by an Institutional Animal Care and Use Committee. Cadaveric human islet cells were encapsulated with alginate, poly-l-lysine, and perfluorooctyl bromide (PFOB) or perfluoropolyether (PFPE). In vitro viability and the glucose-stimulation index for insulin were determined over the course of 2 weeks and analyzed by using a cross-sectional time series regression model. The sensitivity of multimodality (computed tomography [CT], ultrasonography [US], and fluorine 19 [(19)F] magnetic resonance [MR] imaging) detection was determined for fluorocapsules embedded in gel phantoms. C57BL/6 mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) islet-containing fluorocapsules and control mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) fluorocapsules without islets were monitored for human C-peptide (insulin) secretion during a period of 55 days. Mice underwent (19)F MR imaging at 9.4 T and micro-CT. Swine (n = 2) receiving 9000 PFOB capsules through renal artery catheterization were imaged with a clinical multidetector CT scanner. Signal intensity was evaluated by using a paired t test. RESULTS: Compared with nonfluorinated alginate microcapsules, PFOB fluorocapsules increased insulin secretion of encapsulated human islets, with values up to 18.5% (3.78 vs 3.19) at 8-mmol/L glucose concentration after 7 days in culture (P < .001). After placement of the immunoprotected encapsulated cells into mice, a sustained insulin release was achieved with human C-peptide levels of 19.1 pmol/L ± 0.9 (standard deviation) and 33.0 pmol/L ± 1.0 for PFPE and PFOB capsules, respectively. Fluorocapsules were readily visualized with (19)F MR imaging, US imaging, and CT with research- and clinical-grade imagers for all modalities. CONCLUSION: Fluorocapsules enhance glucose responsiveness and insulin secretion in vitro, enable long-term insulin secretion by xenografted islet cells in vivo, and represent a novel contrast agent platform for multimodality imaging.

αB-crystallin negative astrocytic inclusions.

We report on an unusual pathological finding of astrocytes, observed in the brain of a 16-year-old African-American male with severe intellectual disability and spastic quadriplegia. The brain showed bilateral pericentral, perisylvian polymicrogyria and pachygyria, in conjunction with a large number of hypertrophic astrocytes with eosinophilic granular cytoplasmic inclusions. The astrocytic abnormality was more severe in the dysgenetic area but present throughout the cerebral cortex. Astrocytic inclusions stained with acid fuchsin, azocarmine and Holzer's stain, and were immunoreactive for GFAP, S-100, and ubiquitin, but not for αB-crystallin, filamin, vimentin, nestin, tau or α-synuclein. Based on the case and a review of the literature, the authors postulate that these astrocytic inclusions in the cerebral cortex reflect abnormalities in radial glial developmental processes, such as migration, differentiation, or glial-neuronal interaction function during neuronal migration.

Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor.

Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser(3), an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.

Cytopathologic analysis of paratracheal masses: a study of 737 cases with clinicoradiologic correlation.

OBJECTIVE: To analyze the cytopathologic findings of a series of paratracheal space (PTS) masses in the context of clinicoradiologic correlation. STUDY DESIGN: Retrospective review of our cytopathology files revealed 131 cases of PTS lesions in a 14-year period (1991-2005). Cytologic material was obtained under radiologic guidance. Radiologic findings, clinical data and subsequently performed tissue biopsies were reviewed and correlated. RESULTS: Radiologic imaging disclosed masses in the PTS ranging from 1 to 7 cm. Of the 131 cases, 103 (79%) were deemed diagnostic. Of these, 41 (40%) revealed nonneoplastic lesions, and 62 (60%) yielded malignant neoplasms. Nonneoplastic entities included: 31 (73%) hyperplastic lymph nodes and 10 (24%) sarcoidosis. Of the malignant cases, 45 (73%) were metastatic tumors: adenocarcinoma (ACA) 19, small cell carcinoma 12, squamous cell carcinoma (SQCC) 11 and other tumors, from lung 34, esophagus 4 and other sites. Malignant neoplasms from local spread included lung non-small cell carcinoma 6, SQCC 3 and ACA 3, papillary thyroid carcinoma 3 and other 2. CONCLUSION: Fine needle aspiration (FNA) of PTS has a high diagnostic yield (79%) with a sensitivity of 97% and specificity of 100%. The most common diagnosis is a malignant tumor (60%), with metastatic carcinoma (73%) the most common neoplasm (lung ACA the most common primary source). The most common benign entity is a hyperplastic lymph node (24%). Ancillary studies (immunoctyochemistry, fluorescence in situ hybridization and electron microscopy) were helpful and provided definitive diagnosis in 30% of the initially nondiagnostic FNA samples.