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Huang T, Liang R-B, Zhang L-J, Shu H-Y, Ge Q-M, Liao X-L, Wu J-L, Su T, Pan Y-C, Zhou Q, Shao Y. Retinal microvasculature alteration in patients with systemic sclerosis and chloroquine treatment. Quant Imaging Med Surg 2022;12(10):4885-4899.Abstract
Background: Retinal vascular abnormality is an important part of ocular systemic sclerosis (SSc), and long-term use of chloroquine can lead to retinal toxicity. This study was conducted to evaluate retinal microvascular changes using optical coherence tomography angiography (OCTA) in patients with SSc and SSc patients on long-term chloroquine treatment. Methods: Fifteen SSc patients without chloroquine (30 eyes), 15 SSc patients taking long-term chloroquine (30 eyes) and 15 healthy controls (30 eyes) were recruited to this cross-sectional study. OCTA was used to examine the superficial and deep retinal capillary plexus in the macular retina of each eye. The densities of microvessels (MIR), macrovessels (MAR) and total microvessels (TMI) in the superficial and deep retina of the three groups were calculated and compared. We used the hemisphere segmentation method [superior right (SR), superior left (SL), inferior left (IL), and inferior right (IR)] and Early Treatment Diabetic Retinopathy Study (ETDRS) method [right (R), superior (S), left (L), and inferior (I)] to analyze changes in retinal microvascular density. Results: The superficial and deep retinal MIR density in SSc patients decreased (P<0.05) compared with the healthy control group. This significant difference was found in both superficial and deep layers in S, L, SR, SL and IL regions (P<0.05), and additionally in the R and I regions in the superficial layer (P<0.05). Similarly, compared with SSc patients who did not take chloroquine, the superficial and deep retinal MIR density of SSc patients on long-term chloroquine also decreased (P<0.05). This significant difference was found in both superficial and deep layers in R, I and IL regions (P<0.05), and additionally in the IR region in the superficial layer (P<0.05). Conclusions: The OCTA results suggest that retinal MIR density is decreased in SSc patients, and that long-term use of chloroquine will aggravate this damage, resulting in a further decrease in retinal MIR density.
Marcus DM, Silva PS, Liu D, Aiello LP, Antoszyk A, Elman M, Friedman S, Glassman AR, Googe JM, Jampol LM, Martin DF, Melia M, Preston CM, Wykoff CC, Sun JK, Sun JK. Association of Predominantly Peripheral Lesions on Ultra-Widefield Imaging and the Risk of Diabetic Retinopathy Worsening Over Time. JAMA Ophthalmol 2022;140(10):946-954.Abstract
Importance: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective: To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results: Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Conclusions and Relevance: Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.
Micheletti S, Merabet LB, Galli J, Fazzi E. VISUAL INTERVENTION IN EARLY ONSET VISUAL IMPAIRMENT: A REVIEW. Eur J Neurosci 2022;Abstract
Vision is a primary and motivating sense. Early visual experience derived from the external world is known to have an important impact on the development of central visual pathways and, not surprisingly, visual impairment constitutes a risk factor for overall development. In light of the role of vision in early brain development, infants and young children with visual impairment should be thus entitled to early and effective visual intervention programs. In this review, we discuss early visual interventions in infants and young children with visual impairment, focusing on their contents and outcomes. We defined a PICO format to critically review different models with a particular focus on parent-mediated and therapist-mediated approaches. We consider protocols that involved direct manipulation or improvement of the infants' visual inputs or were based on behavioral strategies and communication towards infants with visual impairment. We also provide an overview of the effectiveness of these protocols. A total of nine intervention protocols were selected for the purposes of this review. Substantial agreement regarding the importance of promoting the enrichment of infant environments, and more specifically in the context of active play that engages the whole family, has been reported in most of the studies. However, there is no clear agreement on methodological aspects, including clinical population characteristics, outcome measures, length of treatment, and follow-up programs. Further high-quality, carefully designed and adequately reported studies are needed in order to improve the clinical efficacy of these approaches to treating infants with visual impairment.
