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Jamshidi F, Place EM, Mehrotra S, Navarro-Gomez D, Maher M, Branham KE, Valkanas E, Cherry TJ, Lek M, MacArthur D, Pierce EA, Bujakowska KM. Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration. Genet Med 2019;21(3):694-704.Abstract
PURPOSE: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis. METHODS: IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing. RESULTS: Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro. CONCLUSION: Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.
Higgs C, Crow YJ, Adams DM, Chang E, Hayes D, Herbig U, Huang JN, Himes R, Jajoo K, Johnson BF, Reynolds SD, Yonekawa Y, Armanios M, Boulad F, DiNardo CD, Dufour C, Goldman FD, Khan S, Kratz C, Myers KC, Raghu G, Alter BP, Aubert G, Bhala S, Cowen EW, Dror Y, El-Youssef M, Friedman B, Giri N, Helms Guba L, Khincha PP, Lin TF, Longhurst H, McReynolds LJ, Nelson A, Olson T, Pariser A, Perona R, Sasa G, Schratz K, Simonetto DA, Townsley D, Walsh M, Stevens K, Agarwal S, Bertuch AA, Savage SA, for (CCCTAA) CCCT-associated A. Understanding the evolving phenotype of vascular complications in telomere biology disorders. Angiogenesis 2019;22(1):95-102.Abstract
Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.
Borboli-Gerogiannis S, Jeng-Miller KW, Koulisis N, Moustafa GA, Chang KK, Chen SH, Gardiner MF, Greenstein SH, Luo Z, Chen TC, Loewenstein JI, Miller JW, Haviland MJ, Kloek CE. A Comprehensive Surgical Curriculum Reduced Intra-operative Complication Rates of Resident-performed Cataract Surgeries. J Surg Educ 2019;76(1):150-157.Abstract
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.
Sun JK, Glassman AR, Beaulieu WT, Stockdale CR, Bressler NM, Flaxel C, Gross JG, Shami M, Jampol LM, Jampol LM. Rationale and Application of the Protocol S Anti-Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy. Ophthalmology 2019;126(1):87-95.Abstract
PURPOSE: To present the rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S. DESIGN: Post hoc analyses from a randomized clinical trial. PARTICIPANTS: Three hundred five participants (394 study eyes) having PDR without prior panretinal photocoagulation (PRP). METHODS: Intravitreous ranibizumab (0.5 mg) versus PRP for PDR. Ranbizumab-assigned eyes (n = 191) received monthly injections for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. Panretinal photocoagulation could be initiated for failure or futility criteria. MAIN OUTCOME MEASURES: Neovascularization status through 2 years. RESULTS: At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes showed complete neovascularization resolution and an additional 60% (113) showed improvement. At 6 months, 52% (80 of 153) showed neovascularization resolution, 3% (4) were improved, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; n = 73) versus 7 (4-11; n = 67; P < 0.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) showed neovascularization resolution, 5% (7) showed improvement, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years. CONCLUSIONS: The DRCR.net treatment algorithm for PDR can provide excellent clinical outcomes through 2 years for patients initiating anti-vascular endothelial growth factor (VEGF) therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic method and anticipated patient compliance with follow-up and treatment recommendations.
Liu Y, Rajamanickam VP, Parikh RS, Loomis SJ, Kloek CE, Kim LA, Hitchmoth DL, Song BJ, Xerras DC, Pasquale LR. Diabetic Retinopathy Assessment Variability Among Eye Care Providers in an Urban Teleophthalmology Program. Telemed J E Health 2019;25(4):301-308.Abstract
BACKGROUND: Teleophthalmology is an evidence-based method for diabetic eye screening. It is unclear whether the type of eye care provider performing teleophthalmology interpretation produces significant variability. INTRODUCTION: We assessed grading variability between an optometrist, general ophthalmologist, and retinal specialist using images from an urban, diabetic retinopathy teleophthalmology program. METHODS: Three readers evaluated digital retinal images in 100 cases (178 eyes from 90 patients with type 2 diabetes). Fisher's exact test, percent agreement, and the observed proportion of positive (P) or negative agreement (P) were used to assess variability. RESULTS: Among cases deemed gradable by all three readers (n = 65), there was substantial agreement on absence of any retinopathy (88% ± 4.6%, P = 0.91-0.95), presence of moderate nonproliferative or worse retinopathy (87% ± 3.9%, P = 0.67-1.00), and presence of macular edema (99% ± 0.9%, P = 0.67-1.00). There was limited agreement regarding presence of referable nondiabetic eye pathology (61% ± 11%, P = 0.21-0.59) and early, nonroutine referral for a follow-up clinical eye exam (66% ± 8.1%, P = 0.19-0.54). Among all cases (n = 100), there was acceptable agreement regarding which had gradable images (77% ± 5.0%, P = 0.50-0.90). DISCUSSION: Inclusion of multiple types of eye care providers as teleophthalmology readers is unlikely to produce significant variability in the assessment of diabetic retinopathy among high-quality images. Greater variability was found regarding image gradability, nondiabetic eye pathology, and recommended clinical referral times. CONCLUSIONS: Our results suggest that more extensive training and uniform referral standards are needed to improve consensus on image gradability, referable nondiabetic eye pathology, and recommended clinical referral times.
