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Mitchell W, Marmamula S, Zebardast N, Ng W, Locascio JJ, Kumbam T, Brahmanandam S, Barrenkala NR. Psychometric validation techniques applied to the IND-VFQ-33 visual function questionnaire: the Hyderabad ocular morbidity in the elderly study (HOMES). BMC Med Res Methodol 2021;21(1):26.Abstract
BACKGROUND: Over 2 billion people suffer from vision impairment or blindness globally, and access to validated visual measurement tools in imperative in accurately describing and managing the burden of eye disease. The present study applies contemporary psychometric validation techniques to the widely used 33-item Indian Visual Function Questionnaire (IND-VFQ-33). METHODS: We first estimated the polychoric correlation between each pair of items. Next, an unrotated and oblique Promax rotated factor analysis, item response theory (IRT, using a graded response model (GRM)), and differential item functioning (DIF) testing were applied to the IND-VFQ-33. We subsequently propose a validated IND-VFQ-33 questionnaire after psychometric testing, data reduction, and adjustment. RESULTS: Exploratory unrotated factor analysis identified two factors; one with a particularly high eigenvalue (18.1) and a second with a lower eigenvalue still above our threshold (1.1). A subsequent oblique Promax factor rotation was undertaken for a 2-factor solution, revealing two moderately correlated factors (+ 0.68) with clinically discrete item loadings onto either Factor 1 (21 items; collectively labelled "daily activities") or Factor 2 (5 items; collectively labelled "bright lights"). IRT confirmed high item discrimination for all remaining items with good separation between difficulty thresholds. We found significant DIF on depression for six items in Factor 1 (all uniform DIF, except item 21 (non-uniform DIF) with no substantive difference in beta thresholds for any item and no substantive difference in expected individual or sum score, by depression at baseline. For Factor 2, only one item demonstrated significant uniform DIF on gender, similarly without major differences in beta thresholds or expected total score between gender at baseline. Consequently, no further item recalibration or reduction was undertaken after IRT and DIF analysis. CONCLUSION: Applying IRT and DIF validation techniques to the IND-VFQ-33 identified 2 discrete factors with 26 uniquely-loading items, clinically representative of difficulty performing daily activities and experiencing difficulty due to bright lights/glare respectively. The proposed modified scale may be useful in evaluating symptomatic disease progression or response to treatment in an Indian population.
Ludwig CA, Moon J, Garg I, Miller JB. Ultra-Widefield Imaging for Evaluation of the Myopic Eye. Semin Ophthalmol 2021;36(4):185-190.Abstract
Topic : Ultra-widefield (UWF) imaging of the myopic eye. Clinical Relevance : Myopes, and particularly high and pathologic myopes, present a unique challenge in fundoscopic imaging. Critical pathology is often located in the anteriormost portion of the retina, variations in posterior segment contour are difficult to capture in two-dimensional images, and extremes in axial length make simply focusing imaging devices difficult. Methods: We review the evolution of modalities for ophthalmic imaging (color fundus photography [CFP], optical coherence topography [OCT], angiography, artificial intelligence [AI]) to present day UWF technology and its impact on our understanding of myopia. Results: Advances in UWF technology address many of the challenges in fundoscopic imaging of myopes, providing new insights into the structure and function of the myopic eye. UWF CFP improves our ability to detect and document anterior peripheral pathology prevalent in approximately half of all high myopes. UWF OCT better captures the staphylomatous contour of the myopic eye, providing enhanced visualization of the vitreoretinal interface and progressive development of myopic traction maculopathy. UWF angiography highlights the posterior vortex veins, thin choriocapillaris, far peripheral avascularity, and peripheral retinal capillary microaneurysms more prevalent in the myopic eye. Researchers have demonstrated the ability of AI algorithms to predict refractive error, and great potential remains in the use of AI technology for the screening and prevention of myopic disease. Conclusion: We note significant progress in our ability to capture anterior pathology and improved image quality of the posterior segment of high and pathologic myopes. The next jump forward for UWF imaging will be the ability to capture a high quality ora to ora multimodal fundoscopic image in a single scan that will allow for sensitive AI-assisted screening of myopic disease.
