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VanderVeen DK, Oke I, Nihalani BR. Deviations From Age-Adjusted Normative Biometry Measures in Children Undergoing Cataract Surgery: Implications for Postoperative Target Refraction and IOL Power Selection. Am J Ophthalmol 2022;239:190-201.Abstract
PURPOSE: To evaluate whether pediatric eyes that deviate from age-adjusted normative biometry parameters predict variation in myopic shift after cataract surgery. METHODS: This is a single institution longitudinal cohort study combining prospectively collected biometry data from normal eyes of children <10 years old with biometry data from eyes undergoing cataract surgery. Refractive data from patients with a minimum of 5 visits over ≥5 years of follow-up were used to calculate myopic shift and rate of refractive growth. Cataractous eyes that deviated from the middle quartiles of the age-adjusted normative values for axial length and keratometry were studied for variation in myopic shift and rate of refractive growth to 5 years and last follow-up visit. Multivariable analysis was performed to determine the association between myopic shift and rate of refractive growth and factors of age, sex, laterality, keratometry, axial length, intraocular lens power, and follow-up length. RESULTS: Normative values were derived from 100 eyes; there were 162 eyes in the cataract group with a median follow-up of 9.6 years (interquartile range: 7.3-12.2 years). The mean myopic shift ranged from 5.5 D (interquartile range: 6.3-3.5 D) for 0- to 2-year-olds to 1.0 D (interquartile range: 1.5-0.6 D) for 8- to 10-year-olds. Multivariable analysis showed that more myopic shift was associated with younger age (P < .001), lower keratometry (P = .01), and male gender (P = .027); greater rate of refractive growth was only associated with lower keratometry measures (P = .001). CONCLUSIONS: Age-based tables for intraocular lens power selection are useful, and modest adjustments can be considered for eyes with lower keratometry values than expected for age.
Tam EK, Laver NV, Thakore-James M, Mooney MA, Daly MK, Lefebvre DR. ARHGEF-10 gene mutation presenting as orbital inflammatory syndrome. BMJ Case Rep 2022;15(3)Abstract
Rho guanine nucleotide exchange factor 10 (ARHGEF-10) is a RHO GTPase that has a role for neural morphogenesis, however its effect on the eyes remains unknown. Here, we report a 44-year-old man who presented with eyelid swelling along with a history of bilateral hand contractures, high-arched feet and muscle wasting, who was found to have an ARHGEF-10 mutation. Neuroimaging was significant for numerous nerve-based cystic abnormalities in the bilateral orbits and throughout the neuraxis, and an orbital biopsy revealed S-100 and SOX-10 positive lesion consistent with pseudocysts. While the role of ARHGEF-10 remains unclear, further research is warranted to further describe its clinical manifestations.
Vingopoulos F, Garg I, Lee Kim E, Thomas M, Silverman RF, Kasetty M, Hassan ZY, Yu G, Joltikov K, Choi EY, Laíns I, Kim LA, Zacks DN, Miller JB. Quantitative contrast sensitivity test to assess visual function in central serous chorioretinopathy. Br J Ophthalmol 2022;Abstract
BACKGROUND: To characterise the contrast sensitivity function (CSF) in central serous chorioretinopathy (CSCR) compared with healthy controls using novel computerised contrast sensitivity (CS) testing with active learning algorithms. METHODS: Prospective observational study measuring CSF in CSCR eyes and controls using the Manifold Platform (Adaptive Sensory Technology, San Diego, California). Mixed effects multivariate regression models were used. Outcomes included area under the log CSF (AULCSF), CS thresholds at 1, 1.5, 3, 12 and 18 cycles per degree (cpd) and best-corrected visual acuity (BCVA). Associations of contrast outcomes with structural findings on optical coherence tomography (OCT) and subjective symptomatology were investigated. RESULTS: Forty CSCR eyes and 89 controls were included with median BCVA logarithm of median angle of resolution 0.10 (20/25) versus 0.00 (20/20), respectively (p=0.01). When accounting for age, CSCR was associated with significantly reduced median AULCSF (p=0.02, β=-0.14) and reduced CS thresholds at 6 cpd (p=0.009, β=-0.18), 12 cpd (p<0.001, β=-0.23) and 18 cpd (p=0.04, β=-0.09), versus controls. Within the CSCR group, subjectively perceived visual impairment (N=22) was associated with significantly decreased CS thresholds at all spatial frequencies and in AULCSF compared with asymptomatic CSCR eyes (N=18). Ellipsoid zone attenuation and subfoveal fluid on OCT were associated with decreased AULCSF and CS thresholds specifically at 3, 6 and 12 cpd, whereas presence of extrafoveal fluid at 1.5 and 3 cpd. CONCLUSION: Contrast sensitivity is significantly reduced in CSCR, and strongly correlates with subjective visual impairment. Different structural biomarkers correlate with contrast thresholds reductions at different spatial frequencies.