Hutchinson AK, Kraker RT, Pineles SL, VanderVeen DK, Wilson LB, Galvin JA, Lambert SR. The Use of β-Blockers for the Treatment of Periocular Hemangiomas in Infants: A Report by the American Academy of Ophthalmology. Ophthalmology 2019;126(1):146-155.Abstract
PURPOSE: To review the published literature assessing the efficacy of β-blockers for the treatment of periocular hemangioma in infants. METHODS: Literature searches were conducted in May 2018 in PubMed with no date restrictions and limited to studies published in English and in the Cochrane Library database without any restrictions. The combined searches yielded 437 citations. Of these,16 articles were deemed appropriate for inclusion in this assessment and assigned a level of evidence rating by the panel methodologist. RESULTS: None of the 16 studies included in this assessment were rated level I, 3 were rated level II, and 13 were rated level III. The most common treatment regimen was 2 mg/kg daily oral propranolol, but intralesional and topical β-blockers were also used. Treatment effect was most often measured in terms of reduction in the size of the lesions, which occurred in the majority of patients. β-Blockers were consistently shown to reduce astigmatism, but this reduction was shown to be statistically significant in only 2 series. The effect of β-blockers on amblyopia was not adequately documented. β-Blockers were generally well tolerated and had mild side effects (fatigue, gastrointestinal upset/diarrhea, restlessness/sleep disturbances, minor wheezing, and cold extremities). Complications severe enough to require cessation of treatment occurred in only 2 patients out of a total of 229 who received β-blockers. CONCLUSIONS: There is limited evidence to support the safety and efficacy of both topical and systemic β-blockers to promote regression of periocular hemangiomas. Additional research may confirm the best dosage and route of administration to maximize efficacy in reducing induced astigmatism and amblyopia associated with periocular hemangiomas while minimizing side effects.
Wolkow N, Weinberg DA, Bersani TA, Yoon MK, Lefebvre DR, Lee NG, Sutula FC, Mandeville JT, Hatton MP, Freitag SK. Ophthalmic Plastic Surgery in Patients 100 Years and Older. Ophthalmic Plast Reconstr Surg 2019;35(1):71-76.Abstract
PURPOSE: The centenarian population is growing and ophthalmic plastic surgeons are providing care to an increasing number of elderly patients. Outcomes of centenarians have not been previously studied in the ophthalmic plastic surgery literature. The goal of the current review was to examine the baseline characteristics, surgical problems, and outcomes of this select group of patients. METHODS: A retrospective chart review was performed. Patients who underwent ophthalmic plastic surgery at age 100 or older between January 2000 and June 2016 by a member of the New England Oculoplastics Society were included in the study. RESULTS: Fifteen patients met inclusion criteria. The majority (66%) were female. More than half (60%) presented with a surgical problem of an urgent nature. Most disorders involved the lacrimal system or eyelids, and many were the result of trauma or infection. There were no cases of orbital tumor or thyroid eye disease. There were no surgical or anesthesia-related complications. Most patients (80%) had no documented history of dementia, and only 1 was diabetic. Notably, 33% of patients presented with no light perception vision in at least 1 eye. CONCLUSIONS: Ophthalmic plastic surgery can be performed safely in select patients 100 years of age and older. Formal prospective studies are needed to improve surgical care in this group.