André C, Durand ML, Buckley T, Cadorette J, Gilmore MS, Ciolino JB, Bispo PJM. A Cluster of Corneal Donor Rim Cultures Positive for Achromobacter Species Associated With Contaminated Eye Solution. Cornea 2021;40(2):223-227.Abstract
PURPOSE: To investigate a cluster of corneoscleral rim cultures positive for Achromobacter species over a 6-month period at Massachusetts Eye and Ear. METHODS: An increased rate of positive corneal donor rim cultures was noted at Massachusetts Eye and Ear between July and December 2017. Positive cultures were subjected to identification and antimicrobial susceptibility testing by phenotypic (MicroScan WalkAway) and genotypic (16S rDNA sequencing) methods. Samples of the eye wash solution (GeriCare) used in the eye bank were also evaluated. Antimicrobial activity of Optical-GS against Achromobacter spp. at 4°C and 37°C was assessed by time-kill kinetics assay. RESULTS: Of 99 donor rims cultured, 14 (14.1%) grew bacteria with 11 (78.6%) due to uncommon nonfermenting Gram-negative bacilli. These had been identified by standard automated methods as Achromobacter (n = 3), Alcaligenes (n = 3), Ralstonia (n = 2), Pseudomonas (n = 2), and Stenotrophomonas (n = 1). Eight of these 11 isolates were subsequently available for molecular identification, and all were identified as Achromobacter spp. Six bottles of eyewash solution were evaluated and were positive for abundant Achromobacter spp. (3.4 × 105 ± 1.1 CFU/mL). Optisol-GS had no bactericidal activity against Achromobacter spp. at 4°C after 24-hour incubation but was bactericidal at 37°C. None of the patients who had received the contaminated corneas developed postoperative infection. CONCLUSIONS: An eyewash solution arising from a single lot was implicated in the contamination of donor rims by Achromobacter spp. The isolates were able to survive in the Optisol-GS medium at the recommended storage temperature. This highlights the need to continue improving protocols for tissue preparation and storage.
Brommer B, He M, Zhang Z, Yang Z, Page JC, Su J, Zhang Y, Zhu J, Gouy E, Tang J, Williams P, Dai W, Wang Q, Solinsky R, Chen B, He Z. Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury. Nat Commun 2021;12(1):781.Abstract
After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI.
Baker TL, Greiner JV, Vesonder M. SARS-CoV-2 safety: Guidelines for shielding frontline nurses. Nursing 2021;51(3):32-42.Abstract
ABSTRACT: Protecting nurses in healthcare facilities from SARS-CoV-2 infection is essential for maintaining an adequate nursing force. Foundational guidelines, consistently utilized, protect the nursing staff from infection. This article describes guidelines designed to reduce acute infection and associated morbidity and mortality among nursing staff and improve compliance with infection prevention protocols.
Chan YK, Wang SK, Chu CJ, Copland DA, Letizia AJ, Costa Verdera H, Chiang JJ, Sethi M, Wang MK, Neidermyer WJ, Chan Y, Lim ET, Graveline AR, Sanchez M, Boyd RF, Vihtelic TS, Inciong RGCO, Slain JM, Alphonse PJ, Xue Y, Robinson-McCarthy LR, Tam JM, Jabbar MH, Sahu B, Adeniran JF, Muhuri M, Tai PWL, Xie J, Krause TB, Vernet A, Pezone M, Xiao R, Liu T, Wang W, Kaplan HJ, Gao G, Dick AD, Mingozzi F, McCall MA, Cepko CL, Church GM. Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses. Sci Transl Med 2021;13(580)Abstract
Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can "cloak" the vector from inducing unwanted immune responses in multiple, but not all, models. This "coupled immunomodulation" strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods.
