OBJECTIVE: To compare clinical outcomes of cataract surgery in eyes with and without pseudoexfoliation (PXF). DESIGN: Retrospective deidentified data analysis. PARTICIPANTS: A total of 123 PXF and 4776 non-PXF eyes of patients who underwent cataract surgery. METHODS: We compared data on visual acuity, Visual Function Questionnaire (VFQ)-based quality of life, and complications in PXF and non-PXF eyes from the Veterans Affairs (VA) Ophthalmic Surgery Outcomes Data Project across 5 VA medical centres. RESULTS: Pupillary expansion devices were used in 31 (25.2%) PXF cases and 398 (8.4%) non-PXF cases (p < 0.0001). Capsular tension rings were used in 6 (4.9%) PXF cases and 55 (1.2%) non-PXF cases (p < 0.004). The following complications occurred more frequently in PXF cases: zonular dehiscence without vitrectomy (4 [3.3%] PXF cases vs 40 [0.8%] non-PXF cases p = 0.02), persistent inflammation (28 [24.1%] vs 668 [14.5%]; p = 0.007), and persistent intraocular pressure elevation (5 [4.3%] vs 68 [1.5%]; p = 0.03). Best corrected visual acuity (BCVA) improved in both groups after 1 month, but 87 (83.7%) PXF cases achieved postoperative BCVA better than or equal to 20/40 compared to 3991 (93.8%) non-PXF cases (p = 0.0003). There was no significant difference in the postoperative composite VFQ scores between PXF (82.1 ± 16.9) and non-PXF cases (84.2 ± 16.8, p = 0.09). CONCLUSIONS: Several complications occurred more frequently in the PXF group compared to the non-PXF group, and fewer PXF cases achieved BCVA better than or equal to 20/40. Despite this, both groups experienced similar improvement in vision-related quality of life after cataract surgery.
Rare or novel gene variants in patients with proliferative diabetic retinopathy may contribute to disease development. We performed whole exome sequencing (WES) on patients at the phenotypic extremes of diabetic retinal complications: 57 patients diagnosed with proliferative diabetic retinopathy (PDR) as cases and 13 patients with no diabetic retinopathy despite at least 10years of type 2 diabetes as controls. Thirty-one out of the 57 cases and all 13 controls were from the African American Proliferative Diabetic Retinopathy Study (AA). The rest of the cases were of mixed ethnicities (ME). WES identified 721 candidate genes with rare or novel non-synonymous variants found in at least one case with PDR and not present in any controls. After filtering for genes with null alleles in greater than two cases, 28 candidate genes were identified in our ME cases and 16 genes were identified in our AA cases. Our analysis showed rare and novel variants within these genes that could contribute to the development of PDR, including rare non-synonymous variants in FAM132A, SLC5A9, ZNF600, and TMEM217. We also found previously unidentified variants in VEGFB and APOB. We found that VEGFB, VPS13B, PHF21A, NAT1, ZNF600, PKHD1L1 expression was reduced in human retinal endothelial cells (HRECs) cultured under high glucose conditions. In an exome sequence analysis of patients with PDR, we identified variants in genes that could contribute to pathogenesis. Six of these genes were further validated and found to have reduced expression in HRECs under high glucose conditions, suggestive of an important role in the development of PDR.
Enterococci are ancient commensal bacteria that recently emerged as leading causes of antibiotic-resistant, hospital-acquired infection. Vancomycin-resistant enterococci (VRE) epitomize why drug-resistant enterococcal infections are a problem: VRE readily colonize the antibiotic-perturbed gastrointestinal (GI) tract where they amplify to large numbers, and from there, they infect other body sites, including the bloodstream, urinary tract, and surgical wounds. VRE are resistant to many antimicrobials and host defenses, which facilitates establishment at the site of infection and confounds therapeutic clearance. Having evolved to colonize the GI tract, VRE are comparatively ill adapted to the human bloodstream. A recent study by Honsa and colleagues (E. S. Honsa et al., mBio 8:e02124-16, 2017, https://doi.org/10.1128/mBio.02124-16) found that a strain of vancomycin-resistant Enterococcus faecium evolved antibiotic tolerance within the bloodstream of an immunocompromised host by activating the stringent response through mutation of relA Precisely how VRE colonize and infect and the selective pressures that led to the outgrowth of relA mutants are the subjects of ongoing research.
