2019

PURPOSE OF REVIEW: Spatial neglect is asymmetric orienting and action after a brain lesion, causing functional disability. It is common after a stroke; however, it is vastly underdocumented and undertreated. This article addresses the implementation gap in identifying and treating spatial neglect, to reduce disability and improve healthcare costs and burden. RECENT FINDINGS: Professional organizations published recommendations to implement spatial neglect care. Physicians can lead an interdisciplinary team: functionally relevant spatial neglect assessment, evidence-based spatial retraining, and integrated spatial and vision interventions can optimize outcomes. Research also strongly suggests spatial neglect adversely affects motor systems. Spatial neglect therapy might thus "kick-start" rehabilitation and improve paralysis recovery. Clinicians can implement new techniques to detect spatial neglect and lead interdisciplinary teams to promote better, integrated spatial neglect care. Future studies of brain imaging biomarkers to detect spatial neglect, and real-world applicability of prism adaptation treatment, are needed.

Lipopeptide daptomycin is a last-line cell-membrane-targeting antibiotic to treat multidrug-resistant Alarmingly, daptomycin-resistant isolates have emerged. The mechanisms underlying daptomycin resistance are diverse and share similarities with resistances to cationic antimicrobial peptides and other lipopeptides, but they remain to be fully elucidated. We selected mutants with increased resistance to daptomycin from a library of transposon insertions in sequent type 8 (ST8) HG003. Insertions conferring increased daptomycin resistance were localized to two genes, one coding for a hypothetical lipoprotein (SAOUHSC_00362, Dsp1), and the other for an alkaline shock protein (SAOUHSC_02441, Asp23). Markerless loss-of-function mutants were then generated for comparison. All transposon mutants and knockout strains exhibited increased daptomycin resistance compared to those of wild-type and complemented strains. Null and transposon insertion mutants also exhibited increased resistance to cationic antimicrobial peptides. Interestingly, the mutant also showed increased resistance to vancomycin, a cell-wall-targeting drug with a different mode of action. Null mutations in both and resulted in increased tolerance as reflected by reduced killing to both daptomycin and vancomycin, as well as an increased tolerance to surfactant (Triton X-100). Neither mutant exhibited increased resistance to lysostaphin, a cell-wall-targeting endopeptidase. These findings identified two genes core to the species that make previously uncharacterized contributions to antimicrobial resistance and tolerance in .

Children born preterm with periventricular leukomalacia (PVL) demonstrate increased difficulties with tasks requiring visuomotor integration. The visuomotor integration network encompasses brain regions within frontal, parietal, and occipital cortices. Because of their proximity to the lateral ventricle the underlying white matter pathways are at a high risk of damage following PVL-related hypoxic-ischemic white matter injury. This study provides an exploratory analysis of the structural and functional connections within the visuomotor integration network, along with an a priori evaluation of the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and frontal aslant tract. For each pathway, tracts within both hemispheres revealed decreased volume and number of reconstructed fibers and an increase in quantitative anisotropy and generalized fractional anisotropy. The connectivity results also indicate that there may be changes to both the structural integrity and functional integration of neural networks involved with visuomotor integration functions in children with PVL.

The complete assessment of vision-related abilities should consider visual function (the performance of components of the visual system) and functional vision (visual task-related ability). Assessment methods are highly dependent upon individual characteristics (eg, the presence and type of visual impairment). Typical visual function tests assess factors such as visual acuity, contrast sensitivity, color, depth, and motion perception. These properties each represent an aspect of visual function and may impact an individual's level of functional vision. The goal of any functional vision assessment should be to measure the visual task-related ability under real-world scenarios. Recent technological advancements such as virtual reality can provide new opportunities to improve traditional vision assessments by providing novel objective and ecologically valid measurements of performance, and allowing for the investigation of their neural basis. In this review, visual function and functional vision evaluation approaches are discussed in the context of traditional and novel acquisition methods.

LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common noncoding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (OR=0.63, p=6.33x10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 (stimulated by retinoic acid receptor 6), apparently mediated by allele-specific binding of the transcription factor THRβ (thyroid hormone receptor beta). We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven retinoic acid signaling pathway. siRNA-mediated downregulation of retinoic acid signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolismare involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.

Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is the most bothersome symptom accompanying an attack. Using subjective psychophysical assessments, we showed that migraine patients are more sensitive to all colors of light during ictal than during interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in both phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual-evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b wave, which was consistently larger (by 14%-19% in the light-adapted and 18%-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a wave or the visual-evoked potentials that differs most strikingly between the 2 groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that nonmigraineurs feel as if they are in a cave.

The gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work.

PURPOSE: To evaluate the defocus curves of 4 presbyopia-correcting intraocular lenses (IOLs). SETTING: Department of Ophthalmology, Goethe University, Frankfurt, Germany. DESIGN: Prospective case series. METHODS: Patients included in the study had bilateral surgery with implantation of diffractive panfocal, diffractive trifocal, segmental refractive (SegRef), or extended-depth-of-focus (EDOF) presbyopia-correcting IOLs. The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, uncorrected intermediate and near visual acuities, distance-corrected intermediate (DCIVA) and near (DCNVA) visual acuities, defocus curve, and spectacle independence were measured. RESULTS: The UDVA and CDVA were not significantly different between groups (P > .05); however, the EDOF group had worse near CDVA (P < .001). The trifocal and EDOF groups showed better DCIVA than the panfocal and SegRef group at 80 cm (P < .001); the EDOF and panfocal groups had comparable DCIVA at 60 cm (P > .05). Defocus curves showed no significant between-group differences from 4 m to 2 m (P > .05). The EDOF group had better visual acuity from 1 m to 67 cm than the trifocal and SegRef groups and better visual acuity than the panfocal group at 1 m (P > .05). Compared with the other IOLs, the panfocal IOL yielded significantly better visual acuity at 50 cm (P < .001) and the EDOF IOL worse visual acuity at 40 cm (P < .01). There was a significant difference in spectacle independence between the panfocal group and EDOF group (P < .05) but no difference between the other groups. CONCLUSIONS: The 4 IOLs provided equally good CDVA. The EDOF IOL yielded slightly better DCIVA but worse DCNVA than the other IOLs. Only the panfocal IOL gave better DCIVA at 50 cm.

OBJECTIVES: To evaluate the impact of a comprehensive cataract surgery curriculum on the incidence of intraoperative complications. DESIGN: We retrospectively compared the total number of cataract surgeries that the residents performed in all of the teaching sites, and the incidences of intraoperative complications (anterior capsule tear, posterior capsule rent, vitreous loss, anterior vitrectomy, zonular dialysis, iris trauma, hemorrhage, dropped lens fragment, corneal wound burn, incorrect intraocular lens) for the surgeries performed at Massachusetts Eye & Ear by residents in the pre-intervention group (residents graduating in 2004 and 2005), before the implementation of a surgical curriculum, and the residents in the post-intervention group (residents graduating in 2014 and 2015). SETTING: Ophthalmology residency program at a major academic institution. PARTICIPANTS: Residents graduating in 2004, 2005, 2014, and 2015. RESULTS: We reviewed 4373 charts. 2086 of those surgeries were performed at Massachusetts Eye & Ear. The incidence of posterior capsule rent/vitreous loss/anterior vitrectomy was lower in the post-intervention group (1.4% versus 7.7%, p < 0.0001). Other complications were also lower in the post-intervention group. CONCLUSIONS: Implementation of a comprehensive cataract surgery curriculum focusing on pre-operative, intra-operative and post-operative interventions, with an emphasis on patient outcomes resulted in a decrease in the rate of intraoperative complications.

