2022

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Huang JJ, Geduldig JE, Jacobs EB, Tai TYT, Ahmad S, Chadha N, Buxton DF, Vinod K, Wirostko BM, Kang JH, Wiggs JL, Ritch R, Pasquale LR. Head and Neck Region Dermatological Ultraviolet-Related Cancers are Associated with Exfoliation Syndrome in a Clinic-Based Population. Ophthalmol Glaucoma 2022;5(6):663-671.Abstract
OBJECTIVE: We assessed the relationship between ultraviolet (UV)-associated dermatological carcinomas (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) and exfoliation syndrome (XFS) or exfoliation glaucoma (XFG). DESIGN: Case-control study. PARTICIPANTS: Between 2019 and 2021, 321 participants and control subjects (XFS or XFG = 98; primary open-angle glaucoma [POAG] = 117; controls = 106; ages 50-90 years) were recruited. METHODS: A cross-sectional survey assessing medical history, maximum known intraocular pressure, cup-to-disc ratio, Humphrey visual field 24-2, the propensity to tan or burn in early life, history of BCC or SCC, and XFS or XFG diagnosis. The multivariable models adjusted for age, sex, medical history, eye color, hair color, and likeliness of tanning versus burning at a young age. MAIN OUTCOME MEASURES: History of diagnosed XFS or XFG. RESULTS: Any history of BCC or SCC in the head and neck region was associated with a 2-fold higher risk of having XFS or XFG versus having POAG or being a control subject (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.04-3.89) in a multivariable-adjusted analysis. We observed a dose-response association in which the chance of having XFS or XFG increased by 67% per head and neck BCC or SCC occurrence (OR, 1.67; 95% CI, 1.09-2.56). When we excluded POAG participants, head and neck BCC or SCC was associated with a 2.8-fold higher risk of XFS or XFG (OR, 2.80; 95% CI, 1.12-7.02), and each additional occurrence had a 2-fold higher risk of XFS or XFG (OR, 1.97; 95% CI, 1.09-3.58). The association between head and neck region BCC or SCC and POAG compared with the control subjects was null (OR, 1.42; 95% CI, 0.58-3.48). With BCC or SCC located anywhere on the body, there was a nonsignificantly higher risk of having XFS or XFG compared with having POAG or being a control subject (OR, 1.65; 95% CI, 0.88-3.09). CONCLUSIONS: Head and neck region BCCs or SCCs are associated with a higher risk of having XFS or XFG. These findings support prior evidence that head and neck UV exposure may be a risk factor for XFS.
Huang S, Liu C-H, Wang Z, Fu Z, Britton WR, Blomfield AK, Kamenecka TM, Dunaief JL, Solt LA, Chen J. REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2. Redox Biol 2022;51:102261.Abstract
Retinal pigment epithelium (RPE) dysfunction and atrophy occur in dry age-related macular degeneration (AMD), often leading to photoreceptor degeneration and vision loss. Accumulated oxidative stress during aging contributes to RPE dysfunction and degeneration. Here we show that the nuclear receptor REV-ERBα, a redox sensitive transcription factor, protects RPE from age-related degeneration and oxidative stress-induced damage. Genetic deficiency of REV-ERBα leads to accumulated oxidative stress, dysfunction and degeneration of RPE, and AMD-like ocular pathologies in aging mice. Loss of REV-ERBα exacerbates chemical-induced RPE damage, and pharmacological activation of REV-ERBα protects RPE from oxidative damage both in vivo and in vitro. REV-ERBα directly regulates transcription of nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase to counter oxidative damage. Moreover, aged mice with RPE specific knockout of REV-ERBα also exhibit accumulated oxidative stress and fundus and RPE pathologies. Together, our results suggest that REV-ERBα is a novel intrinsic protector of the RPE against age-dependent oxidative stress and a new molecular target for developing potential therapies to treat age-related retinal degeneration.