PURPOSE: To review the available evidence on the ocular safety and efficacy of anti-vascular endothelial growth factor (VEGF) agents for the treatment of retinopathy of prematurity (ROP) compared with laser photocoagulation therapy. METHODS: A literature search of the PubMed and Cochrane Library databases was conducted last on September 6, 2016, with no date restrictions and limited to articles published in English. This search yielded 311 citations, of which 37 were deemed clinically relevant for full-text review. Thirteen of these were selected for inclusion in this assessment. The panel methodologist assigned ratings to the selected articles according to the level of evidence. RESULTS: Of the 13 citations, 6 articles on 5 randomized clinical trials provided level II evidence supporting the use of anti-VEGF agents, either as monotherapy or in combination with laser therapy. The primary outcome for these articles included recurrence of ROP and the need for retreatment (3 articles), retinal structure (2 articles), and refractive outcome (1 article). Seven articles were comparative case series that provided level III evidence. The primary outcomes included the effects of anti-VEGF treatment on development of peripheral retinal vessels (1 article), refractive outcomes (1 article), or both structural and refractive or visual outcomes (5 articles). CONCLUSIONS: Current level II and III evidence indicates that intravitreal anti-VEGF therapy is as effective as laser photocoagulation for achieving regression of acute ROP. Although there are distinct ocular advantages to anti-VEGF pharmacotherapy for some cases (such as eyes with zone I disease or aggressive posterior ROP), the disadvantages are that the ROP recurrence rate is higher, and vigilant and extended follow-up is needed because retinal vascularization is usually incomplete. After intravitreal injection, bevacizumab can be detected in serum within 1 day, and serum VEGF levels are suppressed for at least 8 to 12 weeks. The effects of lowering systemic VEGF levels on the developing organ systems of premature infants are unknown, and there are limited long-term data on potential systemic and neurodevelopmental effects after anti-VEGF use for ROP treatment. Anti-VEGF agents should be used judiciously and with awareness of the known and unknown or potential side effects.
Purpose: The long-term, low-resolution vision experienced by individuals affected by retinal disease that causes central vision loss (CVL) may change their perception of blur through adaptation. This study used a short-term adaptation paradigm to evaluate adaptation to blur and sharpness in patients with CVL. Methods: A variation of Webster's procedure was used to measure the point of subjective neutrality (PSN). The image that appeared normal after adaptation to each of seven blur and sharpness levels (PSN) was measured in 12 patients with CVL (20/60 to 20/320) and 5 subjects with normal sight (NS). Patients with CVL used a preferred retinal locus to view the images. Small control studies investigated the effects of long-term and medium-term (1 hour) defocus and diffusive blur. Results: Adaptation was reliably measured in patients with CVL and in the peripheral vision of NS subjects. The shape of adaptation curves was similar in patients with CVL and both central and peripheral vision of NS subjects. No statistical correlations were found between adaptation and age, visual acuity, retinal eccentricity, or contrast sensitivity. Long-term blur experience by a non-CVL myopic participant caused a shift in the adaptation function. Conversely, medium-term adaptation did not cause a shift in the adaptation function. Conclusions: Blur and sharp short-term adaptation occurred in peripheral vision of normal and diseased retinas. In most patients with CVL, neither adaptation nor blur perception was affected by long-term attention to peripheral low-resolution vision. The impact of blur/sharp adaptation on the benefit of image enhancement techniques for patients with CVL is discussed.
Acute transient or permanent retinal occlusive disease requires prompt medical attention and can be an ophthalmological emergency. Central retinal artery occlusion leads to permanent and severe monocular visual loss in the majority of patients. Transient monocular vision loss leaves no permanent deficits, but requires the same level of clinical vigilance, as it portends possible future adverse events, including loss of vision and stroke. Acute treatment options remain limited, and secondary prevention of cerebral ischemic events is the mainstay of management. This article reviews the current evidence for managing patients with retinal ischemia.
