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Halawa OA, Jin Q, Pasquale LR, Kang JH, Lorch AC, Sobrin L, Miller JW, Li Y, Eslami M, Wang M, Zebardast N, Elze T. Race and Ethnicity Differences in Disease Severity and Visual Field Progression Among Glaucoma Patients. Am J Ophthalmol 2022;242:69-76.Abstract
PURPOSE: Investigate associations of race/ethnicity and preferred language with baseline glaucoma severity, VF test frequency and disease progression. DESIGN: Retrospective cohort study. METHODS: Patients receiving VF testing at a tertiary eyecare center between 1998 and 2020 with self-identified race, ethnicity and preferred language were included. Outcome measures were VF MD and age at first visit, VF test frequency, VF MD progression. RESULTS: Among 29,891 patients with VF measurements between 1998 and 2020, 55.1% were female, 71.0% self-identified as White/Caucasian, 14.0% as Black/African American, 7.4% as Asian and 6.4% as Hispanic, and 11.2% preferred a language other than English. Mean VF MD at presentation was worse among Black (-9.3±9.7 dB), Asian (-6.2±7.6 dB) and Hispanic (-8.3±9.3 dB) patients (vs. Whites [-5.5±7.3 dB, p<0.001] or non-Hispanics [-6.2±7.8 dB, p<0.001]). After controlling for age, gender and English proficiency, disparities in glaucoma severity at presentation were reduced, especially among Asian and Hispanic patients. Despite greater severity at presentation, Black patients had lower VF test frequency/person-years (1.07±0.53) compared to Whites (1.12±0.52, p=0.006) and worse VF MD progression (-0.43 dB/year, 95% CI -0.67 to -0.28, p<0.001). In contrast, Hispanics had a higher VF frequency vs. non-Hispanics (1.18±0.64 vs. 1.11±0.52, p<0.001), and no difference in VF progression (p=0.77). CONCLUSIONS: Black, Asian and Hispanic patients had greater baseline severity vs. Whites. Unlike other groups, Black patients had a lower VF frequency vs. Whites and greater VF progression. Disparities in baseline severity were partially explained by English proficiency, especially for Asian and Hispanic patients.
Wu M, Matar DY, Yu Z, Chen Z, Knoedler S, Ng B, Darwish OA, Sohrabi S, Friedman L, Haug V, Murphy GF, Rinkevich Y, Orgill DP, Panayi AC. Continuous NPWT Regulates Fibrosis in Murine Diabetic Wound Healing. Pharmaceutics 2022;14(10)Abstract
Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this study, we investigate the impact of micromechanical forces exerted through negative pressure wound therapy (NPWT) on the pathophysiology of fibrosis. Full-thickness excisional dorsal skin wounds were created on diabetic (db/db) mice which were treated with occlusive covering (control) or NPWT (continuous, -125 mmHg, 7 days; NPWT). Analysis was performed on tissue harvested 10 days after wounding. NPWT was associated with increased YAP (p = 0.04) but decreased En1 (p = 0.0001) and CD26 (p &lt; 0.0001). The pro-fibrotic factors Vimentin (p = 0.04), α-SMA (p = 0.04) and HSP47 (p = 0.0008) were decreased with NPWT. Fibronectin was higher (p = 0.01) and collagen deposition lower in the NPWT group (p = 0.02). NPWT increased cellular proliferation (p = 0.002) and decreased apoptosis (p = 0.03). Western blotting demonstrated increased YAP (p = 0.02) and RhoA (p = 0.03) and decreased Caspase-3 (p = 0.03) with NPWT. NPWT uncouples YAP from EPF activation, through downregulation of Caspace-3, a pro-apoptotic factor linked to keloid formation. Mechanotransduction decreases multiple pro-fibrotic factors. Through this multifactorial process, NPWT significantly decreases fibrosis and offers promising potential as a mode to improve scar appearance.