Huang YY, Hrycaj SM, Chan MP, Stagner AM, Patel RM, Bresler SC. PRAME Expression in Junctional Melanocytic Proliferations of the Conjunctiva: A Potential Biomarker for Primary Acquired Melanosis/Conjunctival Melanocytic Intraepithelial Lesions. Am J Dermatopathol 2022;44(10):734-740.Abstract
ABSTRACT: Conjunctival melanocytic proliferations are diagnostically challenging, often complicated by small specimen size, and are separated into 3 broad categories. The first group includes benign nevi and primary acquired melanosis (PAM) without atypia. The second group includes junctional melanocytic proliferations with a risk of progression to invasive melanoma (PAM with atypia). The last category is conjunctival melanoma, of which 65% of tumors arise in the setting of PAM with atypia. Preferentially expressed antigen in melanoma (PRAME) immunohistochemistry has been widely adopted to differentiate cutaneous nevi and melanoma. However, there are limited studies on its utility in the evaluation of conjunctival melanocytic proliferations with little data regarding its potential utility in stratifying PAM. Twenty-eight clinically annotated cases (14 PAM without atypia and 14 PAM with atypia) were retrospectively evaluated with PRAME/MART-1 duplex immunohistochemistry and were assigned the commonly used PRAME immunoreactivity score: 0 for no staining, 1+ for 1%-25% of cells positive, 2+ for 26%-50%, 3+ for 51%-75%, and 4+ for >75%. PAM without atypia showed low (0-3+) PRAME expression in 14 of 14 cases (100%). PAM with atypia showed strong and diffuse (4+) PRAME expression in 12 of 14 cases (86.7%). Seven of eight (87.5%) PAM with severe atypia, 4 of 4 PAM (100%) with moderate atypia, and 1 of 2 PAM (50%) with mild atypia showed 4+ PRAME expression. In addition, all 5 cases that recurred or progressed (all classified as PAM with atypia) showed 4+ PRAME expression. Although additional larger studies are needed, PRAME seems to be a useful adjunct in evaluating junctional melanocytic proliferations of the conjunctiva.
Huang X, Saki F, Wang M, Elze T, Boland MV, Pasquale LR, Johnson CA, Yousefi S. An Objective and Easy-to-Use Glaucoma Functional Severity Staging System Based on Artificial Intelligence. J Glaucoma 2022;Abstract
OBJECTIVE: To develop an objective and easy-to-use glaucoma staging system based on visual fields (VFs). SUBJECTS AND PARTICIPANTS: A total of 13,231 VFs from 8077 subjects were used to develop models and 8024 VFs from 4445 subjects were used to validate models. METHODS: We developed an unsupervised machine learning model to identify clusters with similar VF values. We annotated the clusters based on their respective mean deviation (MD). We computed optimal MD thresholds that discriminate clusters with highest accuracy based on Bayes minimum error principle. We evaluated the accuracy of the staging system and validated findings based on an independent validation dataset. RESULTS: The unsupervised k-means algorithm discovered four clusters with 6784, 4034, 1541, and 872 VFs and average MDs of 0.0▒dB (±1.4: Standard Deviation), -4.8▒dB (±1.9), -12.2▒dB (±2.9), and -23.0▒dB (±3.8), respectively. The supervised Bayes minimum error classifier identified optimal MD thresholds of -2.2▒dB, -8.0▒dB, and -17.3▒dB for discriminating normal eyes and eyes at the early, moderate, and advanced stages of glaucoma. The accuracy of the glaucoma staging system was 94%, based on identified MD thresholds with respect to the initial k-means clusters. CONCLUSIONS: We discovered that four severity levels based on MD thresholds of -2.2▒dB, -8.0▒dB, and -17.3▒dB, provides the optimal number of severity stages based on unsupervised and supervised machine learning. This glaucoma staging system is unbiased, objective, easy-to-use, and consistent, which makes it highly suitable for use in glaucoma research and for day-to-day clinical practice.
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.
