The Microbiome, Ocular Surface, and Corneal Disorders.

The ocular surface microbiome is an emerging field of study that seeks to understand how the community of microorganisms found on the ocular surface may help maintain homeostasis or can potentially lead to disease and dysbiosis. Initial questions include whether the organisms detected on the ocular surface inhabit that ecological niche and, if so, whether there exists a core microbiome found in most or all healthy eyes. Many questions have emerged around whether novel organisms and/or a redistribution of organisms play a role in disease pathogenesis, response to therapies, or convalescence. Although there is much enthusiasm about this topic, the ocular surface microbiome is a new field with many technical challenges. These challenges are discussed in this review as well as a need for standardization to adequately compare studies and advance the field. In addition, this review summarizes the current research on the microbiome of various ocular surface diseases and how these findings may impact treatments and clinical decision-making.

A Retrospective Analysis of Tear Film and Blink Parameters in Patients With Ocular Surface Disease.

OBJECTIVES: We had two objectives: (1) to investigate differences in tear film and blink parameters in patients with six ocular surface diseases (OSD): ocular graft versus host disease (oGVHD), Stevens-Johnson syndrome (SJS), lax eyelid syndrome, meibomian gland dysfunction (MGD), obstructive sleep apnea, and dry eye disease; and (2) to characterize the relationships between lipid layer thickness (LLT), meiboscore, Schirmer I test, and three blink parameters: partial blink rate (PBR), interblink interval (IBI), and interpalpebral fissure height (IPFH) in this group of patients. METHODS: This is a single-site retrospective analysis of 228 patients (456 eyes) with six different primary OSD at Loyola University Medical Center between January 2018 and July 2020. Objective parameters included: LLT, IBI, PBR, IPFH, Pult meiboscore, and Schirmer I score. Linear mixed effects models were used to analyze the relationships between these parameters. RESULTS: The meiboscore was highest in patients with SJS compared with the other five groups. There was significant variability in IPFH across different groups, with patients with oGVHD having the smallest height. An increase in IPFH was associated with increases in IBI, PBR, and Schirmer score. Patients with no partial blinks demonstrated a statistically significant higher IBI than patients who showed 1%-50% partial blinks. Finally, no statistically significant relationship was found between the following: (1) meiboscore and LLT, (2) OSDI and IPFH, (3) Schirmer score and IBI, or (4) LLT and IBI. CONCLUSIONS: There were fewer than anticipated differences in objective tear film and blink parameters between patients with six different OSD. A statistically significant association was found between IPFH and Schirmer score and IPFH and IBI, representing new findings in tear film research. Further investigation of the relationship between IPFH and IBI is needed.

Hardware complications and reoperations following precontoured plate fixation of the olecranon: a population-based study.

BACKGROUND: Several fixation techniques have been described to treat acute olecranon fractures. Plate fixation is often used because of its superior mechanical properties. The reported rates of reoperation after olecranon plate fixation have been quite heterogeneous. The purpose of this study was to establish an updated reoperation rate based on modern precontoured plate constructs. METHODS: This retrospective cohort study used population-level administrative data to identify all surgically treated adult patients with olecranon fractures at 4 hospitals in Edmonton, AB, Canada, between 2010 and 2015. Radiographic review was conducted to identify patients who underwent precontoured olecranon plate fixation. Fracture characteristics including Mayo fracture classification and other concomitant upper-extremity injuries were identified. Chart reviews were performed to determine patient characteristics and patients who required reoperation. The primary reason for and type of reoperation were determined. RESULTS: Six hundred patients were surgically treated for olecranon fractures. Precontoured plate fixation was used in 321 patients. The average age of included patients was 56 years (standard deviation [SD], 19.4 years), and there were 173 female patients (53.9%). Reoperation was required in 90 patients (28%). For 50 patients, implant-related irritation was the primary reason for reoperation, representing 55.6% of the patients who underwent reoperation (50 of 90) and 15.6% of the total cohort (50 of 321). Other reasons for reoperation included hardware failure in 17 patients (5.3%), infection in 9 (2.8%), and contracture in 9 (2.8%). Patients who required reoperation were significantly younger (52.9 years [SD, 18.1 years] vs. 57.7 years [SD, 19.4 years]; P = .048) and had significantly higher rates of type III olecranon fractures (17.8% [16 of 90] vs. 8.2% [19 of 231]; P = .04) and Monteggia fractures (13.3% [12 of 90] vs. 4.8% [11 of 231]; P = .008). A multivariate logistic regression model also demonstrated increased odds ratios (ORs) for overall reoperation in patients with Monteggia fractures (OR, 2.99 [95% confidence interval, 1.25-7.17]; P = .014) and for reoperation due to implant-related irritation in younger patients (OR, 0.98 [95% confidence interval, 0.96-0.996]; P = .018). No discerning factors were identified for the 50 patients who underwent hardware removal for implant-related irritation compared with the whole reoperation group (n = 90). CONCLUSION: This study found that patients with olecranon fractures treated with precontoured plates experienced a hardware removal rate of 15.6% for implant-related irritation. Patients who sustained more complex fractures, such as Monteggia injuries, demonstrated higher rates of reoperation. Increasing age may be associated with lower rates of reoperation. In patients who required reoperation, there were no identifiable radiographic or clinical characteristics that were associated with implant-related irritation as their primary reason for reoperation.