Wu M, Matar DY, Yu Z, Karvar M, Chen Z, Ng B, Knoedler S, Darwish O, Agarwal S, Orgill DP, Panayi AC. Xenogenic induction of adipose tissue and maintenance through pre- and post-conditioning using external volume expansion. Biomed Mater 2022;17(6)Abstract
External volume expansion (EVE) has been shown to improve fat graft survival. In this study, we investigated the xenogenic implantation of human allograft adipose matrix (AAM) in non-immunocompromised mice in combination with pre- and post-conditioning with EVE to assess long-term adipose tissue survival. Sixty-eight recipient sites in thirty-four eight-week-old wild type (C57BL/6J) mice were separated into four groups. Thirty-four sites received no conditioning and either a subcutaneous injection of 300 μl saline (n= 17; PBS group) or AAM (n= 17; AAM group). Thirty-four sites received pre-conditioning with EVE (Day -7-3 pre-grafting) and 300 μl of AAM. Seventeen of these sites received immediate post-conditioning (Day 1-5 post-grafting) and 17 delayed post-conditioning (Day 28-32 post-grafting). Tissue was harvested at week 12 for analysis. At 12 weeks, immediate and delayed post-conditioning enabled higher volume retention (p= 0.02 andp< 0.0001, respectively). Adipose Stem Cells were greater in the AAM+Del-EVE group compared to the AAM (p= 0.01). Microvessel density was lower in the AAM group compared to the AAM+Imm-EVE (p= 0.04) and AAM+Del-EVE group (p= 0.02). Macrophage infiltration was lower in the AAM+Imm-EVE (p= 0.002) and AAM+Del-EVE (p= 0.003) groups compared to the AAM group. PCR analysis and Western blotting identified a significantly higher expression of PPAR-γ, LPL and VEGF with delayed-conditioning. Pre- and post-conditioning, particularly delayed-post-conditioning, of the recipient site optimized the microenvironment allowing significant adipogenesis and survival of neo-adipose tissue through robust angiogenesis. This study supports that xenogenic transplantation of adipose matrix allows adipose tissue formation and survival with EVE as an adjuvant.
Freedman SF, Hercinovic A, Wallace DK, Kraker RT, Li Z, Bhatt AR, Boente CS, Crouch ER, Hubbard BG, Rogers DL, Vanderveen D, Yang MB, Cheung NL, Cotter SA, Holmes JM, Holmes JM. Low- and Very Low-Dose Bevacizumab for Retinopathy of Prematurity: Reactivations, Additional Treatments, and 12-Month Outcomes. Ophthalmology 2022;129(10):1120-1128.Abstract
PURPOSE: Low-dose and very low-dose intravitreal bevacizumab (IVB) have been reported to be successful in short-term treatment of type 1 retinopathy of prematurity (ROP), down to an initial dose of 0.004 mg. We now report 12-month outcomes for these infants. DESIGN: Masked, multicenter, dose de-escalation study. PARTICIPANTS: One hundred twenty prematurely born infants with type 1 ROP. METHODS: A cohort of 120 infants with type 1 ROP in at least 1 eye from 2 sequential dose de-escalation studies of low-dose IVB (0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg) or very low-dose IVB (0.016 mg, 0.008 mg, 0.004 mg, and 0.002 mg) to the study eye; the fellow eye (if also type 1) received 1 dose level higher of IVB. After primary success or failure at 4 weeks, clinical management was at investigator discretion, including all additional treatment. MAIN OUTCOME MEASURES: Reactivation of severe ROP by 6 months corrected age, additional treatments, retinal and other ocular structural outcomes, and refractive error at 12 months corrected age. RESULTS: Sixty-two of 113 study eyes (55%) and 55 of 98 fellow eyes (56%) received additional treatment. Of the study eyes, 31 (27%) received additional ROP treatment, and 31 (27%) received prophylactic laser therapy for persistent avascular retina. No trend toward a higher risk of additional ROP treatment related to initial IVB doses was found. However, time to reactivation among study eyes was shorter in eyes that received very low-dose IVB (mean, 76.4 days) than in those that received low-dose IVB (mean, 85.7 days). At 12 months, poor retinal outcomes and anterior segment abnormalities both were uncommon (3% and 5%, respectively), optic atrophy was noted in 10%, median refraction was mildly myopic (-0.31 diopter), and strabismus was present in 29% of infants. CONCLUSIONS: Retinal structural outcomes were very good after low- and very low-dose IVB as initial treatment for type 1 ROP, although many eyes received additional treatment. The rate of reactivation of severe ROP was not associated with dose; however, a post hoc data-driven analysis suggested that reactivation was sooner with very low doses.
