Unilateral conjunctival Classic Kaposi Sarcoma following a COVID 19 booster.

Purpose: We describe a case of Classic Kaposi's sarcoma in a functionally monocular patient following a COVID19 vaccine booster and provide compelling evidence that suggests the booster was a relevant co-factor in the initiation of the disease process. Observations: The patient presented with red, irritated conjunctival area described as "bubbling" in her right eye. While her past medical history includes hypercholesterolemia and hypertension, she had no history of a compromised immune system. Her ophthalmologic history is more complex including treatment for glaucoma. The patient has 20/20 uncorrected vision OD and LP OS. Due to her ocular co-morbidities, the patient initially received interferon alpha 2-B qid for 6 weeks. However, topical therapy failed to decrease the size of the conjunctival lesions. After referral to Radiation Oncology, the right eye/orbit was treated with electron beam therapy for 1 month which caused a marked decrease in the size and vascularity of the conjunctival lesions. A slow improvement continued during followup. Conclusion and importance: In that the vaccine booster preceded the cancer, it appears etiologic to the appearance of Kaposi's sarcoma. The patient's monocular vision and glaucoma complicated her treatment. This case expands on current concepts of cofactors needed for the development of Kaposi's sarcoma in that vaccine booster administration was relevant to tumor progression and both clinical and mechanistic evidence is presented to support this hypothesis.

Orbital Fractures and Risk Factors for Ocular Injury.

Purpose: To identify factors predictive of serious ocular injury requiring urgent consultation by ophthalmology in patients presenting with blunt trauma orbital fractures. Methods: This is a retrospective study of adult patients diagnosed with orbital fractures after blunt trauma at a university medical center emergency room. Patient records were examined over a three-year period. Data including mechanism of injury, fracture location, ocular symptoms, and examination findings were recorded. Ocular injuries were divided into three levels of severity: mild, moderate, and severe. Fracture characteristics, patient demographics, and examination findings were analyzed using multinomial regression to identify risk factors for more severe injury. Results: One hundred and eighty-six patients met inclusion criteria. For 29.6% of patients, urgent ophthalmologic consultation was required. Ruptured globes occurred in 2.2% of injuries. There was a statistically significant association between severe ocular injury and three examination findings: poor vision (OR 14.5; p < 0.001), afferent pupillary defect (OR 44.8; p < 0.001), and abnormal pupillary reaction (OR 28.0; p < 0.001). Likewise, blurry vision (OR 3.6; p = 0.018), ocular pain (OR 3.7; p = 0.011), and facial pain (OR 4.4; p = 0.031) were also associated with an increased risk of severe ocular injury. Abnormal pupillary reaction was associated with moderate injury (OR 4.5; p = 0.041). Demographic factors, mechanism of injury, anti-coagulant use, fracture location, diplopia, no documented vision, subconjunctival hemorrhage, chemosis, and motility restriction were not associated with injury severity. Conclusion: Most patients who presented to the emergency room with an orbital fracture did not require urgent ophthalmologic consultation. The presence of blurry vision, ocular pain, facial pain, poor vision, and afferent pupillary defect significantly increased the odds of severe injury. Abnormal pupillary reaction was associated with both moderate and severe injury.

Bilateral microsporidial keratoconjunctivitis in a clinically healthy female receiving intravitreal steroid injections: Associations and potential risk factors.