Inflammation and oxidative stress induced by lipid peroxidation metabolite 4-hydroxynonenal in human corneal epithelial cells.

PURPOSE: Oxidative stress is widely known to be a major contributor in the pathogenesis of dry eye disease (DED). 4-Hydroxynonenal (4-HNE), a well-known byproduct frequently measured as an indicator of oxidative stress-induced lipid peroxidation, has been shown to be elevated in both human and murine corneal DED samples. This study aims to investigate if 4-HNE is responsible for the oxidative stress in human corneal epithelial cells (HCECs) and explores the underlying mechanism by which it confers its effects. METHODS: SV40-immortalized HCECs were cultured in minimum essential media (MEM) with 1% penicillin/streptomycin and 10% fetal bovine serum. HCECs were exposed to media with or without 4-HNE and cell culture supernatants were collected at 4 and 24 h. Cellular reactive oxygen species (ROS) measurement was performed using a 2',7'-dichlorofluorescein diacetate (DCFDA) assay kit according to the manufacturer's instructions. Protein levels of antioxidant enzymes copper/zinc superoxide dismutase 1 (SOD1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were analyzed by Western blot. NF-κB activation and expression of IL-6 and IL-8 were measured using an NF-κB p65 Total SimpleStep ELISA Kit and Proteome Profiler Human Cytokine Array Kit. Cell viability was evaluated by LDH cytotoxicity assay. RESULTS: Treatment with 4-HNE decreased cell viability of HCECs. Band intensities corresponding to levels of ROS production showed a significant increase in ROS generation after treatment with 4-HNE. 4-HNE decreased SOD1 levels and upregulated NQO1 expression in HCECs. A significant increase in activation of NF-κB and production of pro-inflammatory cytokines IL-6 and IL-8 was observed after treatment with 4-HNE. Exposure to N-acetylcysteine (NAC), an antioxidant and ROS scavenger, antagonized the oxidative effects of 4-HNE on HCECs. CONCLUSION: 4-HNE induces oxidative stress in corneal epithelial cells by increasing levels of ROS generation and modifying the expression of antioxidant enzyme levels, decreasing cell viability of HCECs in vitro. This study demonstrates a potential pathway by which 4-HNE functions to confer its detrimental effects and provides a new therapeutic target for the treatment of DED.

Zidovudine protects hyperosmolarity-stressed human corneal epithelial cells via antioxidant pathway.

Dry Eye Disease (DED) is a very common disorder that can result in severe disability and vision loss. Although the pathogenesis of DED is not fully understood, hyperosmolarity, inflammation, and tear film instability are recognized as hallmarks of DED. Recently, Nucleoside Reverse Transcriptase Inhibitors (NRTIs), a class of medication used to treat HIV, have been shown to inhibit inflammation in a mouse model of retinal atrophy. In this study, we investigated whether Zidovudine (AZT) can inhibit human corneal epithelial cell (HCEC) inflammatory responses under hyperosmotic conditions. HCECs were cultured in hyperosmotic media containing AZT. Cell viability, cytokine production, and reactive oxygen species (ROS) production were measured. We found that AZT decreased nuclear factor kappa B (NF-κB) and Interleukin-6 (IL-6) levels, increased Superoxide Dismutase 1 (SOD1) production, decreased ROS production, and increased cell viability. These results support the novel use of AZT in the reduction of ocular surface inflammation and the promotion of corneal health in the context of DED.

Ethics - The Social Dimension of Health Care Ethics.