Lu Y-C, Tsai Y-H, Chan Y-H, Hu C-J, Huang C-Y, Xiao R, Hsu C-J, Vandenberghe LH, Wu C-C, Cheng Y-F. Gene therapy with a synthetic adeno-associated viral vector improves audiovestibular phenotypes in Pjvk-mutant mice. JCI Insight 2022;7(20)Abstract
Recessive PJVK mutations that cause a deficiency of pejvakin, a protein expressed in both sensory hair cells and first-order neurons of the inner ear, are an important cause of hereditary hearing impairment. Patients with PJVK mutations garner limited benefits from cochlear implantation; thus, alternative biological therapies may be required to address this clinical difficulty. The synthetic adeno-associated viral vector Anc80L65, with its wide tropism and high transduction efficiency in various inner ear cells, may provide a solution. We delivered the PJVK transgene to the inner ear of Pjvk mutant mice using the synthetic Anc80L65 vector. We observed robust exogenous pejvakin expression in the hair cells and neurons of the cochlea and vestibular organs. Subsequent morphologic and audiologic studies demonstrated significant restoration of spiral ganglion neuron density and hair cells in the cochlea, along with partial recovery of sensorineural hearing impairment. In addition, we observed a recovery of vestibular ganglion neurons and balance function to WT levels. Our study demonstrates the utility of Anc80L65-mediated gene delivery in Pjvk mutant mice and provides insights into the potential of gene therapy for PJVK-related inner ear deficits.
Whitman MC, Gilette NM, Bell JL, Kim SA, Tischfield M, Engle EC. TWIST1, a gene associated with Saethre-Chotzen syndrome, regulates extraocular muscle organization in mouse. Dev Biol 2022;490:126-133.Abstract
Heterozygous loss of function mutations in TWIST1 cause Saethre-Chotzen syndrome, which is characterized by craniosynostosis, facial asymmetry, ptosis, strabismus, and distinctive ear appearance. Individuals with syndromic craniosynostosis have high rates of strabismus and ptosis, but the underlying pathology is unknown. Some individuals with syndromic craniosynostosis have been noted to have absence of individual extraocular muscles or abnormal insertions of the extraocular muscles on the globe. Using conditional knock-out alleles for Twist1 in cranial mesenchyme, we test the hypothesis that Twist1 is required for extraocular muscle organization and position, attachment to the globe, and/or innervation by the cranial nerves. We examined the extraocular muscles in conditional Twist1 knock-out animals using Twist2-cre and Pdgfrb-cre drivers. Both are expressed in cranial mesoderm and neural crest. Conditional inactivation of Twist1 using these drivers leads to disorganized extraocular muscles that cannot be reliably identified as specific muscles. Tendons do not form normally at the insertion and origin of these dysplastic muscles. Knock-out of Twist1 expression in tendon precursors, using scleraxis-cre, however, does not alter EOM organization. Furthermore, developing motor neurons, which do not express Twist1, display abnormal axonal trajectories in the orbit in the presence of dysplastic extraocular muscles. Strabismus in individuals with TWIST1 mutations may therefore be caused by abnormalities in extraocular muscle development and secondary abnormalities in innervation and tendon formation.