Purpose: To present a unique case of bilateral microsporidial keratoconjunctivitis in a clinically healthy female receiving intravitreal steroid injections, and explore several associations and potential risk factors. Observations: A 75-year-old woman with chronic idiopathic anterior uveitis was receiving regular intravitreal steroid in both eyes for secondary cystoid macular edema. Flare-ups of iritis were usually treated with topical non-steroidal anti-inflammatory drops, but in the left eye the patient also received a few limited courses of topical corticosteroid. The patient regularly instilled topical cyclosporine 0.05% for dry eyes. She was otherwise clinically healthy but had low serum Immunoglobulin (Ig) M levels. There was no history of trauma or exposure to contamination. In her course of treatment, she developed a bilateral punctate keratitis. Corneal scrapings were diagnostic of Microsporidia. Topical voriconazole and moxifloxacin, as well as corneal debridement, were effective in resolving the infection. Conclusions and importance: We propose that the factors and associations described in this case--intravitreal steroid, topical steroid, topical cyclosporine, and IgM deficiency--contributed variably to create relative, local, immunologic suppression in our patient. Among these potential risk factors, we believe that intravitreal steroid exposure may be prominent. In aggregate, they facilitated development of her opportunistic microsporidial corneal infection. Eye care specialists should have a high index of suspicion for microsporidial keratitis, if they observe an atypical chronic punctate keratitis in patients with similar clinical associations.

Comparison of Comorbid Associations and Ocular Complications in Herpes Simplex and Zoster Keratitis.

A retrospective chart review examined adult patients with herpes simplex (HSV) and zoster (HZO) keratitis at a single institution. Patients who suffered a poor outcome (defined as visually significant corneal scarring, neurotrophic keratitis, secondary glaucoma, or requiring corneal surgery) were identified and each outcome type was analyzed in relation to age, sex, diabetes mellitus, immunosuppression, and a prior history of ≥2 ocular procedures.Advanced age, diabetes mellitus, and a prior history of ≥2 ocular procedures may be risk factors for poor outcomes in HSV, but not HZO, keratitis. In HSV, older age and DM were specifically associated with visually significant corneal scarring, while older age and male sex were associated with secondary glaucoma. Future prospective studies are warranted to determine the ideal management (including prophylaxis) in patients with these characteristics.

Transcriptional control of CBX5 by the RNA binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia.

RNA binding proteins (RBPs) are key arbiters of post-transcriptional regulation and are found to be found dysregulated in hematological malignancies. Here, we identify the RBP RBMX and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX/L1 are overexpressed in acute myeloid leukemia (AML) primary patients compared to healthy individuals, and RBMX/L1 loss delayed leukemia development. RBMX/L1 loss lead to significant changes in chromatin accessibility, as well as chromosomal breaks and gaps. We found that RBMX/L1 directly bind to mRNAs, affect transcription of multiple loci, including CBX5 (HP1α), and control the nascent transcription of the CBX5 locus. Forced CBX5 expression rescued the RBMX/L1 depletion effects on cell growth and apoptosis. Overall, we determine that RBMX/L1 control leukemia cell survival by regulating chromatin state through their downstream target CBX5. These findings identify a mechanism for RBPs directly promoting transcription and suggest RBMX/L1, as well as CBX5, as potential therapeutic targets in myeloid malignancies.

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation.

Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia. IKZF2 is highly expressed in leukemic stem cells (LSCs), and its deficiency results in defective LSC function. IKZF2 depletion in acute myeloid leukemia (AML) cells reduced colony formation, increased differentiation and apoptosis, and delayed leukemogenesis. Gene expression, chromatin accessibility, and direct IKZF2 binding in MLL-AF9 LSCs demonstrate that IKZF2 regulates a HOXA9 self-renewal gene expression program and inhibits a C/EBP-driven differentiation program. Ectopic HOXA9 expression and CEBPE depletion rescued the effects of IKZF2 depletion. Thus, our study shows that IKZF2 regulates the AML LSC program and provides a rationale to therapeutically target IKZF2 in myeloid leukemia.

Dual Strategies for Argonaute2-Mediated Biogenesis of Erythroid miRNAs Underlie Conserved Requirements for Slicing in Mammals.