Betzler BK, Putera I, Testi I, Distia Nora RL, Kempen J, Md OMK, Pavesio C, Gupta V, Agrawal R. Anti-tubercular therapy in the treatment of tubercular uveitis: A systematic review and meta-analysis. Surv Ophthalmol 2022;Abstract
We quantitatively evaluated the efficacy of antitubercular therapy (ATT) in tubercular uveitis (TBU) patients. Main outcome measures include inflammation recurrence, inflammation reduction, complete resolution of inflammation, improved visual acuity (VA), ability to taper corticosteroids to < 10 mg/day without inflammatory progression, and use of adjunctive immunosuppressants while on ATT. This review is prospectively registered in PROSPERO (CRD42020206845). Forty-nine studies reporting data for 4,017 TBU patients were included. In comparative studies, the odds ratio (OR) of inflammatory recurrence was 0.33 (95%CI:0.19-0.60) for TBU patients treated with ATT±corticosteroid versus no ATT. For TBU patients treated with ATT±corticosteroid, the pooled absolute incidences of inflammatory recurrence, inflammatory reduction, complete resolution of inflammation, and visual acuity improvement were 13% (n=310/2,216; 95%CI:9-18), 81% (n=217/276; 95%CI: 62-95), 83% (n=1,167/1,812; 95%CI: 77-89), and 65% (n=347/542; 95%CI:51-78), respectively. Corticosteroids were tapered to <10 mg/day without inflammatory progression in 91% (n=326/395; 95%CI:78-99) of patients, 9% (n=121/1,376; 95%CI:6-13) of whom were administered concomitant immunosuppressive agents alongside ATT. We conclude that treatment of TBU with ATT±corticosteroid is associated with a high level of control or improvement of inflammation. More prospective studies with detailed reporting of ATT regimens, patient subgroups, and outcomes are required to better evaluate ATT effectiveness.
Elhusseiny AM, Abbasian J. Topical netarsudil 0.02% as adjunctive therapy in refractory pediatric glaucoma. J AAPOS 2022;Abstract
PURPOSE: To evaluate the efficacy of topical netarsudil 0.02% as adjunctive therapy in children with refractory pediatric glaucoma. METHODS: The medical records of patients ≤18 years diagnosed with pediatric glaucoma or ocular hypertension treated with topical netarsudil 0.02% from June 2019 to March 2022 were reviewed retrospectively. Data collected included age, sex, ethnicity, etiology of glaucoma, history of previous or subsequent glaucoma surgery, and intraocular pressure (IOP) before and after the addition of topical netarsudil. RESULTS: A total of 21 eyes of 16 patients (11 males) were included. Five patients used topical netarsudil in both eyes. Eight patients were Hispanic. The mean number of glaucoma surgeries and medications before initiating topical netarsudil was 1.8 ± 1.2 and 3.7 ± 0.5, respectively. The mean age prior to starting topical netarsudil was 8.9 ± 4.1 years. The mean follow-up after initiating topical netarsudil was 11.3 ± 8.2 months. The IOP was significantly reduced from 26.3 ± 6.2 mm Hg before topical netarsudil to 19.6 ± 6.02 mm Hg at 1 month in 15 eyes (P < 0.01), 18.2 ± 6.9 mm Hg at 3-months in 20 eyes (P < 0.01), 18.3 ± 7.3 mm Hg at 6 months in 13 eyes (P = 0.01), 17.6 ± 5.07 mm Hg at 9 months in 14 eyes (P = 0.002), and 17.4 ± 3.1 mm Hg at 12 months in 13 eyes (P = 0.002). Nine eyes (43%) underwent additional glaucoma surgery due to long-term failure of topical netarsudil to reduce IOP despite an initial reduction, and one eye had persistent IOP elevation ≥21 mm Hg despite the addition of topical netarsudil. CONCLUSIONS: In our small cohort of patients with refractory pediatric glaucoma, the addition of topical netarsudil reduced IOP, potentially delaying the need for surgery.
Hoyek S, Peacker BL, Acaba-Berrocal LA, Al-Khersan H, Zhao Y, Hartnett ME, Berrocal AM, Patel NA. The Male to Female Ratio in Treatment-Warranted Retinopathy of Prematurity: A Systematic Review and Meta-analysis. JAMA Ophthalmol 2022;140(11):1110-1120.Abstract
IMPORTANCE: Literature and anecdotal evidence suggest a relationship between male sex and retinopathy of prematurity (ROP). It is not known whether a difference, if present, is sex-related pathophysiologic predisposition or sex difference in meeting ROP screening criteria. OBJECTIVE: To evaluate the association of sex with the development of treatment-warranted ROP. DATA SOURCES: PubMed, Embase, and Web of Science databases were searched from 2000 to 2022. The search strategy used keywords including retinopathy of prematurity or ROP or retrolental fibroplasia and treatment or anti-VEGF or bevacizumab or ranibizumab or aflibercept or conbercept or laser or cryotherapy and gender or sex or male or female and medical subject headings terms. STUDY SELECTION: All studies reporting on treatment with anti-vascular endothelial growth factor, laser photocoagulation, and/or cryotherapy for ROP were identified. Studies reporting sex distribution in the treatment group were included in the meta-analysis. Exclusion criteria included case reports, case series of fewer than 10 treated patients, systematic reviews, conference abstracts, letters to the editor, animal studies, and non-English records. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened and extracted the data following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The proportions of treated male and female infants were combined using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Numbers and percentages of male and female infants treated for ROP. RESULTS: Of 11 368 identified studies, 316 met inclusion criteria, yielding a total of 31 026 treated patients. A higher percentage of male infants were treated for ROP (55% [95% CI, 0.54%-0.55%]), with low heterogeneity between studies (I2 = 34%; P < .001). Thirty-eight studies reported sex distribution in the screened population (170 053 patients; 92 612 [53%] male vs 77 441 [47%] female). There was no significant difference in the odds of receiving treatment between screened male and female infants (pooled odds ratio, 1.04 [95% CI, 0.91-1.18]; P = .67). CONCLUSIONS AND RELEVANCE: More male infants are treated for ROP than female infants. This could be due to a known relative pathophysiological fragility of preterm male infants in addition to a difference in ROP screening rates, with more male infants meeting the criteria than female infants. These findings have implications for future studies and may prompt more careful clinical monitoring of male neonates.