Moustafa GA, Liebman DL, Kabarriti G, Lorch AC, Vasan RA, Samal L, Nagykaldi ZJ, Osman NY, Kloek CE. Primary Care Provider Familiarity and Compliance with Preferred Practice Patterns for Comprehensive Eye Examinations. Am J Ophthalmol 2022;Abstract
PURPOSE: To assess primary care practitioners' (PCPs) familiarity with American Academy of Ophthalmology Preferred Practice Pattern (PPP) guidelines on the frequency of comprehensive eye examinations (CEEs) and explore their opinions and practices on counseling and referring patients for CEEs. DESIGN: Cross-sectional study. METHODS: Between February 1, 2019, and June 25, 2019, an anonymous survey was emailed to clinicians holding an MD, DO, PA, or NP degree, and residents at Brigham and Women's Hospital and University of Oklahoma. Descriptive statistics of participants' responses were reported. RESULTS: Regarding patient counseling on CEEs, 15.4% of PCPs reported "always", 48.1% "usually", and 36.5% "seldom" or "never" doing so. Few PCPs (11.1%) reported able to describe the guidelines and 63.9% were unaware of their existence. A strong majority of PCPs (90.7%) correctly referred a type 2 diabetic at their time of diagnosis, but a similar majority (77.8%) prematurely referred a newly-diagnosed type 1 diabetic. One in 7 (13.4%) PCPs would refer a patient with family history of glaucoma only upon developing visual/ocular symptoms. Compared to other providers, PAs/NPs were more likely to recommend unnecessary CEEs for low-risk individuals (p=0.009), while residents counseled patients less frequently (p=0.003), were less likely to be familiar with PPP guidelines (p=0.026), and less likely to recommend appropriate follow-ups for patients with family history of glaucoma (p=0.004). CONCLUSIONS: PCPs' awareness and familiarity with AAO CEE guidelines is variable and improves with provider age and experience. Efforts to improve PCP guideline awareness may be especially well-suited for residents and mid-level practitioners.
Cespedes JF, Arévalo-Alquichire S, Diaz LE, Valero MF. Assessment of the Anti-Thrombogenic Activity of Polyurethane Starch Composites. J Funct Biomater 2022;13(4)Abstract
The increasing morbidity and mortality of patients due to post-surgery complications of coronary artery bypass grafts (CABPG) are related to blood-material interactions. Thus, the characterization of the thrombogenicity of the biomaterial for cardiovascular devices is of particular interest. This research evaluated the anti-thrombogenic activity of polyurethanes-starch composites. We previously synthesized polyurethane matrices that were obtained from polycaprolactone diol (PCL), polyethylene glycol (PEG), pentaerythritol (PE), and isophorone diisocyanate (IPDI). In addition, potato starch (AL-N) and zwitterionic starch (AL-Z) were added as fillers. The anti-thrombogenic property was characterized by the clot formation time, platelet adhesion, protein absorption, TAT complex levels, and hemolysis. Additionally, we evaluated the cell viability of the endothelial and smooth muscle cells. Statically significant differences among the polyurethane matrices (P1, P2, and P3) were found for protein absorption and the blood clotting time without fillers. The polyurethanes composites with AL-Z presented an improvement in the anti-thrombogenic property. On the other hand, the composites with AL-Z reduced the viability of the endothelial cells and did not significantly affect the AoSCM (except for P1, which increased). These results classify these biomaterials as inert; therefore, they can be used for cardiovascular applications.