While Slicer activity of Argonaute is central to RNAi, conserved roles of slicing in endogenous regulatory biology are less clear, especially in mammals. Biogenesis of erythroid Dicer-independent mir-451 involves Ago2 catalysis, but mir-451-KO mice do not phenocopy Ago2 catalytic-dead (Ago2-CD) mice, suggesting other needs for slicing. Here, we reveal mir-486 as another dominant erythroid miRNA with atypical biogenesis. While it is Dicer dependent, it requires slicing to eliminate its star strand. Thus, in Ago2-CD conditions, miR-486-5p is functionally inactive due to duplex arrest. Genome-wide analyses reveal miR-486 and miR-451 as the major slicing-dependent miRNAs in the hematopoietic system. Moreover, mir-486-KO mice exhibit erythroid defects, and double knockout of mir-486/451 phenocopies the cell-autonomous effects of Ago2-CD in the hematopoietic system. Finally, we observe that Ago2 is the dominant-expressed Argonaute in maturing erythroblasts, reflecting a specialized environment for processing slicing-dependent miRNAs. Overall, the mammalian hematopoietic system has evolved multiple conserved requirements for Slicer-dependent miRNA biogenesis.

Moraxella atlantae keratitis presenting with an infectious ring ulcer.

PURPOSE: Moraxella atlantae is a rare pathogen. Keratitis from this organism has never been specifically reported or described. In this report we provide the first clinical description and photograph of Moraxella atlantae infectious keratitis. OBSERVATIONS: A 41 year-old man presented with a three day history of left eye pain. He was found to have a corneal ring ulcer and infiltrate from which Moraxella atlantae was cultured. The patient was successfully treated with intensive topical gatifloxacin (0.5%) and fortified tobramycin (1.5%); oral doxycycline was added to reduce corneal thinning. The patient's infection resolved with a residual scar and final best corrected visual acuity of 20/200 OS. CONCLUSIONS AND IMPORTANCE: Moraxella atlantae can present as a ring-shaped infectious corneal infiltrate and ulcer. Ring infiltrates have been observed with other microorganisms, including several other gram negative bacteria and classically, acanthamoeba. Frequently presumed to be purely immunologic, corneal ring infiltrates can have a number of other etiologies, including infectious and toxic. There are different types of immunologic rings as well, making differentiation of corneal rings sometimes difficult for the ophthalmologic generalist and subspecialist alike. In this paper we discuss characteristics of various corneal ring infiltrates, along with their immune pathophysiology. Infectious rings are distinguished from immunologic Wessely rings.

The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.

Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells.

The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis. Gene expression profiling of SYNCRIP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program. SYNCRIP and MSI2 interact indirectly though shared mRNA targets. SYNCRIP maintains HOXA9 translation, and MSI2 or HOXA9 overexpression rescued the effects of SYNCRIP depletion. Altogether, our data identify SYNCRIP as a new RBP that controls the myeloid leukemia stem cell program. We propose that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.

Improved refractive outcomes of postgraduate year 4 cataract surgery after implementing a stepwise biometry lecture series reinforced by self-assessment at a teaching program.

PURPOSE: To determine whether a structured biometry course improves refractive outcomes of resident phacoemulsification. SETTING: Northeast Veterans Administration Hospital, Northport, New York, USA. DESIGN: Retrospective case study. METHODS: Phacoemulsification surgeries performed by residents before and after a biometry curriculum were reviewed. The inclusion criterion was phacoemulsification performed by residents. Patients with fewer than 3 months of follow-up were excluded. The main outcome measure-the mean absolute difference between the target and final refraction-was compared using a linear mixed model. RESULTS: Phacoemulsification surgeries performed by 4 residents before (n = 223) and by 4 residents after (n = 242) a biometry curriculum was implemented were reviewed. All measured preoperative factors were similar in both groups, including age, visual acuity, axial length, steep and flat keratometry values, astigmatism, anterior chamber depth, and lens thickness. Before the biometry course was instituted, 10% of patients had a mean absolute difference of less than 0.25 diopter (D); the percentage was 35% afterward. The mean absolute difference was less than 0.50 D in 40% before the curriculum was initiated and 70% after. The mean absolute difference was less than 1.00 D in 75% before the curriculum was initiated versus 94% after (all P < .05). The corrected distance visual acuities were similar in both groups, with 83% and 80%, respectively, having an acuity of at least 20/25 (P > .05). CONCLUSION: Residents' refractive predictions significantly improved after a formal biometry curriculum, showing that improvements in resident surgical outcomes are possible with structured curriculums reinforcing outcome measures. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Early-onset methicillin-resistant Staphylococcus aureus keratitis and late-onset infectious keratitis in astigmatic keratotomy incision following femtosecond laser-assisted cataract surgery.