Böhm M, Leon P, Wylęgała A, Ong Tone S, Condron T, Jurkunas U. Cost-effectiveness analysis of preloaded versus non-preloaded Descemet membrane endothelial keratoplasty for the treatment of Fuchs endothelial corneal dystrophy in an academic centre. Br J Ophthalmol 2021;Abstract
AIMS: To determine the cost-effectiveness of preloaded Descemet membrane endothelial keratoplasty (pDMEK) versus non-preloaded DMEK (n-pDMEK) for the treatment of Fuchs endothelial corneal dystrophy (FECD). METHODS: From a societal and healthcare perspective, this retrospective cost-effectiveness analysis analysed a cohort of 58 patients with FECD receiving pDMEK (n=38) or n-pDMEK (n=30) from 2016 to 2018 in the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, USA. Exclusion criteria were previous ocular surgeries (other than uncomplicated cataract surgery), including other keratoplasty procedures, ocular pathological conditions as glaucoma, amblyopia, laser treatments, or any retinal or corneal disease. The main outcome parameters were the incremental cost-utility ratio (ICUR) and net monetary benefit (NMB). RESULTS: pDMEK was less costly compared with n-pDMEK (healthcare: $13 886 vs $15 329; societal: $20 805 vs $22 262), with a slighter greater utility (QALY 0.6682 vs QALY 0.6640) over a time horizon of 15 years. pDMEK offered a slightly higher clinical effectiveness (+0.0042 QALY/patient) at a lower cost (healthcare: -$1444 per patient; societal: -$1457 per patient) in improving visual acuity in this cohort of patients with FECD. pDMEK achieved a favourable ICUR and NMB compared with n-pDMEK. Based on sensitivity analyses performed, the economic model was robust. CONCLUSIONS: From the societal and healthcare perspective, pDMEK was less costly and generated comparable utility values relative to n-pDMEK. Therefore, pDMEK appears to be cost-effective and cost saving with respect to n-pDMEK. Further long-term follow-up data are needed to confirm these findings.
Wai KM, Vingopoulos F, Garg I, Kasetty M, Silverman RF, Katz R, Laíns I, Miller JW, Husain D, Vavvas DG, Kim LA, Miller JB. Contrast sensitivity function in patients with macular disease and good visual acuity. Br J Ophthalmol 2021;Abstract
INTRODUCTION: Contrast sensitivity function (CSF) may better estimate a patient's visual function compared with visual acuity (VA). Our study evaluates the quick CSF (qCSF) method to measure visual function in eyes with macular disease and good letter acuity. METHODS: Patients with maculopathies (retinal vein occlusion, macula-off retinal detachment, dry age-related macular degeneration and wet age-related macular degeneration) and good letter acuity (VA ≥20/30) were included. The qCSF method uses an intelligent algorithm to measure CSF across multiple spatial frequencies. All maculopathy eyes combined and individual macular disease groups were compared with healthy control eyes. Main outcomes included area under the log CSF (AULCSF) and six CS thresholds ranging from 1 cycle per degree (cpd) to 18 cpd. RESULTS: 151 eyes with maculopathy and 93 control eyes with VA ≥20/30 were included. The presence of a maculopathy was associated with significant reduction in AULCSF (β: -0.174; p<0.001) and CS thresholds at all spatial frequencies except for 18 cpd (β: -0.094 to -0.200 log CS, all p<0.01) compared with controls. Reductions in CS thresholds were most notable at low and intermediate spatial frequencies (1.5 cpd, 3 cpd and 6 cpd). CONCLUSION: CSF measured with the qCSF active learning method was found to be significantly reduced in eyes affected by macular disease despite good VA compared with healthy control eyes. The qCSF method is a promising clinical tool to quantify subtle visual deficits that may otherwise go unrecognised by current testing methods.
Waksmunski AR, Song YE, Kinzy TG, Laux RA, Sewell J, Fuzzell D, Fuzzell S, Miller S, Wiggs JL, Pasquale LR, Skarie JM, Haines JL, Cooke Bailey JN. The GGLEAM Study: Understanding Glaucoma in the Ohio Amish. Int J Environ Res Public Health 2021;18(4)Abstract
Glaucoma leads to millions of cases of visual impairment and blindness around the world. Its susceptibility is shaped by both environmental and genetic risk factors. Although over 120 risk loci have been identified for glaucoma, a large portion of its heritability is still unexplained. Here we describe the foundation of the Genetics of GLaucoma Evaluation in the AMish (GGLEAM) study to investigate the genetic architecture of glaucoma in the Ohio Amish, which exhibits lower genetic and environmental heterogeneity compared to the general population. To date, we have enrolled 81 Amish individuals in our study from Holmes County, Ohio. As a part of our enrollment process, 62 GGLEAM study participants (42 glaucoma-affected and 20 unaffected individuals) received comprehensive eye examinations and glaucoma evaluations. Using the data from the Anabaptist Genealogy Database, we found that 80 of the GGLEAM study participants were related to one another through a large, multigenerational pedigree containing 1586 people. We plan to integrate the health and kinship data obtained for the GGLEAM study to interrogate glaucoma genetics and pathophysiology in this unique population.