Silpa-Archa S, Sapthanakorn W, Foster SC. ISOLATED RETINAL VASCULITIS: Prognostic Factors and Expanding the Role of Immunosuppressive Treatment in Retinal Vasculitis Associated With Positive QuantiFERON-TB Gold Test. Retina 2022;42(10):1897-1908.Abstract
PURPOSE: To identify prognostic factors for poor visual outcomes in patients with isolated retinal vasculitis and to elucidate the outcome of immunosuppressive treatment without the use of antituberculosis drugs for patients with retinal vasculitis associated with a positive QuantiFERON-TB Gold In-Tube (QFT) test. METHODS: A retrospective chart review was performed of patients presenting with retinal vasculitis. After the diagnosis of active retinal vasculitis had been confirmed by fluorescein angiography and other possible causes of retinal vasculitis had been excluded, patients were categorized into two groups by their QFT result. Potential associated factors between the poor and good visual outcome groups were statistically analyzed by the chi-square test and logistic regression model with generalized estimating equations. RESULTS: Seventy-three eyes (48 patients) were enrolled in this study. After univariate analysis, multivariate logistic regression analysis was performed and revealed that logMAR visual acuity at the initial visit ( P = 0.01) and outer retinal disruption ( P = 0.03) were the two factors significantly associated with poor visual outcomes. Systemic corticosteroids were administered without the use of antituberculosis drugs to all 16 cases of presumed tuberculous retinal vasculitis associated with positive QFT (26 eyes), 10 (63%) of whom were given nonsteroidal immunosuppressive drugs and achieved inflammatory control and treatment success. CONCLUSION: Risk factors leading to poor visual outcome in patients with isolated retinal vasculitis have been identified. Immunosuppressive treatment without antituberculosis drugs seems to be a promising regimen for selected patients with presumed tuberculous retinal vasculitis under vigilant care.
Choudhury A, Reyes N, Galor A, Mehra D, Felix E, Moulton EA. Clinical neuroimaging of photophobia in individuals with chronic ocular surface pain. Am J Ophthalmol 2022;Abstract
PURPOSE: To examine neural mechanisms underlying photophobia in individuals with chronic ocular surface pain using functional magnetic resonance imaging (fMRI). DESIGN: Cross-sectional case/control analysis METHODS: 16 subjects from the Miami Veterans Affairs eye clinic underwent comprehensive ocular surface evaluations and were surveyed for ocular surface symptoms. Cases included subjects who reported chronic ocular surface pain symptoms and light sensitivity at least most of the time over one week. Controls included subjects without chronic ocular surface pain who reported no or minimal light sensitivity. All subjects viewed light stimuli during two fMRI scans, one before and one after topical anesthetic instillation, and rated their level of pain intensity to the stimulus at the end of each scan. Areas of brain activation in response to light stimuli presentation were correlated to pain responses and examined post- vs. pre-anesthesia. RESULTS: Cases (n=8) reported higher pain intensity ratings than controls (n=8) in response to light stimuli during fMRI. Case ratings correlated more with light-evoked activation in pain-related areas within the trigeminal brainstem, primary somatosensory cortex (S1), anterior mid-cingulate cortex (aMCC), and insula than with controls. Topical anesthesia led to varying responses in pain ratings among cases as well as decreased light-evoked activation in S1 and aMCC. CONCLUSIONS: The trigeminal nociceptive system may contribute to photophobia in individuals with chronic ocular surface pain. We demonstrate modulation of cortical structures in this pathway with topically applied anesthetic to the eyes. Further understanding of modulatory interactions that govern ocular surface pain and photophobia is critical for developing effective, precision-based therapies.
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.

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