Huh DD, Wang J, Fliotsos MJ, Beal CJ, Boente CS, Wisely EC, De Andrade LM, Lorch AC, Ramanathan S, Reinoso MA, Swamy RN, Waxman EL, Woreta FA, Srikumaran D. Association Between Parental Leave and Ophthalmology Resident Physician Performance. JAMA Ophthalmol 2022;140(11):1066-1075.Abstract
IMPORTANCE: Although parental leave is essential in enhancing resident wellness and fostering inclusive workplace environments, residents may often feel discouraged from using parental leave owing to perceived stigma and concerns about possible negative effects on their training. OBJECTIVE: To examine parental leave usage across multiple institutions and compare residency performance metrics between residents who took parental leave vs their peers who did not take leave. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cross-sectional analysis conducted from April 1, 2020, to July 28, 2022, of educational records. Multicenter data were obtained from 10 Accreditation Council for Graduate Medical Education (ACGME)-accredited ophthalmology programs across the US. Included ophthalmology residents graduated between 2015 and 2019. Data were analyzed from August 15, 2021, to July 25, 2022. EXPOSURES: Performance metrics of residents who used parental leave during residency were compared with those of residents who did not take parental leave. MAIN OUTCOMES AND MEASURES: Measures of performance included the Ophthalmic Knowledge Assessment Program (OKAP) scores, ACGME milestones scores, board examination pass rates, research activity, and surgical volumes. RESULTS: Of the 283 ophthalmology residents (149 male [52.7%]) included in the study, 44 (15.5%) took a median (IQR) parental leave of 4.5 (2-6) weeks. There were no differences in average OKAP percentiles, research activity, average ACGME milestones scores, or surgical volume between residents who took parental leave and those who did not. Residents who pursued fellowship were less likely to have taken parental leave (odds ratio [OR], 0.43; 95% CI, 0.27-0.68; P < .001), and residents who practiced in private settings after residency were more likely to have taken parental leave (OR, 3.56; 95% CI, 1.79-7.08; P < .001). When stratified by sex, no differences were identified in performance between female residents who took parental leave compared with residents who did not take leave, except a mild surgical number difference in 1 subspecialty category of keratorefractive procedures (difference in median values, -2; 95% CI, -3.7 to -0.3; P = .03). CONCLUSIONS AND RELEVANCE: In this multicenter cross-sectional study, no differences in performance metrics were identified between residents taking parental leave compared with their peers. These findings may provide reassurance to trainees and program directors regarding the unlikelihood, on average, that taking adequate parental leave will affect performance metrics adversely.
Hunter DG. Enhancing comparison of different vision screening approaches. J AAPOS 2022;
Hynnekleiv L, Magno M, Vernhardsdottir RR, Moschowits E, Tønseth KA, Dartt DA, Vehof J, Utheim TP. Hyaluronic acid in the treatment of dry eye disease. Acta Ophthalmol 2022;100(8):844-860.Abstract
Dry eye disease (DED) is a highly prevalent and debilitating condition affecting several hundred million people worldwide. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan commonly used in the treatment of DED. This review aims to critically evaluate the literature on the safety and efficacy of artificial tears containing HA used in DED treatment. Literature searches were conducted in PubMed, including MEDLINE, and in Embase via Ovid with the search term: "(hyaluronic acid OR hyaluronan OR hyaluronate) AND (dry eye OR sicca)". A total of 53 clinical trials are included in this review, including eight placebo-controlled trials. Hyaluronic acid concentrations ranged from 0.1% to 0.4%. Studies lasted up to 3 months. A broad spectrum of DED types and severities was represented in the reviewed literature. No major complications or adverse events were reported. Artificial tears containing 0.1% to 0.4% HA were effective at improving both signs and symptoms of DED. Two major gaps in the literature have been identified: 1. no study investigated the ideal drop frequency for HA-containing eyedrops, and 2. insufficient evidence was presented to recommend any specific HA formulation over another. Future investigations assessing the optimal drop frequency for different concentrations and molecular weights of HA, different drop formulations, including tonicity, and accounting for DED severity and aetiology are essential for an evidence-based, individualized approach to DED treatment.