UNLABELLED: A 79-year-old woman had uneventful femtosecond laser-assisted cataract surgery including paired laser astigmatic keratotomies (AKs) in the right eye. Three weeks postoperatively, a corneal infiltrate developed in the superotemporal AK incision. Cultures grew methicillin-resistant Staphylococcus aureus. The infection was treated with topical fortified vancomycin and tobramycin; full resolution required several months of therapy. Five months after cataract surgery, the patient presented with a second stromal infiltrate, also in the superotemporal AK incision. Despite negative cultures, the infiltrate resolved quickly on a short course of broad-spectrum fortified antibiotics. At 6 months, the corrected distance visual acuity was 20/30. This case demonstrates that infectious keratitis can occur following uneventful femtosecond laser-assisted AK performed concurrently with cataract surgery. We reviewed the literature on infectious keratitis following refractive keratotomy and femtosecond laser-assisted procedures. Several recommendations to prevent these infections are proposed. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, tolerability, safety, and future applications.

Eye disease due to herpes simplex virus (HSV) is a leading cause of ocular morbidity and the number one infectious cause of unilateral corneal blindness in the developed parts of the globe. Recurrent keratitis can result in progressive corneal scarring, thinning, and vascularization. Antiviral agents employed against HSV have primarily been nucleoside analogs. Early generation drugs included idoxuridine, iododesoxycytidine, vidarabine, and trifluridine. While effective, they tended to have low bioavailability and measurable local cellular toxicity due to their nonselective mode of action. Acyclovir 0.3% ointment is a more selective agent, and had become a first-line topical drug for acute HSV keratitis in Europe and other places outside of the US. Ganciclovir 0.15% gel is the most recently approved topical treatment for herpes keratitis. Compared to acyclovir 0.3% ointment, ganciclovir 0.15% gel has been shown to be better tolerated and no less effective in several Phase II and III trials. Additionally, topical ganciclovir does not cause adverse systemic side effects and is therapeutic at lower concentrations. Based on safety, efficacy, and tolerability, ganciclovir 0.15% gel should now be considered a front-line topical drug in the treatment of dendritic herpes simplex epithelial keratitis. Topics of future investigation regarding other potential uses for ganciclovir gel may include the prophylaxis of recurrent HSV epithelial keratitis, treatment of other forms of ocular disease caused by herpesviruses and adenovirus, and ganciclovir gel as an adjunct to antitumor therapy.

Infectious crystalline keratopathy associated with Klebsiella oxytoca.

PURPOSE: The purpose of this study is to report a novel case of a Klebsiella oxytoca-associated infectious crystalline keratopathy METHODS: This is a case report study. RESULTS: An 80-year-old woman presented with complaint of noticing a white spot in the left eye for 2 to 3 days, as well as mild soreness and discharge. Past ocular history was notable for a failed left corneal transplant for which she was taking prednisolone acetate 1 % twice per day. On slit-lamp examination, there was an extensive stromal ulcer and infiltrate in the inferior half of the transplant. Extending superiorly in the graft were branching, needle-like deep stromal opacities, characteristic of infectious crystalline keratopathy. Diagnostic scrapings revealed Gram-negative bacilli, subsequently identified on culture as K. oxytoca. There was also light growth of Staphylococcus species. The patient was placed on double topical antibiotic therapy with moxifloxacin and fortified tobramycin. After 2 months of treatment there was gradual resolution of the infection. CONCLUSIONS: K. oxytoca is a microorganism which can be associated with clinical infectious crystalline keratopathy, presenting as a mixed infection along with Staphylococcus species.