Xiong X, Tian S, Yang P, Lebreton F, Bao H, Sheng K, Yin L, Chen P, Zhang J, Qi W, Ruan J, Wu H, Chen H, Breault DT, Wu H, Earl AM, Gilmore MS, Abraham J, Dong M. Emerging enterococcus pore-forming toxins with MHC/HLA-I as receptors. Cell 2022;Abstract
Enterococci are a part of human microbiota and a leading cause of multidrug resistant infections. Here, we identify a family of Enterococcus pore-forming toxins (Epxs) in E. faecalis, E. faecium, and E. hirae strains isolated across the globe. Structural studies reveal that Epxs form a branch of β-barrel pore-forming toxins with a β-barrel protrusion (designated the top domain) sitting atop the cap domain. Through a genome-wide CRISPR-Cas9 screen, we identify human leukocyte antigen class I (HLA-I) complex as a receptor for two members (Epx2 and Epx3), which preferentially recognize human HLA-I and homologous MHC-I of equine, bovine, and porcine, but not murine, origin. Interferon exposure, which stimulates MHC-I expression, sensitizes human cells and intestinal organoids to Epx2 and Epx3 toxicity. Co-culture with Epx2-harboring E. faecium damages human peripheral blood mononuclear cells and intestinal organoids, and this toxicity is neutralized by an Epx2 antibody, demonstrating the toxin-mediated virulence of Epx-carrying Enterococcus.
White E, Walsh L. The impact of occlusion therapy and predictors on amblyopia dose-response relationship. Strabismus 2022;30(2):78-89.Abstract
This study aimed to calculate the dose-response relationship and predictors of visual acuity (VA) improvement following occlusion therapy at the IWK Health Center Eye Clinic and to add to amblyopia therapy dose-response relationship literature. A retrospective chart review was performed, considering patients who reached an occlusion therapy outcome at the IWK Eye Clinic between 2012 and 2019. The treatment outcome was defined as equal VA or stable VA for three consecutive clinical visits despite reported compliance. Subjective patching hours from parental reports, not prescribed hours, were used for statistical analyses. One hundred and thirty-four patients (66 females and 68 males) ages 2-11 years were included. Results showed a dose-response relationship of 224 hours/0.1logMAR increase in VA and total dose of 1344 hours for full-time occlusion and 504 hours for part-time occlusion was required to reach outcome VA. The fastest VA improvement occurred with younger age at treatment initiation, during the first 4 weeks of treatment, and in patients with strabismic and/or severe amblyopia. Classification of amblyopia, age, VA chart, initial distance VA (amblyopic eye), and treatment dose predicted the hour dose-response relationship. Dose-response relationship was faster in younger participants, in participants with strabismic and severe amblyopia, and during the first month of occlusion. Additionally, by creating a GLM model of dose-response relationship, relationship calculations can be performed. Therefore, an estimated timeline can be developed to allow allocation of clinical resources and to prepare patients for the treatment duration required and possibly increase treatment compliance.
Chen Y, Wang S, Alemi H, Dohlman T, Dana R. Immune regulation of the ocular surface. Exp Eye Res 2022;218:109007.Abstract
Despite constant exposure to various environmental stimuli, the ocular surface remains intact and uninflamed while maintaining the transparency of the cornea and its visual function. This 'immune privilege' of the ocular surface is not simply a result of the physical barrier function of the mucosal lining but, more importantly, is actively maintained through a variety of immunoregulatory mechanisms that prevent the disruption of immune homeostasis. In this review, we focus on essential molecular and cellular players that promote immune quiescence in steady-state conditions and suppress inflammation in disease-states. Specifically, we examine the interactions between the ocular surface and its local draining lymphoid compartment, by encompassing the corneal epithelium, corneal nerves and cornea-resident myeloid cells, conjunctival goblet cells, and regulatory T cells (Treg) in the context of ocular surface autoimmune inflammation (dry eye disease) and alloimmunity (corneal transplantation). A better understanding of the immunoregulatory mechanisms will facilitate the development of novel, targeted immunomodulatory strategies for a broad range of ocular surface inflammatory disorders.