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Ichhpujani P, Thakur S, Singh T, Singh RB, Kumar S. Effect of laser peripheral iridotomy on contrast sensitivity using Spaeth/Richman Contrast Sensitivity test. Ther Adv Ophthalmol 2022;14:25158414221078142.Abstract
Background: Laser peripheral iridotomy (LPI) is the current standard of care for primary angle-closure glaucoma. The existing literature lacks evidence regarding the effects of LPI on contrast sensitivity (CS) after the procedure. Objective: This study evaluates central and peripheral CS in patients undergoing LPI using the computer-based, Spaeth/Richman Contrast Sensitivity (SPARCS) test. Methods: We performed a pilot, prospective, interventional cohort study including 30 patients of primary angle-closure suspect (PACS) or primary angle closure (PAC) in both eyes. LPI was performed after a detailed history and clinical examination using standard procedure in all eyes. Intraocular pressure (IOP) and CS testing using SPARCS was performed before, 2 weeks and 3 months after LPI. Results: Data analyses revealed female predominance (66.67%, 20/30); the mean age of enrolled patients was 49.93 ± 10.43 years, and presenting acuity was 0.02 ± 0.06 (Log of Minimum Angle of Resolution [LogMAR]). The mean vertical cup-to-disc ratio (VCDR), mean deviation (MD in dB) and pattern standard deviation (PSD in dB) were 0.34 ± 0.09, -2.36 ± 1.72 and 2.34 ± 0.81, respectively. There was a statistically significant decrease between the pre- (15.17 ± 3.83 mmHg) and 2 weeks post-LPI (11.70 ± 1.53 mmHg) IOP (p < 0.001). However, CS in the pre- (73.47 ± 9.88) and 3 months post-LPI (75.20 ± 11.98) SPARCS scores did not reveal any statistical difference. The group-wise analysis showed a similar trend between PAC and PACS patients. Conclusion: LPI does not affect central as well as peripheral CS assessment in patients with the primary angle-closure disease.
Islam MM, Chivu A, AbuSamra DB, Saha A, Chowdhuri S, Pramanik B, Dohlman CH, Das D, Argüeso P, Rajaiya J, Patra HK, Chodosh J. Crosslinker-free collagen gelation for corneal regeneration. Sci Rep 2022;12(1):9108.Abstract
Development of an artificial cornea can potentially fulfil the demand of donor corneas for transplantation as the number of donors is far less than needed to treat corneal blindness. Collagen-based artificial corneas stand out as a regenerative option, having promising clinical outcomes. Collagen crosslinked with chemical crosslinkers which modify the parent functional groups of collagen. However, crosslinkers are usually cytotoxic, so crosslinkers need to be removed from implants completely before application in humans. In addition, crosslinked products are mechanically weak and susceptible to enzymatic degradation. We developed a crosslinker free supramolecular gelation strategy using pyrene conjugated dipeptide amphiphile (PyKC) consisting of lysine and cysteine; in which collagen molecules are intertwined inside the PyKC network without any functional group modification of the collagen. The newly developed collagen implants (Coll-PyKC) are optically transparent and can effectively block UV light, are mechanically and enzymatically stable, and can be sutured. The Coll-PyKC implants support the growth and function of all corneal cells, trigger anti-inflammatory differentiation while suppressing the pro-inflammatory differentiation of human monocytes. Coll-PyKC implants can restrict human adenovirus propagation. Therefore, this crosslinker-free strategy can be used for the repair, healing, and regeneration of the cornea, and potentially other damaged organs of the body.