Hellström A, Nilsson AK, Wackernagel D, Pivodic A, Vanpee M, Sjöbom U, Hellgren G, Hallberg B, Domellöf M, Klevebro S, Hellström W, Andersson M, Lund A-M, Löfqvist C, Elfvin A, Sävman K, Hansen-Pupp I, Hård A-L, Smith LEH, Ley D. Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial. JAMA Pediatr 2021;175(4):359-367.Abstract
Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.
Wolfe JM. Guided Search 6.0: An updated model of visual search. Psychon Bull Rev 2021;28(4):1060-1092.Abstract
This paper describes Guided Search 6.0 (GS6), a revised model of visual search. When we encounter a scene, we can see something everywhere. However, we cannot recognize more than a few items at a time. Attention is used to select items so that their features can be "bound" into recognizable objects. Attention is "guided" so that items can be processed in an intelligent order. In GS6, this guidance comes from five sources of preattentive information: (1) top-down and (2) bottom-up feature guidance, (3) prior history (e.g., priming), (4) reward, and (5) scene syntax and semantics. These sources are combined into a spatial "priority map," a dynamic attentional landscape that evolves over the course of search. Selective attention is guided to the most active location in the priority map approximately 20 times per second. Guidance will not be uniform across the visual field. It will favor items near the point of fixation. Three types of functional visual field (FVFs) describe the nature of these foveal biases. There is a resolution FVF, an FVF governing exploratory eye movements, and an FVF governing covert deployments of attention. To be identified as targets or rejected as distractors, items must be compared to target templates held in memory. The binding and recognition of an attended object is modeled as a diffusion process taking > 150 ms/item. Since selection occurs more frequently than that, it follows that multiple items are undergoing recognition at the same time, though asynchronously, making GS6 a hybrid of serial and parallel processes. In GS6, if a target is not found, search terminates when an accumulating quitting signal reaches a threshold. Setting of that threshold is adaptive, allowing feedback about performance to shape subsequent searches. Simulation shows that the combination of asynchronous diffusion and a quitting signal can produce the basic patterns of response time and error data from a range of search experiments.
Arroyo JG, Seto B, Yamada K, Zeng K, Minturn R, Lemire CA. Rapid reduction of macular edema due to retinal vein occlusion with low-dose normobaric hyperoxia. Graefes Arch Clin Exp Ophthalmol 2021;259(8):2113-2118.Abstract
PURPOSE: We investigated the effects of a relatively inexpensive, non-invasive, short-term treatment with low-dose normobaric hyperoxia (NBH) on macular edema in patients with retinal vein occlusion (RVO). METHODS: Participants with macular edema associated with RVO were treated with 5 LPM of NBH via facemask (40% fraction of inspired oxygen, FIO2) for 3 h. Patients with non-fovea involving edema who elected to be observed returned for a second treatment 1 month later to test reproducibility. RESULTS: A 3-h session of NBH (n = 45) resulted in decreased maximum macular thickness (MMT) (mean 7.10%, t34=9.63 P<.001) and central macular thickness (CMT) (mean 4.64%, t34=6.90, P<.001) when compared to untreated eyes with RVO measured over the same period of time (n = 12) or their healthy fellow eye (n = 34; MMT:t34=-9.60, P<.001;CMT: t34=-6.72, P<.001). Patients who had a second NBH treatment 1 month later experienced a recurrence of their edema, but demonstrated a similar significant reduction in MMT and CMT after the second NBH treatment. CONCLUSIONS: Three-hour treatment with 40% FIO2 NBH results in a significant reduction in MMT and CMT. This study supports an ischemic mechanism for macular edema associated with retinal vein occlusion. TRANSLATIONAL RELEVANCE: Short-term low-dose normobaric hyperoxia is a simple, inexpensive, and ubiquitous treatment that may provide an alternate or adjunctive approach to treating macular edema in patients who are resistant to or cannot afford anti-VEGF medications.
Zhang YJ, Jimenez L, Azova S, Kremen J, Chan Y-M, Elhusseiny AM, Saeed H, Goldsmith J, Al-Ibraheemi A, O'Connell AE, Kovbasnjuk O, Rodan L, Agrawal PB, Thiagarajah JR. Novel variants in the stem cell niche factor WNT2B define the disease phenotype as a congenital enteropathy with ocular dysgenesis. Eur J Hum Genet 2021;29(6):998-1007.Abstract
WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein's putative involvement in multiple developmental and stem cell maintenance pathways.

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