Chang TC, Calderon-Candelario RA, Berrocal AM, Briceño CA, Chen J, Shoham-Hazon N, Berco E, Solá-Del Valle D, Vanner EA. LGBTQ+ Identity and Ophthalmologist Burnout. Am J Ophthalmol 2022;Abstract
PURPOSE: To evaluate lesbian, gay, bisexual, transgender, questioning and other sexual/gender minority (LGBTQ+) orientation as a burnout risk factor among an international ophthalmologist cohort. METHODS: An anonymous, cross-sectional electronic survey was distributed via an internet platform to characterize the relationship between demographic factors, including LGBTQ+ orientation, and burnout as measured by the Copenhagen Burnout Inventory (CBI). Univariable data analysis (linear) by sexual orientation was performed and variables with association with p-value < 0.15 in univariable analysis were included in the multiple linear regression modeling. RESULTS: A total of 403 ophthalmologists participated in the survey, the majority self-identified as "White" (69.2%), were from North America (72.0% United States, 18.6% Canada), and were evenly distributed between age of 30 and 65 years. Overall, 13.2% of participants identified as LGBTQ+, 98.2% as cisgender. Approximately 12% had witnessed or experienced LGBTQ+-related workplace discrimination or harassment. The personal and work-related burnout scores and confidence limits of those identified as LGBTQ+ were higher and non-overlapping than those reported as non-LGBTQ+. Multivariable analysis identified significant risk factors for higher personal and work-related burnout scores: LGBTQ+ (11.8 and 11.1, P = .0005 and .0023), female gender (5.36 and 4.83, P = .0153 and .0434), older age (19.1 and 19.2, P = .0173 and .0273) and caretaker stress (6.42 and 5.97, P = .0085 and .0239). CONCLUSIONS: LGBTQ+ orientation is a burnout risk factor among ophthalmologists, and LGBTQ+ workplace discrimination may be a contributing factor. Support from ophthalmology organization to address LGBTQ+-, gender- and age-related work-place discrimination may decrease burnout.
Goldstein JE, Guo X, Swenor BK, Boland MV, Smith K. Using Electronic Clinical Decision Support to Examine Vision Rehabilitation Referrals and Practice Guidelines in Ophthalmology. Transl Vis Sci Technol 2022;11(10):8.Abstract
Purpose: To examine ophthalmologist use of an electronic health record (EHR)-based clinical decision support system (CDSS) to facilitate low vision rehabilitation (LVR) care referral. Methods: The CDSS alert was designed to appear when best documented visual acuity was <20/40 or hemianopia or quadrantanopia diagnosis was identified during an ophthalmology encounter from November 6, 2017, to April 5, 2019. Fifteen ophthalmologists representing eight subspecialties from an academic medical center were required to respond to the referral recommendation (order, don't order). LVR referral rates and ophthalmologist user experience were assessed. Encounter characteristics associated with LVR referrals were explored using multilevel logistic regression analysis. Results: The alert appeared for 3625 (8.9%) of 40,931 eligible encounters. The referral rate was 14.8% (535/3625). Of the 3413 encounters that met the visual acuity criterion only, patients who were worse than 20/60 were more likely to be referred, and 32.4% of referred patients were between 20/40 and 20/60. Primary reasons for deferring referrals included active medical or surgical treatment, refractive-related issues, and previous connection to LVR services. Eleven of the 13 ophthalmologists agreed that the alert was useful in identifying candidates for LVR services. Conclusions: A CDSS for patient identification and referral offers an acceptable mechanism to apply practice guidelines and prompt ophthalmologists to facilitate LVR care. Further study is warranted to optimize ophthalmologist user experience while refining alert criteria beyond visual acuity. Translational Relevance: The CDSS provides the framework for multi-center research to assess the development of pragmatic algorithms and standards for facilitating LVR care.
Kuo A, Checa A, Niaudet C, Jung B, Fu Z, Wheelock CE, Singh SA, Aikawa M, Smith LE, Proia RL, Hla T. Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis. Elife 2022;11Abstract
Serine palmitoyl transferase (SPT), the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL), is needed for embryonic development, physiological homeostasis, and response to stress. The functions of de novo SL synthesis in vascular endothelial cells (EC), which line the entire circulatory system, are not well understood. Here, we show that the de novo SL synthesis in EC not only regulates vascular development but also maintains circulatory and peripheral organ SL levels. Mice with an endothelial-specific gene knockout of SPTLC1 (Sptlc1 ECKO), an essential subunit of the SPT complex, exhibited reduced EC proliferation and tip/stalk cell differentiation, resulting in delayed retinal vascular development. In addition, Sptlc1 ECKO mice had reduced retinal neovascularization in the oxygen-induced retinopathy model. Mechanistic studies suggest that EC SL produced from the de novo pathway are needed for lipid raft formation and efficient VEGF signaling. Post-natal deletion of the EC Sptlc1 also showed rapid reduction of several SL metabolites in plasma, red blood cells, and peripheral organs (lung and liver) but not in the retina, part of the central nervous system (CNS). In the liver, EC de novo SL synthesis was important for acetaminophen-induced rapid ceramide elevation and hepatotoxicity. These results suggest that EC-derived SL metabolites are in constant flux between the vasculature, circulatory elements, and parenchymal cells of non-CNS organs. Taken together, our data point to the central role of the endothelial SL biosynthesis in maintaining vascular development, neovascular proliferation, non-CNS tissue metabolic homeostasis, and hepatocyte response to stress.