Ismail AM, Saha A, Lee JS, Painter DF, Chen Y, Singh G, Condezo GN, Chodosh J, San Martín C, Rajaiya J. RANBP2 and USP9x regulate nuclear import of adenovirus minor coat protein IIIa. PLoS Pathog 2022;18(6):e1010588.Abstract
As intracellular parasites, viruses exploit cellular proteins at every stage of infection. Adenovirus outbreaks are associated with severe acute respiratory illnesses and conjunctivitis, with no specific antiviral therapy available. An adenoviral vaccine based on human adenovirus species D (HAdV-D) is currently in use for COVID-19. Herein, we investigate host interactions of HAdV-D type 37 (HAdV-D37) protein IIIa (pIIIa), identified by affinity purification and mass spectrometry (AP-MS) screens. We demonstrate that viral pIIIa interacts with ubiquitin-specific protease 9x (USP9x) and Ran-binding protein 2 (RANBP2). USP9x binding did not invoke its signature deubiquitination function but rather deregulated pIIIa-RANBP2 interactions. In USP9x-knockout cells, viral genome replication and viral protein expression increased compared to wild type cells, supporting a host-favored mechanism for USP9x. Conversely, RANBP2-knock down reduced pIIIa transport to the nucleus, viral genome replication, and viral protein expression. Also, RANBP2-siRNA pretreated cells appeared to contain fewer mature viral particles. Transmission electron microscopy of USP9x-siRNA pretreated, virus-infected cells revealed larger than typical paracrystalline viral arrays. RANBP2-siRNA pretreatment led to the accumulation of defective assembly products at an early maturation stage. CRM1 nuclear export blockade by leptomycin B led to the retention of pIIIa within cell nuclei and hindered pIIIa-RANBP2 interactions. In-vitro binding analyses indicated that USP9x and RANBP2 bind to C-terminus of pIIIa amino acids 386-563 and 386-510, respectively. Surface plasmon resonance testing showed direct pIIIa interaction with recombinant USP9x and RANBP2 proteins, without competition. Using an alternative and genetically disparate adenovirus type (HAdV-C5), we show that the demonstrated pIIIa interaction is also important for a severe respiratory pathogen. Together, our results suggest that pIIIa hijacks RANBP2 for nuclear import and subsequent virion assembly. USP9x counteracts this interaction and negatively regulates virion synthesis. This analysis extends the scope of known adenovirus-host interactions and has potential implications in designing new antiviral therapeutics.
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J K, MT KN, H A, MM P, R D, JL W, AP K, LR P, JH K, and for International Glaucoma Genetics Consortium (IGGC), UK Biobank Eye and Vision Consortium MRFG. Statin Use in Relation to Intraocular Pressure, Glaucoma, and Ocular Coherence Tomography Parameters in the UK Biobank. Invest Ophthalmol Vis Sci 2022;63(5):3.
Jacoba CMP, Ashraf M, Cavallerano JD, Tolson AM, Tolls D, Pellegrini E, Fleming A, Sun JK, Aiello LP, Silva PS. Association of Maximizing Visible Retinal Area by Manual Eyelid Lifting With Grading of Diabetic Retinopathy Severity and Detection of Predominantly Peripheral Lesions When Using Ultra-Widefield Imaging. JAMA Ophthalmol 2022;140(4):421-425.Abstract
Importance: Methods that increase visible retinal area (VRA; measured in millimeters squared) may improve identification of diabetic retinopathy (DR) lesions. Objective: To evaluate the association of dilation and manual eyelid lifting (MLL) with VRA on ultra-widefield imaging (UWFI) and the association of VRA with grading of DR severity and detection of predominantly peripheral lesions (PPLs). Design, Setting, and Participants: Retrospective, comparative case-control study at the Joslin Diabetes Center, Boston, Massachusetts. Nonmydriatic UWFI with MLL was acquired from a DR teleophthalmology program (Joslin Vision Network [JVN]). A second cohort of mydriatic UWFI was acquired at an academic retina practice (Beetham Eye Institute [BEI]) from November 6, 2017, to November 6, 2018, and with MLL thereafter until November 6, 2019. Fully automated algorithms determined VRA and hemorrhage and/or microaneurysm (HMA) counts. Predominantly peripheral lesions and HMAs were defined as present when at least 1 field had greater HMA number in the peripheral retina than within the corresponding Early Treatment Diabetic Retinopathy Study field. Participants included 3014 consecutive patients (5919 eyes) undergoing