PURPOSE: To ascertain the incidence of unexpected management changes at the postoperative week 1 visit in asymptomatic patients who have had an uncomplicated cataract surgery and a routine postoperative day 1 examination. DESIGN: Retrospective observational study. METHODS: A retrospective chart review was conducted of all cases of cataract extraction by phacoemulsification with intraocular lens insertion performed by the Comprehensive Ophthalmology Service at Massachusetts Eye and Ear between January 1, 2014 and December 31, 2014. The preoperative consultation, operative report, and postoperative day 1 and week 1 (postoperative days 5-14) visits were reviewed. Cases with intraoperative complications, as well as clinical findings at postoperative day 1 requiring close follow-up, were excluded. The main outcome measure was incidence of unexpected management changes at the postoperative week 1 visit after cataract surgery, defined as an unanticipated change in postoperative drops, additional procedures, or urgent referral to a specialty service. RESULTS: Overall, 1938 surgical cases of 1471 patients were reviewed, and 1510 cases (77.9%) underwent uncomplicated phacoemulsification with intraocular lens implantation with a routine postoperative day 1 examination. Of these 1510 cases, 238 (15.8%) reported symptoms at the postoperative week 1 visit, including flashes, floaters, redness, pain, or decreased vision, which warranted an examination. In total, 1272 cases were asymptomatic, and only 11 of these cases (0.9%) had an unexpected management change at postoperative week 1. Eight of 11 patients were asymptomatic steroid responders requiring alteration of their postoperative drops. Two of these patients had an intraocular pressure >30 mm Hg. CONCLUSIONS: Unexpected management changes at the postoperative week 1 timepoint after cataract surgery are rare in asymptomatic patients who have had uncomplicated cataract surgery and a routine postoperative day 1 examination. Limited data are available to outline an optimal postoperative regimen after cataract surgery. The results of this study suggest that postoperative week 1 examinations could potentially be performed on an as-needed basis in the appropriate subgroup of patients after cataract surgery.

PURPOSE: To evaluate outcomes of unilateral cataract surgery in children 7 to 24 months of age. DESIGN: Retrospective case series at 10 Infant Aphakia Treatment Study (IATS) sites. PARTICIPANTS: The Toddler Aphakia and Pseudophakia Study is a registry of children treated by surgeons who participated in the IATS. METHODS: Children underwent unilateral cataract surgery with or without intraocular lens (IOL) placement during the IATS enrollment years of 2004 and 2010. MAIN OUTCOME MEASURES: Intraoperative complications, adverse events (AEs), visual acuity, and strabismus. RESULTS: Fifty-six children were included with a mean postoperative follow-up of 47.6 months. Median age at cataract surgery was 13.9 months (range, 7.2-22.9). Ninety-two percent received a primary IOL. Intraoperative complications occurred in 4 patients (7%). At 5 years of age, visual acuity of treated eyes was very good (≥20/40) in 11% and poor (≤20/200) in 44%. Adverse events were identified in 24%, with a 4% incidence of glaucoma suspect. An additional unplanned intraocular surgery occurred in 14% of children. Neither AEs nor intraocular reoperations were more common for children with surgery at 7 to 12 months of age than for those who underwent surgery at 13 to 24 months of age (AE rate, 21% vs. 25% [P = 0.60]; reoperation rate, 13% vs. 16% [P = 1.00]). CONCLUSIONS: Although most children underwent IOL implantation concurrent with unilateral cataract removal, the incidence of complications, reoperations, and glaucoma was low when surgery was performed between 7 and 24 months of age and compared favorably with same-site IATS data for infants undergoing surgery before 7 months of age. Our study showed that IOL implantation is relatively safe in children older than 6 months and younger than 2 years.