Clinical course and management of postoperative methicillin-resistant Staphylococcus aureus keratitis in immunocompromised patients: two case reports.

We describe the clinical course and successful treatment of two cases of methicillin-resistant Staphylococcus aureus (MRSA) keratitis. In case 1, MRSA keratitis occurred 5 days after cataract extraction, associated with endophthalmitis; in case 2, diagnosis was made 19 months after penetrating keratoplasty. Treatment in both cases consisted of topical fortified vancomycin and fortified bacitracin. A third topical antibiotic, polymyxin B-trimethoprim, was added to the therapeutic regimen in case 2, one month into the treatment. Oral doxycycline was prescribed to reduce collagenase activity and treat blepharitis. Mupirocin nasal ointment and skin antiseptics were used to decrease and eliminate potential MRSA colonization. Topical prednisolone acetate 1% was applied conservatively to mitigate inflammation in both cases. In case 2, topical cyclosporine A was also used for similar purposes. Keratitis may have worsened while on these immune-modulating drops, especially in case 2, and eradication of infection may have been slowed. Eventually both patients achieved full resolution of infection. Duration of keratitis was 3 and 1.5 months, respectively. Polyantimicrobial therapy is effective in eradicating MRSA-related postoperative keratitis. Topical fortified vancomycin and fortified bacitracin were used in both cases, with a third topical antibiotic, polymyxin B-trimethoprim, also required in case 2. Oral doxycycline, nasal mupirocin, and antiseptic soap may be useful adjuncts in management. Treatment time to achieve full resolution may be prolonged relative to other types of bacterial keratitis. Alterations in immune status may have lengthened the time of treatment. Our two patients were immune compromised and were also susceptible to endophthalmitis. It is possible that topical immune-modulating drops such as prednisolone acetate may potentiate MRSA infection, and if used, should be only done so with great caution.

Preoperative ketorolac tromethamine 0.4% in phacoemulsification outcomes: pharmacokinetic-response curve.

PURPOSE: To assess the clinical benefit, relative efficacy, and pharmacokinetic-response curve of preoperative and postoperative ketorolac tromethamine 0.4% (Acular LS) to improve outcomes during and after cataract surgery. SETTING: Private clinical practice. METHODS: One hundred patients were randomized in a double-masked fashion to 4 groups of 25 to receive ketorolac for 3 days, 1 day, or 1 hour or a placebo before phacoemulsification. All treatment groups received ketorolac 0.4% for 3 weeks postoperatively; the placebo group received vehicle. Outcomes measures were preservation of preoperative mydriasis, phacoemulsification time and energy, operative time, corneal clarity, endothelial cell counts, postoperative inflammation, intraoperative and postoperative discomfort, complications, and incidence of clinically significant cystoid macular edema (CME). RESULTS: Maintenance of pupil size with 3-day ketorolac dosing was significantly better than with 1-day dosing (P<.01), which was significantly better than with 1-hour or placebo dosing (P<.01). Both 3-day and 1-day dosing were superior to 1-hour or placebo dosing. No patient receiving ketorolac 0.4% for 1 or 3 days developed CME compared with 12% of patients in the control (placebo) group and 4% in the 1-hour group. Three-day and 1-day dosing of ketorolac reduced surgical time, phacoemulsification time and energy, and endothelial cell loss and improved visual acuity in the immediate postoperative period compared with 1-hour predosing and the placebo (P<.05). CONCLUSION: The preoperative use of ketorolac tromethamine 0.4% for 3 days followed by 1-day of predosing provided optimum efficacy and superior outcomes relative to 1-hour pretreatment and a placebo.