retinal imaging at JVN and BEI. Exposures: Dilation and MLL performed at the time of UWFI. Main Outcomes and Measures: Visible retinal area, DR severity, and presence of PPLs. Results: Of the 3014 participants, mean (SD) age was 56.1 (14.5) years, 1302 (43.2%) were female, 2450 (81.3%) were White, and mean (SD) diabetes duration was 15.9 (11.4) years. All images from 5919 eyes with UWFI were analyzed. Mean (SD) VRA was 665.1 (167.6) mm2 for all eyes (theoretical maximal VRA, 923.9 mm2), 550.8 (240.7) mm2 for nonmydriatic JVN with MLL (1418 eyes [24.0%]), 688.1 (119.9) mm2 for mydriatic BEI images (3650 eyes [61.7%]), and 757.0 (69.7) mm2 for mydriatic and MLL BEI images (851 eyes [14.4%]). Dilation increased VRA by 25% (P < .001) and MLL increased VRA an additional 10% (P < .001). Nonmydriatic MLL increased VRA by 11.0%. With MLL, HMA counts in UWFI fields increased by 41.7% (from 4.8 to 6.8; P < .001). Visible retinal area was moderately associated with increasing PPL-HMA overall and in each cohort (all, r = 0.33; BEI, r = 0.29; JVN, r = 0.36; P < .001). In JVN images, increasing VRA was associated with more PPL-HMA (quartile 1 [Q1], 23.7%; Q2, 45.8%; Q3, 60.6%; and Q4, 69.2%; P < .001). Conclusions and Relevance: Using fully automated VRA and HMA detection algorithms, pupillary dilation and eyelid lifting were shown to substantially increase VRA and PLL-HMA detection. Given the importance of HMA and PPL for determining risk of DR progression, these findings emphasize the importance of maximizing VRA for optimal risk assessment in clinical trials and teleophthalmology programs.
Jacobs DS, Lee JK, Shen TT, Afshari NA, Bishop RJ, Keenan JD, Vitale S. Refractive Surgery Preferred Practice Pattern®. Ophthalmology 2023;130(3):P61-P135.
Jacobs HIL, Schoemaker D, Torrico-Teave H, Zuluaga Y, Velilla-Jimenez L, Ospina-Villegas C, Lopera F, Arboleda-Velasquez JF, Quiroz YT. Specific Abnormalities in White Matter Pathways as Interface to Small Vessels Disease and Cognition in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Individuals. Brain Connect 2022;12(1):52-60.Abstract
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by leukoencephalopathy leading to cognitive impairment. Subtle cognitive deficits can be observed early in the course of the disease, before the occurrence of the first stroke. Therefore, markers that can predict disease progression at this early stage, when interventions are likely to alter disease course, are needed. We aimed to examine the biological cascade of microstructural and macrostructural white matter (WM) abnormalities underlying cognitive deficits in CADASIL. Methods: We examined 20 nondemented CADASIL mutation carriers and 23 noncarriers who underwent neuropsychological evaluation and magnetic resonance imaging. Using probabilistic tractography of key WM tracts, we examined group differences in diffusivity measures and WM hyperintensity volume. Successive mediation models examined whether tract-specific WM abnormalities mediated subtle cognitive differences between CADASIL mutation carriers and noncarriers. Results: The largest effect size differentiating the two groups was observed for left superior longitudinal fasciculus-temporal (SLFt) diffusivity (Cohen's f = 0.49). No group differences were observed with a global diffusion measure. These specific microstructural differences in the SLFt were associated with higher WM hyperintensities burden, and subtle executive deficits in CADASIL mutation carriers. Discussion: Worse diffusivity in the left SLFt is related to greater severity of small vessel disease and worse executive functioning in the asymptomatic stage of the disease. Worse diffusivity of the left SLFt may potentially hold promise as an indicator of disease progression. Impact statement Diffusion tensor imaging outperforms conventional imaging of subcortical small vessel disease as a potential marker of future disease progression. Here we identified the left superior longitudinal temporal fasciculus as a critical white matter fiber bundle, of which worse diffusivity can link presence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy mutations to greater severity of small vessel disease and worse executive functioning in asymptomatic stages of the disease. This tract may hold promise and deserves further examination as an early indicator of disease progression.
Jacobs DS. Knowledge. Eye Contact Lens 2022;48(7):277.