Under physiologic conditions, conjunctival goblet cells (CGCs) secrete mucins into the tear film to preserve ocular surface homeostasis. Specialized proresolving mediators (SPMs), like resolvins (Rvs), regulate secretion from CGCs and actively terminate inflammation. The purpose of this study was to determine if RvD2 stimulated mucin secretion and to investigate the cellular signaling components. Goblet cells were cultured from rat conjunctiva. Secretion was measured by an enzyme-linked lectin assay, change in intracellular [Ca] ([Ca]) using Fura-2, and cellular cAMP levels by ELISA. RvD2 (10-10 M) stimulated secretion, increased cellular cAMP levels and the [Ca]. RvD2-stimulated increase in [Ca] and secretion was blocked by Ca chelator 1,2-bis(2-aminophenoxy)ethane-,,','-tetraacetic acid tetrakis and the PKA inhibitor -[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride but not by the cAMP exchange protein inhibitor α-[2-(3-chlorophenyl)hydrazinylidene]-5-(1,1-dimethylethyl)-b-oxo-3-isoxazolepropanenitrile. Forskolin, 3-isobutyl-1-methylxanthine, and 8-bromo-cAMP (8-Br-cAMP) increased [Ca]. Increasing cAMP with 8-Br-cAMP inhibited the increase in [Ca] stimulated by the cAMP-independent agonist cholinergic agonist carbachol. In conclusion, RvD2 uses both cellular cAMP and [Ca] to stimulate glycoconjugate secretion from CGCs, but the interaction of cAMP and [Ca] is context dependent. Thus RvD2 likely assists in the maintenance of the mucous layer of the tear film to sustain ocular surface homeostasis and has potential as a novel treatment for dry eye disease.-Botten, N., Hodges, R. R., Li, D., Bair, J. A., Shatos, M. A., Utheim, T. P., Serhan, C. N., Dartt, D. A. Resolvin D2 elevates cAMP to increase intracellular [Ca] and stimulate secretion from conjunctival goblet cells.

Objectives: Dry eye disease (DED) is a complex multifactorial condition of the ocular surface characterized by symptoms of ocular discomfort, irritation, and visual disturbance. Data previously reported from this study showed an increase in prevalence and incidence of DED with age and over time. The objective of this study was to compare the ranking of DED prevalence among other ocular conditions that led patients to seek eye care. Methods: In this population-based study using the US Department of Defense Military Health System claims database of >9.7 million beneficiaries, indicators of DED and other ocular conditions were analyzed over time. The overall prevalence (2003-2015) and annual incidence (2008-2012) of DED and other ocular conditions were estimated using an algorithm based on two independent indicators derived from selected diagnostic and procedure codes and prescriptions for cyclosporine ophthalmic emulsion for DED and diagnostic codes for the indicators of other common ocular conditions. Results: In 2003-2015, the most common ocular conditions were disorders of refraction and accommodation (25.84%), cataracts (17.14%), glaucoma (7.27%), disorders of the conjunctiva (6.76%), other retinal disorders (5.94%), and DED (5.28%). DED was the fifth most prevalent ocular condition in women (7.78%) and ninth most prevalent in men (2.96%). In 2012, DED had the third highest annual incidence (0.87%), behind disorders of refraction/accommodation (1.87%) and cataracts (1.50%). Conclusion: This study provided further epidemiologic evidence for DED as a commonly occurring condition that drives patients to seek treatment.