Tang SM, Lau T, Rong SS, Yazar S, Chen LJ, Mackey DA, Lucas RM, Pang CP, Yam JC. Vitamin D and its pathway genes in myopia: systematic review and meta-analysis. Br J Ophthalmol 2019;103(1):8-17.Abstract
OBJECTIVE: To conduct a systematic review and meta-analysis of the association of blood vitamin D (25-hydroxyvitamin D, 25(OH)D) concentration and vitamin D pathway genes with myopia. METHODS: We searched the MEDLINE and EMBASE databases for studies published up to 29 January 2018. Cross-sectional or cohort studies which evaluated the blood 25(OH)D concentration, blood 25(OH)D3 concentration or vitamin D pathway genes, in relation to risk of myopia or refractive errors were included. Standard mean difference (SMD) of blood 25(OH)D concentrations between the myopia and non-myopia groups was calculated. The associations of blood 25(OH)D concentrations and polymorphisms in vitamin D pathway genes with myopia using summary ORs were evaluated. RESULTS: We summarised seven studies involving 25 008 individuals in the meta-analysis. The myopia group had lower 25(OH)D concentration than the non-myopia group (SMD=-0.27 nmol/L, p=0.001). In the full analysis, the risk of myopia was inversely associated with blood 25(OH)D concentration after adjusting for sunlight exposure or time spent outdoors (adjusted odds ratio (AOR)=0.92 per 10 nmol/L, p<0.0001). However, the association was not statistically significant for the <18 years subgroup (AOR=0.91 per 10 nmol/L, p=0.13) and was significant only for 25(OH)D3 (likely to be mainly sunlight derived), but not total 25(OH)D (AOR=0.93 per 10 nmol/L, p=0.00007; AOR=0.91 per 10 nmol/L, p=0.15). We analysed four single nucleotide polymorphisms in the VDR gene from two studies; there was no significant association with myopia. CONCLUSIONS: Lower 25(OH)D is associated with increased risk of myopia; the lack of a genetic association suggests that 25(OH)D level may be acting as a proxy for time outdoors.
MacIntosh PW, Fay AM. Update on the ophthalmic management of facial paralysis. Surv Ophthalmol 2019;64(1):79-89.Abstract
Bell's palsy is the most common neurologic condition affecting the cranial nerves. Lagophthalmos, exposure keratopathy, and corneal ulceration are potential complications. In this review, we evaluate various causes of facial paralysis as well as the level 1 evidence supporting the use of a short course of oral steroids for idiopathic Bell's palsy to improve functional outcomes. Various surgical and nonsurgical techniques are also discussed for the management of residual facial dysfunction.
Strauss RW, Kong X, Bittencourt MG, Ho A, Jha A, Schönbach EM, Ahmed MI, Muñoz B, Ervin A-M, Michaelides M, Birch DG, Sahel J-A, Sunness JS, Zrenner E, Bagheri S, Ip M, Sadda SV, West S, Scholl HPN, Scholl HPN. Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) Study: Design and Baseline Characteristics (Report No. 1). Ophthalmic Res 2019;61(1):36-43.Abstract
PURPOSE: To describe the study design and characteristics at first visit of participants in the longitudinal Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study. METHODS: Scotopic microperimetry (sMP) was performed in one designated study eye in a subset of participants with molecularly proven ABCA4-associated Stargardt disease (STGD1) enrolled in a multicenter natural history study (ProgStar). Study visits were every 6 months over a period ranging from 6 to 24 months, and also included fundus autofluorescence (FAF). RESULTS: SMART enrolled 118 participants (118 eyes). At the first visit of SMART, the mean sensitivity in mesopic microperimetry was 11.48 (±5.05; range 0.00-19.88) dB and in sMP 11.25 (±5.26; 0-19.25) dB. For FAF, all eyes had a lesion of decreased autofluorescence (mean lesion size 3.62 [±3.48; 0.10-21.46] mm2), and a total of 76 eyes (65.5%) had a lesion of definitely decreased autofluorescence with a mean lesion size of 3.46 (±3.60; 0.21-21.46) mm2. CONCLUSIONS: Rod function is impaired in STGD1 and can be assessed by sMP. Testing rod function may serve as a potential outcome measure for future clinical treatment trials. This is evaluated in the SMART study.
Wei X, Cho K-S, Thee EF, Jager MJ, Chen DF. Neuroinflammation and microglia in glaucoma: time for a paradigm shift. J Neurosci Res 2019;97(1):70-76.Abstract
Glaucoma is a complex neurodegenerative disease with many clinical subtypes. Some of its rare forms include pigmentary glaucoma, uveitic glaucoma and congenital glaucoma. While they all share common features of progressive retinal ganglion cell (RGC) loss, optic nerve damage and corresponding visual field loss, the exact mechanisms underlying glaucomatous neuron loss are not clear. This has largely hindered the development of a real cure for this disease. Elevated intraocular pressure (IOP) is a known major risk factor of glaucoma; however, progressive degeneration of RGCs and axons can also be found in patients with a normal IOP, i.e., normal tension glaucoma (NTG). Interestingly, patients who carry the gain-of-function mutation of the pro-inflammatory gene TBK1 - tumor necrosis factor (TNF) receptor associated factor NF-κB activator (TANK) binding kinase 1 - are at increased risk to develop NTG. This finding suggests a causal link between neuroinflammatory processes and glaucoma. Various studies have reported the presence of neuroinflammatory responses by microglia, astrocytes and other blood-born immune cells in the optic nerve head (ONH) at early stages of experimental glaucoma. Inhibition of certain pro-inflammatory pathways, particularly those associated with microglial activation, appears to be neuroprotective. In this review, we will focus on the inflammatory responses, in particular the proposed roles of microglia, in the pathogenesis of glaucoma.