Jhaveri CD, Glassman AR, Ferris FL, Liu D, Maguire MG, Allen JB, Baker CW, Browning D, Cunningham MA, Friedman SM, Jampol LM, Marcus DM, Martin DF, Preston CM, Stockdale CR, Sun JK, Sun JK. Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema. N Engl J Med 2022;Abstract
BACKGROUND: In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear. METHODS: At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed. RESULTS: A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group. CONCLUSIONS: In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).
Ji MH, Callaway NF, Ludwig CA, Vail D, Al-Moujahed A, Rosenblatt TR, Leng T, Sanislo SR, Moshfeghi DM. Visual acuity and progression of macular atrophy in patients receiving intravitreal anti-VEGF for age-related macular degeneration. Eur J Ophthalmol 2022;32(1):429-435.Abstract
PURPOSE: Whether intravitreal anti-vascular endothelial growth factors (VEGFs) cause retinal atrophy is still a subject of debate. We reported 13 eyes that received several injections of anti-VEGF for wet age-related macular degeneration (AMD) with good visual acuity despite geographic atrophy on imaging. METHODS: This is a case series study conducted at Byers Eye Institute at Stanford University. Patients of three retina specialists with wet AMD who received six or more intravitreal injection of anti-VEGFs with visual acuity of 20/60 or better and incomplete RPE and outer retina atrophy (iRORA) or complete RPE and outer retinal atrophy (cRORA) were enrolled in this case series. Different imaging modalities were reviewed by three retina specialists comparing the baseline with the most recent exam. RESULTS: About 13 eyes of 10 patients met the selection criteria. Eleven eyes were classified as iRORA and 2 as cRORA. Despite the development of macular atrophy on imaging after an average of 38.1 injections, eyes maintained stable visual acuity. CONCLUSION: The discrepancy between structural and functional findings in this cohort suggests that patients treated by anti-VEGF drugs exhibit divergent clinical outcomes for currently unknown reasons. The authors propose anti-VEGF may affect melanosomes within RPE without disrupting RPE and photoreceptors function completely. This requires further investigation.
Juang J, Xiao M, Chen SH, Macias AA. Impact of perioperative dexmedetomidine use in cataract surgery. J Cataract Refract Surg 2022;48(7):855-857.
Jumelle C, Yung A, Shirzaei Sani E, Taketani Y, Gantin F, Bourel L, Wang S, Yüksel E, Seneca S, Annabi N, Dana R. Development and characterization of a hydrogel-based adhesive patch for sealing open-globe injuries. Acta Biomater 2022;137:53-63.Abstract
Full-thickness wounds to the eye can lead to serious vision impairment. Current standards of care (from suturing to tissue transplantation) usually require highly skilled surgeons and use of an operating theater. In this study, we report the synthesis, optimization, and in vitro and ex vivo testing of photocrosslinkable hydrogel-based adhesive patches that can easily be applied to globe injuries or corneal incisions. According to the type and concentration of polymers used in the adhesive formulations, we were able to finely tune the physical properties of the bioadhesive including viscosity, elastic modulus, extensibility, ultimate tensile strength, adhesion, transparency, water content, degradation time, and swellability. Our in vitro studies showed no sign of cytotoxicity of the hydrogels. Moreover, the hydrogel patches showed higher adhesion on freshly explanted pig eyeballs compared to a marketed ocular sealant. Finally, ex vivo feasibility studies showed that the hydrogel patches could seal complex open-globe injuries such as large incision, cruciform injury, and injury associated with tissue loss. These results suggest that our photocrosslinkable hydrogel patch could represent a promising solution for the sealing of open-globe injuries or surgical incisions. STATEMENT OF SIGNIFICANCE: Current management of severe ocular injuries require advanced surgical skills and access to an operating theater. To address the need for emergent management of wounds that cannot be handled in the operating room, surgical adhesives have gained popularity, but none of the currently available adhesives have optimal bioavailability, adhesive or mechanical properties. This study describes the development, optimization and testing of a light-sensitive adhesive patch that can easily be applied to the eye. After solidification using visible light, the patch shows no toxicity and is more adherent to the tissue than a marketed sealant. Thus this technology could represent a promising solution to stabilize ocular injuries in emergency settings before definitive surgical repair.

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