When you hear "health care ethics," I'm betting your mind goes right to clinical issues: at the bedside, in the intensive care unit, in the operating room, in the physician's office. The more fully informed might think about rationing, access or insurance. But mostly, our notions of health care ethics are rooted in an idea of the person as individual.

Preaching the Good News.

We have just moved into a season where the news of Jesus' triumph over death will be front and center in our liturgical celebrations. As we passed through the celebration of the paschal mystery, we experienced suffering, the tomb of human death and the promise of eternal life fulfilled.

Is There a Cure for Violence?

If you want to avoid violence, stay away from hospitals. The first time I went to an emer- gency room, to pick up an elderly friar who had taken a fall, I was shocked to encounter armed guards, metal detectors, police officers and even a handcuffed prisoner sitting in the waiting area. Was I in a hospital or a jail? This brief, daytime experience changed my im- age of emergency care forever. Since that first visit, I have learned that things are even worse than they appeared that day. Hospitals are dangerous places.

What Do We Make of Differences? How Diversity Can Be Reconciled with Solidarity?

Diversity is one of the hallmarks of our age. We hire and promote for diversity. Corporations have chief diversity officers, and they set diversity goals for their senior executives. We train our associates for cultural competency so that they can relate to our patients with greater sensitivity. In many ways, diversity is like Mom and apple pie ­ who could be against it?

Effects of activated omental cells on rat limbal corneal alkali injury.

Omental cells (OCs) are shown to help wound healing. The purpose of this study is to investigate if OCs improve cornea repair after alkali injury by subconjunctival injection of activated OCs in rats. Forty eight hours after limbal corneal alkali injury, fresh isolated OCs were injected subconjunctivally into the recipient rat's eye. Prior to the injury and at 0, 4 and 8 days after injury, the eyes were examined using slit lamp biomicroscopy. Corneal opacification and corneal neovascularization were graded in a masked fashion. The inflammatory response to the injury was evaluated by counting neutrophil cell numbers in the cornea under microscope. There was no significant difference in corneal opacification between the control and OCs treatment groups; however, the corneal neovascularization was significantly less in the eyes treated with OCs as compared to the controls. Also OCs treatment markedly decreased neutrophil infiltration after corneal-limbal alkali injury. Our results suggest that OCs may have a beneficial role in corneal healing after limbal corneal alkali injury by suppressing inflammatory cell infiltrates and corneal neovascularization.

The Impact of Donor History of Sleep Apnea on Corneal Tissue Evaluation Parameters.

PURPOSE: The goal of this study was to explore whether the donor history of sleep apnea affects corneal tissue evaluation parameters. METHODS: This was a retrospective study assessing the impact of donor history of sleep apnea in a dataset obtained from the Eversight Eye Bank. Comparative analysis and multivariate regression were used to assess differences in key parameters including endothelial cell density (ECD) and central corneal thickness. RESULTS: Data analyzed consisted of 50,170 tissues from 25,399 donors with no history of sleep apnea and 5473 tissues from 2774 donors with a history of sleep apnea. Tissue from donors with a history of sleep apnea showed lower ECD than those from donors with no history of sleep apnea (-51 cells/mm2, P < 0.001). Multivariate linear regression demonstrated that history of sleep apnea was a predictor of lower ECD by 13.72 cells/mm2 (P = 0.0264). Secondary analysis demonstrated that underweight and obese body mass indexes were significant predictors of increased ECD in donors with no history of sleep apnea (P < 0.0001, P = 0.025, respectively). Body mass index category was not a significant predictor of ECD in donors with a history of sleep apnea. In a smaller subset of 10,756 tissues, sleep apnea was not a significant predictor of central corneal thickness. CONCLUSIONS: This is the first study to demonstrate that a donor's history of sleep apnea is associated with a lower ECD in a large eye bank dataset. Future studies are needed to investigate whether history of sleep apnea affects posttransplantation outcomes.

Severe ocular complications of SJS/TEN and associations among pre-onset, acute, and chronic factors: a report from the international ophthalmology collaborative group.