Nilsson AK, Löfqvist C, Najm S, Hellgren G, Sävman K, Andersson MX, Smith LEH, Hellström A. Influence of Human Milk and Parenteral Lipid Emulsions on Serum Fatty Acid Profiles in Extremely Preterm Infants. JPEN J Parenter Enteral Nutr 2019;43(1):152-161.Abstract
BACKGROUND: Infants born prematurely are at risk of a deficiency in ω-6 and ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs) arachidonic acid (AA) and docosahexaenoic acid (DHA). We investigated how fatty acids from breast milk and parenteral lipid emulsions shape serum LC-PUFA profiles in extremely preterm infants during early perinatal life. METHODS: Ninety infants born < 28 weeks gestational age were randomized to receive parenteral lipids with or without the ω-3 LC-PUFAs eicosapentaenoic acid (EPA) and DHA (SMOFlipid: Fresenius Kabi, Uppsala, Sweden, or Clinoleic: Baxter Medical AB, Kista, Sweden, respectively). The fatty acid composition of infant serum phospholipids was determined from birth to postmenstrual age 40 weeks, and in mother's milk total lipids on postnatal day 7. Enteral and parenteral intake of LC-PUFAs was correlated with levels in infant serum. RESULTS: Infants administered parenteral ω-3 LC-PUFAs received 4.4 and 19.3 times more DHA and EPA, respectively, over the first 2 weeks of life. Parenteral EPA but not DHA correlated with levels in infant serum. We found linear relationships between dietary EPA and DHA and infant serum levels in the Clinoleic (Baxter Medical AB) group. The volume of administered SMOFlipid (Fresenius Kabi) was inversely correlated with serum AA, whereas Clinoleic (Baxter Medical AB) inversely correlated with serum EPA and DHA. CONCLUSIONS: There appears to be no or low correlation between the amount of DHA administered parenterally and levels measured in serum. Whether this observation reflects serum phospholipid fraction only or truly represents the amount of accreted DHA needs to be investigated. None of the parenteral lipid emulsions satisfactorily maintained high levels of both ω-6 and ω-3 LC-PUFAs in infant serum.
Cousins CC, Chou JC, Greenstein SH, Brauner SC, Shen LQ, Turalba AV, Houlihan P, Ritch R, Wiggs JL, Knepper PA, Pasquale LR. Resting nailfold capillary blood flow in primary open-angle glaucoma. Br J Ophthalmol 2019;103(2):203-207.Abstract
BACKGROUND/AIMS: An altered haemodynamic profile for various ocular posterior segment capillary beds has been documented in primary open-angle glaucoma (POAG). POAG may also involve abnormal non-ocular blood flow, and the nailfold capillaries, which are not affected by elevated intraocular pressure (IOP), are readily assessable. METHODS: We measured resting nailfold capillary blood flow in 67 POAG and 63 control subjects using video capillaroscopy. Masked readers tracked blood column voids between consecutive, registered image sequence frames, measured vessel diameter and calculated blood flow. We used multiple logistic regression to investigate the relation between nailfold capillary blood flow and POAG. In secondary analyses, we stratified cases by maximum IOP and concurrent topical beta-blocker use. RESULTS: Mean (±SD) blood flow in picolitres per second was 26.8±17.6 for POAG cases and 50.1±24.2 for controls (p<0.0001). After adjustment for demographic and clinical factors including blood pressure and pulse, every picolitre per second increase in resting nailfold blood flow was associated with a 6% (95% CI 0.92 to 0.96) reduced odds of POAG (p<0.0001). Similar relations between nailfold capillary blood flow and POAG were found for cases stratified by maximum known IOP and for cases stratified by concurrent topical beta-blocker use. CONCLUSION: Reduced resting nailfold capillary blood flow is present in POAG independent of covariates such as blood pressure, pulse and IOP.

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