Gardiner SK, Kinast RM, De Moraes CG, Budenz DL, Jeoung JW, Lind JT, Myers JS, Nouri-Mahdavi K, Rhodes LA, Strouthidis NG, Chen TC, Mansberger SL. Clinicians' Use of Quantitative Information while Assessing the Rate of Functional Progression in Glaucoma. Ophthalmol Glaucoma 2022;5(5):498-506.Abstract
PURPOSE: Clinicians use both global and point-wise information from visual fields to assess the rate of glaucomatous functional progression. We asked which objective, quantitative measures best correlated with subjective assessment by glaucoma experts. In particular, we aimed to determine how much that judgment was based on localized rates of change vs. on global indices reported by the perimeter. DESIGN: Prospective cohort study. PARTICIPANTS: Eleven academic, expert glaucoma specialists independently scored the rate of functional progression, from 1 (improvement) to 7 (very rapid progression), for a series of 5 biannual clinical printouts from 100 glaucoma or glaucoma suspect eyes of 51 participants, 20 of which were scored twice to assess repeatability. METHODS: Regression models were used to predict the average of the 11 clinicians' scores based on objective rates of change of mean deviation (MD), visual field index (VFI), pattern standard deviation (PSD), the Nth fastest progressing location, and the Nth fastest progressing of 10 anatomically defined clusters of locations after weighting by eccentricity. MAIN OUTCOME MEASURES: Correlation between the objective rates of change and the average of the 11 clinicians' scores. RESULTS: The average MD of the study eyes was -2.4 dB (range, -16.8 to +2.8 dB). The mean clinician score was highly repeatable, with an intraclass correlation coefficient of 0.95. It correlated better with the rate of change of VFI (pseudo-R2 = 0.73, 95% confidence interval [CI, 0.60-0.83]) than with MD (pseudo-R2 = 0.63, 95% CI [0.45-0.76]) or PSD (pseudo-R2 = 0.41, 95% CI [0.26-0.55]). Using point-wise information, the highest correlations were found with the fifth-fastest progressing location (pseudo-R2 = 0.71, 95% CI [0.56-0.80]) and the fastest-progressing cluster after eccentricity weighting (pseudo-R2 = 0.61, 95% CI [0.48-0.72]). Among 25 eyes with an average VFI of > 99%, the highest observed pseudo-R2 value was 0.34 (95% CI [0.16-0.61]) for PSD. CONCLUSIONS: Expert academic glaucoma specialists' assessment of the rate of change correlated best with VFI rates, except in eyes with a VFI near the ceiling of 100%. Sensitivities averaged within clusters of locations have been shown to detect change sooner, but the experts' opinions correlated more closely with global VFI. This could be because it is currently the only index for which the perimeter automatically provides a quantitative estimate of the rate of functional progression.
Nieves FR, Villegas VM, Patel NA, Berrocal AM, Murray TG. Multimodal treatment of Coats-like exudative vitreoretinopathy in Goldmann-Favre syndrome. Am J Ophthalmol Case Rep 2022;25:101362.Abstract
Purpose: To report a Coats-like exudative vitreoretinopathy in Goldmann-Favre syndrome. Observations: A 64 year-old woman with prior diagnosis of retinal dystrophy presented with decreased vision in the right eye (OD). Ophthalmologic examination was remarkable for bilateral arteriolar attenuation, mid-peripheral bony-spicules, and waxy disc pallor. Coats-like exudative vitreoretinopathy and cystoid macular edema were present OD. Genetic testing showed a homozygous pathogenic mutation in gene NR2E3, variant c.932G>A (p.Arg311Gln), consistent with Goldmann-Favre syndrome. Targeted laser ablation and combination intravitreal therapy were effective in decreasing macular edema. Conclusions and Importance: A Coats-like exudative vitreoretinopathy may occur in the setting of Goldmann-Favre syndrome. Targeted laser ablation in combination with intravitreal therapy can be efficacious in select patients.
Andres-Mateos E, Landegger LD, Unzu C, Phillips J, Lin BM, Dewyer NA, Sanmiguel J, Nicolaou F, Valero MD, Bourdeu KI, Sewell WF, Beiler RJ, McKenna MJ, Stankovic KM, Vandenberghe LH. Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate. Nat Commun 2022;13(1):1359.Abstract
Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders. We previously established the benefits of Anc80L65 in targeting inner and outer hair cells in newborn mice. To accelerate translation to humans, we now report the feasibility and efficiency of the surgical approach and vector delivery in a nonhuman primate model. Five rhesus macaques were injected with AAV1 or Anc80L65 expressing eGFP using a transmastoid posterior tympanotomy approach to access the round window membrane after making a small fenestra in the oval window. The procedure was well tolerated. All but one animal showed cochlear eGFP expression 7-14 days following injection. Anc80L65 in 2 animals transduced up to 90% of apical inner hair cells; AAV1 was markedly less efficient at equal dose. Transduction for both vectors declined from apex to base. These data motivate future translational studies to evaluate gene therapy for human hearing disorders.