We formed an international research collaboration that included Japan, South Korea, Brazil, Thailand, Taiwan, the UK, and the US (682 patients from 13 hospitals between 2005 and 2020), to better evaluate the role of race, ethnicity, and other risk factors in the pathophysiology of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Ophthalmologists often see SJS/TEN patients with severe ocular complications (SOC; frequency 50% SJS/TEN patients) when the patients are referred to them in the chronic stage after the acute stage has passed. Global data were collected using a Clinical Report Form, capturing pre-onset factors, as well as acute and chronic ocular findings. Key conclusions of this retrospective observational cohort study were as follows: (1) Ingestion of cold medications [acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs)] was significantly and positively correlated with trichiasis, symblepharon, and/or conjunctivalization of the cornea in the chronic stage; (2) common cold symptoms prior to onset of SJS/TEN were significantly and positively correlated with acute conjunctivitis and ocular surface erosions in the acute stage and with trichiasis and symblepharon and/or conjunctivalization of the cornea in the chronic stage; (3) patients with SJS/TEN who presented with SOC tended to be female; (4) patients less than 30 years of age are more likely to develop SOC in the acute and chronic stages of SJS/TEN; (5) patients with acute severe conjunctivitis with ocular surface erosion and pseudomembrane formation in the acute stage are more likely to develop ocular sequelae in the chronic stage; and (6) onychopathy in the acute stage was positively correlated with ocular sequelae in the chronic stage. Our findings show that the ingestion of cold medications, common cold symptoms prior to the onset of SJS/TEN, and a young age might strongly contribute to developing the SOC of SJS/TEN.

Concurrent and face validity of a capsulorhexis simulation with respect to human patients.

A prototype version of the ImmersiveTouch® virtual reality simulator was applied to capsulorhexis, the creation of circular tear or "rhexis" in the lens capsule of the eye during cataract surgery. Virtual and live surgery scores by residents were compared. The same three metrics are used in each mode: circularity of the rhexis, duration of surgery (sec), and number of forceps grabs of the capsule per completed rhexis (fewer is better). The average simulator circularity score correlated closely with the average live score (P = 0.0002; N = 4), establishing "concurrent validity" for this metric. Individuals performed similarly to each other in both modes, as shown by the low standard deviations for average circularity (virtual 0.92 ± 0.04; live 0.88 ± 0.04). By contrast, the standard deviations are high for the other two metrics, capsulorhexis duration (virtual 96.91 ± 44.23 sec; live 94.42 ± 65.74 sec, N = 8) and number of forceps grabs (virtual 10.66 ± 4.81; live 10.31 ± 5.23, N = 8). Nevertheless, the simulator was able to demonstrate that the surgeons with wide variations in total duration and number of capsular grabs in 2 to 4 trials of simulated surgery also had similar variations in live surgery, so that the simulator retains some realism or "face validity."

Review of culprit drugs associated with patients admitted to the burn unit with the diagnosis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Syndrome.

PURPOSE: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis Syndrome (TENS) are severe and potentially lethal adverse drug reactions characterized by acute inflammation of the skin, mucous membranes, and ocular surface that typically occurs within weeks of a culprit drug ingestion. The purpose of this study is to report a retrospective trend analysis of SJS spectrum diagnoses and associated culprit drugs in patients admitted to the Loyola University Medical Center (LUMC) Burn Unit, the major referral center in the Chicagoland region for patients with SJS disease spectrum. METHODS: The electronic medical records (EMR) of 163 patients with a diagnosis of SJS/TENS admitted to the LUMC Burn Unit from 2000 to 2019 were reviewed. Clinical data in addition to the well-established algorithm of drug causality for epidermal necrolysis (ALDEN) allowed us to identify the single most probable culprit drug in 131 cases. RESULTS: From 2000 to 2019, the most common spectrum classification was TENS (48.1%), followed by SJS (33.6%) and SJS-TEN Overlap Syndrome (18.3%). Anticonvulsants were found to be the most probable culprit class in 30% of cases followed by Trimethoprim-Sulfamethoxazole in 19% of cases. Beta-lactams were the most probable culprit class in 11% of cases while NSAIDs and allopurinol were each the most probable culprit class/drug in 8.4% of cases. CONCLUSIONS: This is one of the largest single center series of SJS/TENS cases in the United States. Further study into culprit drug distribution by region as well as continuous monitoring of trends is crucial in order to advise prescribing practices.

A novel telemedicine technique for evaluation of ocular exam findings via smartphone images.