Importance: Identifying the factors that are associated with the magnitude of treatment benefits from anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) may help refine treatment expectations. Objective: To identify the baseline factors that are associated with vision and anatomic outcomes when managing DME with anti-VEGF and determine if there are interactions between factors and the agent administered. Design, Setting, and Participants: This post hoc analysis of data from the Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial , Protocol T, was conducted between December 2016 and December 2017. Between August 22, 2012, and August 28, 2013, 660 participants were enrolled with central-involved DME and vision impairment (approximate Snellen equivalent, 20/32-20/320). Interventions: Repeated 0.05-mL intravitreous injections of 2.0-mg aflibercept (201 eyes), 1.25-mg bevacizumab (185 eyes), or 0.3-mg ranibizumab (192 eyes) per protocol. Main Outcomes and Measures: Change in visual acuity (VA) and optical coherence tomography (OCT) central subfield thickness at 2 years and change in VA over 2 years (area under the curve [AUC]). Results: Among 578 participants, the median age (interquartile range) was 61 (54-67) years. Across anti-VEGF treatment groups, each baseline factor was associated with mean improvement in VA and a reduction in central DME compared with the baseline. For every decade of participant age, the mean VA improvement was reduced by 2.1 letters (95% CI, -3.0 to -1.2; P < .001) in the VA and 1.9 letters (95% CI, -2.4 to -1.3; P < .001) in the VA AUC analyses. For each 1% increase in hemoglobin A1c levels, VA improvement was reduced by 1 letter in the VA (95% CI, -1.5 to -0.5; P < .001) and 0.5 letters (95% CI, -0.9 to -0.2; P < .001) in the VA AUC analyses. Eyes with no prior panretinal photocoagulation (PRP) and less than severe nonproliferative diabetic retinopathy had an approximately 3-letter improvement in the VA (95% CI, 0.9-5.4; P = .007) and VA AUC (95% CI, 1.3-4.2; P < .001) analyses compared with eyes with prior PRP. On average, African American participants had greater reductions in central subfield thickness compared with eyes of white participants (-27.3 μm, P = .01), as did eyes with central subretinal fluid compared with eyes without this OCT feature (-22.9 μm, P = .01). There were no interactions between the predictive factors and the specific anti-VEGF agent that was administered for any VA or OCT outcome. Conclusions and Relevance: Lower hemoglobin A1c levels were associated with the magnitude of vision improvement following anti-VEGF therapy, providing further evidence to encourage glycemic control among persons with diabetes. Younger patients and those without prior PRP might expect greater improvement in VA than older patients or those with prior PRP.

Importance: The determination of optical coherence tomography (OCT) central subfield thickness (CST) is an objective measure, and visual acuity (VA) is a subjective measure. Therefore, using OCT CST changes as a surrogate for VA changes in diabetic macular edema seems reasonable. However, studies suggest that change in OCT CST following anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema is correlated with changes in VA but varies substantially among individuals, and so may not be a good surrogate for changes in VA. Objective: To determine associations between changes in VA and changes in OCT CST across 3 anti-VEGF agents (aflibercept, bevacizumab, or ranibizumab) used in a randomized clinical trial for diabetic macular edema. Design, Setting, and Participants: Post hoc analyses were conducted of DRCR Retina Network Protocol T among 652 of 660 participants (98.8%) meeting inclusion criteria for this investigation. The study was conducted between August 22, 2012, and September 23, 2015. The post hoc data collection and analysis were performed from May 29 to July 11, 2018. Interventions: Six monthly intravitreous anti-VEGF injections (unless success was achieved after 3-5 months) were administered; subsequent injections or focal/grid laser photocoagulation treatments were given as needed per protocol to achieve stability. Main Outcomes and Measures: Association between changes in VA letter score with changes in CST at 12, 52, and 104 weeks after randomization to aflibercept, bevacizumab, or ranibizumab. Results: Of the 652 participants, 304 were women (46.6%); median age was 61 years (interquartile range, 54-67 years). The correlation between CST and VA at the follow-up visits was 0.24 (95% CI, 0.16-0.31) in 616 patients at 12 weeks, 0.31 (95% CI, 0.24-0.38) in 609 patients at 52 weeks, and 0.23 (95% CI, 0.15-0.31) in 566 patients at 104 weeks. The correlation coefficients of change in VA vs change in OCT CST for these time intervals were 0.36 (95% CI, 0.29-0.43) at 12 weeks, 0.36 (95% CI, 0.29-0.43) at 52 weeks, and 0.33 (95% CI, 0.26-0.41) at 104 weeks. Conclusions and Relevance: Changes in CST appear to account for only a small proportion of the total variation in changes in VA. These findings do not support using changes in OCT CST as a surrogate for changes in VA in phase 3 clinical trials evaluating anti-VEGF for diabetic macular edema or as a guide to inform the physician or patient about changes in VA after anti-VEGF treatment. Trial Registration: ClinicalTrials.gov identifier: NCT01627249.