Pivodic A, Smith LEH, Hård A-L, Löfqvist C, Almeida AC, Al-Hawasi A, Larsson E, Lundgren P, Sunnqvist B, Tornqvist K, Wallin A, Holmstrom G, Gränse L. Validation of DIGIROP models and decision support tool for prediction of treatment for retinopathy of prematurity on a contemporary Swedish cohort. Br J Ophthalmol 2022;Abstract
BACKGROUND/AIMS: Retinopathy of prematurity (ROP) is currently diagnosed through repeated eye examinations to find the low percentage of infants that fulfil treatment criteria to reduce vision loss. A prediction model for severe ROP requiring treatment that might sensitively and specifically identify infants that develop severe ROP, DIGIROP-Birth, was developed using birth characteristics. DIGIROP-Screen additionally incorporates first signs of ROP in different models over time. The aim was to validate DIGIROP-Birth, DIGIROP-Screen and their decision support tool on a contemporary Swedish cohort. METHODS: Data were retrieved from the Swedish national registry for ROP (2018-2019) and two Swedish regions (2020), including 1082 infants born at gestational age (GA) 24 to <31 weeks. The predictors were GA at birth, sex, standardised birth weight and age at the first sign of ROP. The outcome was ROP treatment. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) with 95% CI were described. RESULTS: For DIGIROP-Birth, the AUC was 0.93 (95% CI 0.90 to 0.95); for DIGIROP-Screen, it ranged between 0.93 and 0.97. The specificity was 49.9% (95% CI 46.7 to 53.0) and the sensitivity was 96.5% (95% CI 87.9 to 99.6) for the tool applied at birth. For DIGIROP-Screen, the cumulative specificity ranged between 50.0% and 78.7%. One infant with Beckwith-Wiedemann syndrome who fulfilled criteria for ROP treatment and had no missed/incomplete examinations was incorrectly flagged as not needing screening. CONCLUSIONS: DIGIROP-Birth and DIGIROP-Screen showed high predictive ability in a contemporary Swedish cohort. At birth, 50% of the infants born at 24 to <31 weeks of gestation were predicted to have low risk of severe ROP and could potentially be released from ROP screening examinations. All routinely screened treated infants, excluding those screened for clinical indications of severe illness, were correctly flagged as needing ROP screening.
Morsing E, Lundgren P, Hård A-L, Rakow A, Hellström-Westas L, Jacobson L, Johnson M, Nilsson S, Smith LEH, Sävman K, Hellström A. Neurodevelopmental disorders and somatic diagnoses in a national cohort of children born before 24 weeks of gestation. Acta Paediatr 2022;111(6):1167-1175.Abstract
AIM: This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. METHODS: Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. RESULTS: We studied 383 children born at a median of 23.3 (range 21.9-23.9) weeks, with a median birthweight of 565 (range 340-874) grams. Three-quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). CONCLUSION: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.
Zhang C, Owen LA, Lillvis JH, Zhang SX, Kim IK, Deangelis MM. AMD Genomics: Non-Coding RNAs as Biomarkers and Therapeutic Targets. J Clin Med 2022;11(6)Abstract
Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that is the world's leading cause of blindness in the aging population. Although the clinical stages and forms of AMD have been elucidated, more specific prognostic tools are required to determine when patients with early and intermediate AMD will progress into the advanced stages of AMD. Another challenge in the field has been the appropriate development of therapies for intermediate AMD and advanced atrophic AMD. After numerous negative clinical trials, an anti-C5 agent and anti-C3 agent have recently shown promising results in phase 3 clinical trials, in terms of slowing the growth of geographic atrophy, an advanced form of AMD. Interestingly, both drugs appear to be associated with an increased incidence of wet AMD, another advanced form of the disease, and will require frequent intravitreal injections. Certainly, there remains a need for other therapeutic agents with the potential to prevent progression to advanced stages of the disease. Investigation of the role and clinical utility of non-coding RNAs (ncRNAs) is a major advancement in biology that has only been minimally applied to AMD. In the following review, we discuss the clinical relevance of ncRNAs in AMD as both biomarkers and therapeutic targets.
Wang X, Jacobs DS. Contact Lenses for Ocular Surface Disease. Eye Contact Lens 2022;48(3):115-118.Abstract
ABSTRACT: Ocular surface disease can be difficult to manage, causing patients discomfort and vision loss. Therapeutic contact lenses are an important treatment option that is often neglected because it is conventional wisdom that eyes that are dry or irritated are not good candidates for contact lens. In this focused review, we consider the substantial literature on the use of bandage soft contact lenses (BSCL), scleral lenses, and customized prosthetic devices in the management of ocular graft-vs-host disease. Reports on BSCLs for recurrent corneal erosion are reviewed, as is literature on scleral lenses and prosthetic replacement of the ocular surface ecosystem treatment for Stevens-Johnson syndrome. Clinical pearls for fitting BSCLs are presented, and the issue of antibiotic prophylaxis is considered.

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