In this study, we compared the assessment of remote smartphone photographs to in-office exams in the diagnosis of two groups of external eye diseases, red-eye pathology and post-operative eyelid surgery complications. Participants were examined and received an in-office diagnosis by either a corneal or oculoplastic specialist. After viewing an educational video on smartphone photography, the patient's companion then took a series of standardized photographs. Two additional corresponding specialists then made a separate diagnosis via the interpretation of only smartphone images and the patient's history. 'Remote' and in-office diagnoses were compared using a kappa test for agreement. The remote and in-office diagnoses were in agreement for 27 of 28 eyes, representing a chance-corrected Kappa agreement rate of 93% (95% confidence interval: 79-99%). Among the 16 red eyes, the diagnoses were in agreement for 15 of 16 red eyes, representing a chance-corrected Kappa agreement rate of 92% (95% confidence interval: 77-99%). Among the 12 eyes with post-operative eyelid surgery complications, the diagnoses were in perfect agreement. Our results suggest that the diagnosis of 1) red-eye pathology and 2) post-operative eyelid surgery complications based on smartphone images may be comparable to in-office exams.

Confocal microscopy of contact lens keratitis presenting as central toxic keratopathy.

OBJECTIVES: Central toxic keratopathy (CTK) after refractive surgery is a syndrome characterized by central corneal opacification, thinning, and a hyperopic shift. We report a similar presentation after extended contact lens wear. No prior confocal imaging has been reported in this contact lens case syndrome. METHODS: A 45-year-old white man presented with 3 weeks of photophobia and foreign body sensation after extended contact lens wear. Initial examination showed central stromal opacities, thinning, and hyperopic shifts, more in the right eye than in the left eye. RESULTS: Initial confocal microscopy showed collagen fibril edema and rearrangement with cellular infiltration and sparse refractile elements similar in appearance to immunoglobulin. The patient was treated with topical corticosteroids and was told to discontinue contact lenses. At 7 months, there was trace corneal haze, resolved corneal thinning, a 2-D residual hyperopic shift in the right eye, and a 1.5-D shift in the left eye. CONCLUSIONS: The clinical findings in our patient having contact lens keratitis resemble those of CTK postrefractive surgery cases, suggesting a similar mechanism. The lack of necrotic debris supports a cytokine-triggered apoptosis over an inflammatory cell-mediated necrosis as the cause of stromal tissue loss. Future confocal microscopy at different stages will help clarify the pathophysiologic condition of this rare syndrome.

Acute and Chronic Management of Ocular Disease in Stevens Johnson Syndrome/Toxic Epidermal Necrolysis in the USA.

Stevens Johnson syndrome and toxic epidermal necrolysis are on a spectrum of a severe, immune-mediated, mucocutaneous disease. Ocular involvement occurs in the vast majority of cases and severe involvement can lead to corneal blindness. Treatment in the acute phase is imperative in mitigating the severity of chronic disease. Advances in acute treatment such as amniotic membrane transplantation have shown to significantly reduce the severity of chronic disease. However, AMT is not a panacea and severe chronic ocular disease can and does still occur even with aggressive acute treatment. Management of chronic disease is equally critical as timely intervention can prevent worsening of disease and preserve vision. This mini-review describes the acute and chronic findings in SJS/TEN and discusses medical and surgical management strategies.

Corneal perforation in ocular graft-versus-host disease.

PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome. METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology. RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal "melt" in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar. CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies.

The Role of IL-13, IL-15 and Granulysin in the Pathogenesis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are Severe Cutaneous Adverse Reactions (SCARS) characterized by fever and mucocutaneous lesions leading to necrosis and sloughing of the epidermis. Conjunctival lesions are reported in 85% of patients. The pathogenesis of SJS/TEN/SCARS is not completely understood. It is hypothesized that IL-13, IL-15 and Granulysin expressed in plasma and skin may play a role. We measured the circulating levels of these cytokines in the plasma using ELISA and their expression in the skin using immunofluorescence microscopy. A total of 12 SJS/TEN skin biopsy samples (8 SJS, 2 SJS/TEN overlap and 2 TEN) were analyzed. Biopsy samples from patients with Lichen Planus (an inflammatory condition of the skin and mucous membranes) served as controls. Studies were also performed in human corneal epithelial cells where expression of these cytokines were measured following a challenge with TNF-α (0, 1, 10 and 100 ng/ml). The intensity of immunofluorescence was measured Using Imaris® software. The results showed significantly increased expression of these cytokines in the skin biopsy samples as measured by the average intensities of IL-13 (6.1 x 133.0 ± 4.231 x 10^8), and Granulysin (4.2 x 123.0 ± 4.231 x 10^8) compared to Lichen planus control (3.0 x 123.0 ±1.62 x 10^5). Increased expression of IL-13 and IL-15 were noted in cell culture studies and in the plasma samples when compared to Normal Human Plasma as controls. It is concluded that IL-13, IL-15 and Granulysin play a role in the pathogenesis of SJS/TEN.