Importance: Intravitreous bevacizumab (0.25 to 0.625 mg) is increasingly used to treat type 1 retinopathy of prematurity (ROP), but there remain concerns about systemic toxicity. A much lower dose may be effective while reducing systemic risk. Objective: To find a dose of intravitreous bevacizumab that was lower than previously used for severe ROP, was effective in this study, and could be tested in future larger studies. Design, Setting, and Participants: Between May 2015 and September 2016, 61 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, phase 1 dose de-escalation study. One eye of 10 to 14 infants received 0.25 mg of intravitreous bevacizumab. If successful, the dose was reduced for the next group of infants (to 0.125 mg, then 0.063 mg, and finally 0.031 mg). Diluted bevacizumab was delivered using 300 µL syringes with 5/16-inch, 30-gauge fixed needles. Interventions: Bevacizumab injections at 0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg. Main Outcomes and Measures: Success was defined as improvement in preinjection plus disease or zone I stage 3 ROP by 5 days after injection or sooner, and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks. Results: Fifty-eight of 61 enrolled infants had 4-week outcomes completed; mean birth weight was 709 g and mean gestational age was 24.9 weeks. Success was achieved in 11 of 11 eyes at 0.25 mg, 14 of 14 eyes at 0.125 mg, 21 of 24 eyes at 0.063 mg, and 9 of 9 eyes at 0.031 mg. Conclusions and Relevance: A dose of bevacizumab as low as 0.031 mg was effective in 9 of 9 eyes in this phase 1 study and warrants further investigation. Identifying a lower effective dose of bevacizumab may reduce the risk for neurodevelopmental disability or detrimental effects on other organs.
PURPOSE: To determine whether botulinum toxin is as effective as strabismus surgery in the treatment of acute-onset comitant esotropia in children. DESIGN: Retrospective, nonrandomized, comparative clinical study. METHODS: Setting: Tertiary care pediatric hospital. STUDY POPULATION: Forty-nine children with acute-onset comitant esotropia. INTERVENTION: Treatment with either botulinum toxin ("chemodenervation group") or standard incisional strabismus surgery ("surgery group"). MAIN OUTCOME MEASURE: Success rate at 6 months (total horizontal deviation of 10 prism diopters or less and evidence of binocular single vision). RESULTS: There were 16 patients in the chemodenervation group and 33 patients in the surgery group. The success rate was not significantly different at 6 months (81% vs 61%, P = .20) or at 18 months (67% vs 58%, P = .74). The median angle of deviation and median stereoacuity were not significantly different at 6 or 18 months. The chemodenervation procedure was not inferior to incisional strabismus surgery at 6 months. The duration of general anesthesia (5 vs 71 min, P < .001) and time in the post-anesthesia care unit (37 vs 93 min, P < .001) were significantly shorter in the chemodenervation group. Botulinum toxin injection payment averaged $874 per procedure compared with $2783 for strabismus surgery. CONCLUSIONS: Botulinum toxin is at least as effective as surgery in the treatment of acute-onset comitant esotropia at 6 months while reducing the duration of general anesthesia and healthcare costs.
Gaze-contingent displays have been widely used in vision research and virtual reality applications. Due to data transmission, image processing, and display preparation, the time delay between the eye tracker and the monitor update may lead to a misalignment between the eye position and the image manipulation during eye movements. We propose a method to reduce the misalignment using a Taylor series to predict the saccadic eye movement. The proposed method was evaluated using two large datasets including 219,335 human saccades (collected with an EyeLink 1000 system, 95% range from 1° to 32°) and 21,844 monkey saccades (collected with a scleral search coil, 95% range from 1° to 9°). When assuming a 10-ms time delay, the prediction of saccade movements using the proposed method could reduce the misalignment greater than the state-of-the-art methods. The average error was about 0.93° for human saccades and 0.26° for monkey saccades. Our results suggest that this proposed saccade prediction method will create more accurate gaze-contingent displays.
Choristomatous lacrimal gland tissue has been detected in many different sites of the ocular adnexa, but has never before been convincingly described in the submucosa of the lacrimal sac. A 77-year-old woman with epiphora had a biopsy of the sac wall preformed during a dacryocystorhinostomy that contained such a lacrimal choristoma. Zymogen granules were found in the cytoplasm of the secretory cells with the periodic acid-Schiff reaction. No mucus-producing cells, as found in normal sac submucosal glands, were detected using the Alcian blue, mucicarmine, and Gomori methenamine silver histochemical stains. Gross cystic fluid protein-15 positivity was demonstrated immunohistochemically. The clinical implications of this choristoma are explored.