Houston KE, Paschalis EI. Feasibility of Magnetic Levator Prosthesis Frame Customization Using Craniofacial Scans and 3-D Printing. Transl Vis Sci Technol 2022;11(10):34.Abstract
Purpose: To determine the feasibility of a custom frame generation approach for nonsurgical management of severe blepharoptosis with the magnetic levator prosthesis (MLP). Methods: Participants (n = 8) with severe blepharoptosis (obscuring the visual axis) in one or both eyes who had previously been using a non-custom MLP had a craniofacial scan with a smartphone app to generate a custom MLP frame. A magnetic adhesive was attached to the affected eyelid. The custom MLP frame held a cylindrical magnet near the eyebrow above the affected eyelid, suspending it in the magnetic field while still allowing blinking. The spectacle magnet could be rotated manually, providing adjustable force via angular translation of the magnetic field. Fitting success and comfort were recorded, and interpalpebral fissure (IPF) was measured from video frames after 20 minutes in-office and one-week at-home use. Preference was documented, custom versus non-custom. Results: Overall, 88% of patients (7/8) were successfully fitted with a median 9/10 comfort (interquartile 7-10) and median ptosis improvement of 2.3 mm (1.3-5.0); P = 0.01). Exact binomial testing suggested, with 80% power, that the true population success rate was significantly greater than 45% (P = 0.05). Five participants took the custom MLP home for one week, with only one case of mild conjunctival redness which resolved without treatment. Highest to lowest force modulation resulted in a marginally significant median IPF adjustment of 1.5 mm (0.8 to 2.7; P = 0.06). All preferred the custom frame. Conclusions: The three-dimensional custom MLP frame generation approach using a smartphone app-based craniofacial scan is a feasible approach for clinical deployment of the MLP. Translational Relevance: First demonstration of customized frame generation for the MLP.
Noro T, Shah SH, Yin Y, Kawaguchi R, Yokota S, Chang K-C, Madaan A, Sun C, Coppola G, Geschwind D, Benowitz LI, Goldberg JL. Elk-1 regulates retinal ganglion cell axon regeneration after injury. Sci Rep 2022;12(1):17446.Abstract
Adult central nervous system (CNS) axons fail to regenerate after injury, and master regulators of the regenerative program remain to be identified. We analyzed the transcriptomes of retinal ganglion cells (RGCs) at 1 and 5 days after optic nerve injury with and without a cocktail of strongly pro-regenerative factors to discover genes that regulate survival and regeneration. We used advanced bioinformatic analysis to identify the top transcriptional regulators of upstream genes and cross-referenced these with the regulators upstream of genes differentially expressed between embryonic RGCs that exhibit robust axon growth vs. postnatal RGCs where this potential has been lost. We established the transcriptional activator Elk-1 as the top regulator of RGC gene expression associated with axon outgrowth in both models. We demonstrate that Elk-1 is necessary and sufficient to promote RGC neuroprotection and regeneration in vivo, and is enhanced by manipulating specific phosphorylation sites. Finally, we co-manipulated Elk-1, PTEN, and REST, another transcription factor discovered in our analysis, and found Elk-1 to be downstream of PTEN and inhibited by REST in the survival and axon regenerative pathway in RGCs. These results uncover the basic mechanisms of regulation of survival and axon growth and reveal a novel, potent therapeutic strategy to promote neuroprotection and regeneration in the adult CNS.

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