BACKGROUND: Whether habitual coffee consumption interacts with the genetic predisposition to obesity in relation to body mass index (BMI) and obesity is unknown. METHODS: We analyzed the interactions between genetic predisposition and habitual coffee consumption in relation to BMI and obesity risk in 5116 men from the Health Professionals Follow-up Study (HPFS), in 9841 women from the Nurses' Health Study (NHS), and in 5648 women from the Women's Health Initiative (WHI). The genetic risk score was calculated based on 77 BMI-associated loci. Coffee consumption was examined prospectively in relation to BMI. RESULTS: The genetic association with BMI was attenuated among participants with higher consumption of coffee than among those with lower consumption in the HPFS (P interaction = 0.023) and NHS (P interaction = 0.039); similar results were replicated in the WHI (P interaction = 0.044). In the combined data of all cohorts, differences in BMI per increment of 10-risk allele were 1.38 (standard error (SE), 0.28), 1.02 (SE, 0.10), and 0.95 (SE, 0.12) kg/m(2) for coffee consumption of < 1, 1-3 and > 3 cup(s)/day, respectively (P interaction < 0.001). Such interaction was partly due to slightly higher BMI with higher coffee consumption among participants at lower genetic risk and slightly lower BMI with higher coffee consumption among those at higher genetic risk. Each increment of 10-risk allele was associated with 78% (95% confidence interval (CI), 59-99%), 48% (95% CI, 36-62%), and 43% (95% CI, 28-59%) increased risk for obesity across these subgroups of coffee consumption (P interaction = 0.008). From another perspective, differences in BMI per increment of 1 cup/day coffee consumption were 0.02 (SE, 0.09), -0.02 (SE, 0.04), and -0.14 (SE, 0.04) kg/m(2) across tertiles of the genetic risk score. CONCLUSIONS: Higher coffee consumption might attenuate the genetic associations with BMI and obesity risk, and individuals with greater genetic predisposition to obesity appeared to have lower BMI associated with higher coffee consumption.
Adeno-associated viruses (AAVs) are used extensively as a gene delivery vehicle for retinal gene therapy, yet its ability to target the anterior segment of the eye, critical to unlocking therapeutic opportunities, is less characterized. Previously, self-complimentary (sc) AAV was shown to be necessary for transduction of the cornea and trabecular meshwork (TM), limiting the size of the gene transfer cassette, likely due to a block in second strand synthesis thought to be required for functional transduction. Here, we evaluated several AAV capsids in a single stranded (ss) genome conformation for their ability to overcome the need for scAAV for targeting corneal endothelium and TM. AAV2, 8, and a recently synthetically developed AAV called Anc80L65 were evaluated in vitro and in vivo by intracameral injection in mice. Results show that although scAAV2 demonstrated superior infectivity in vitro including Human Trabecular meshwork (HTM) immortalized cell lines; Anc80L65 transduced following a single intracameral injection efficiently all components of the mouse anterior segment, including the TM, corneal stroma, and endothelial cells. These results suggest that Anc80L65 is able to overcome the requirement for scAAV genomes to enable TM and corneal targeting, expanding the potential experimental and therapeutic use of AAV gene transfer in the anterior segment of the eye.
Purpose: Optic nerve head astrocytes, a subtype of white-matter astrocytes, become reactive early in the course of glaucoma. It was shown recently that in the DBA/2J mouse model of inherited glaucoma optic nerve astrocytes extend new longitudinal processes into the axon bundles before ganglion cell loss becomes apparent. The present study aims at testing whether this behavior of astrocytes is typical of early glaucomatous damage. Methods: Mice expressing green fluorescent protein in individual astrocytes were used to evaluate the early response of astrocytes in the glial lamina of the optic nerve head after increasing the IOP using the microbead occlusion method. Tissue sections from the glial lamina were imaged consecutively by confocal and electron microscopy. Results: Confocal and electron microscope images show that astrocytes close to the myelination transition zone in the hypertensive nerve heads extend new processes that follow the longitudinal axis of the optic nerve and invade axon bundles in the nerve head. Ultrastructurally, the longitudinal processes were largely devoid of subcellular organelles except for degenerating mitochondria. Conclusions: The longitudinal processes are a common feature of glaucomatous optic nerve astrocytes, whereas they are not observed after traumatic nerve injury. Thus, astrocytes appear to fine-tune their responses to the nature and/or timing of the injury to the neurons that they surround.
PURPOSE: To compare choroidal vascular density (CVD) and volume (CVV) in diabetic eyes and controls, using en face swept-source optical coherence tomography (SS-OCT). DESIGN: Prospective cross-sectional study. METHODS: Setting: Multicenter. PATIENT POPULATION: Total of 143 diabetic eyes-27 with no diabetic retinopathy (DR), 47 with nonproliferative DR (NPDR), 51 with NPDR and diabetic macular edema (DME), and 18 with proliferative DR (PDR)-and 64 age-matched nondiabetic control eyes. OBSERVATION PROCEDURES: Complete ophthalmologic examination and SS-OCT imaging. En face SS-OCT images of the choroidal vasculature were binarized. MAIN OUTCOME MEASURES: CVD, calculated as the percent area occupied by choroidal vessels in the central macular region (6-mm-diameter circle centered on the fovea), and throughout the posterior pole (12 × 9 mm). The central macular CVV was calculated by multiplying the average CVD by macular area and choroidal thickness (obtained with SS-OCT automated software). Multilevel mixed linear models were performed for analyses. RESULTS: Compared to controls (0.31 ± 0.07), central macular CVD was significantly decreased by 9% in eyes with NPDR + DME (0.28 ± 0.06; ß = -0.03, P = .02) and by 15% in PDR (0.26 ± 0.05; ß = -0.04, P = .01). The central macular CVV was significantly decreased by 19% in eyes with PDR (0.020 ± 0.005 mm3, ß = -0.01, P = .01) compared to controls (0.025 ± 0.01 mm3). CONCLUSIONS: Choroidal vascular density and volume are significantly reduced in more advanced stages of diabetic retinopathy. New imaging modalities should allow further exploration of the contributions of choroidal vessel disease to diabetic eye disease pathogenesis, prognosis, and treatment response.
A 17-year-old girl presented with unilateral retrobulbar optic neuritis as well as bilateral funduscopic findings and outer retinal dysfunction suggestive of acute zonal occult outer retinopathy (AZOOR). Fundus autofluorescence abnormalities, visual field loss, and electroretinographic changes were supportive of bilateral AZOOR. MRI was consistent with the diagnosis of clinically isolated syndrome (CIS), which is defined as a central nervous system demyelinating event that may herald the onset of multiple sclerosis (MS). While AZOOR previously has been linked to MS and demyelinating white matter lesions in the brain, our case seems unique due to concurrent development of AZOOR and retrobulbar optic neuritis as a CIS.
Whether change in physical activity over time modifies the genetic susceptibility to long-term weight gain is unknown. We calculated a BMI-genetic risk score (GRS) based on 77 BMI-associated single nucleotide polymorphisms (SNPs) and a body fat percentage (BF%)-GRS based on 12 BF%-associated SNPs in 9,390 women from the Nurses' Health Study (NHS) and 5,291 men from the Health Professionals Follow-Up Study (HPFS). We analyzed the interactions between each GRS and change in physical activity on BMI/body weight change within five 4-year intervals from 1986 to 2006 using multivariable generalized linear models with repeated-measures analyses. Both the BMI-GRS and the BF%-GRS were associated with long-term increases in BMI/weight, and change in physical activity consistently interacted with the BF%-GRS on BMI change in the NHS (P for interaction = 0.025) and HPFS (P for interaction = 0.001). In the combined cohorts, 4-year BMI change per 10-risk allele increment was -0.02 kg/m(2) among participants with greatest increase in physical activity and 0.24 kg/m(2) among those with greatest decrease in physical activity (P for interaction < 0.001), corresponding to 0.01 kg versus 0.63 kg weight changes every 4 years (P for interaction = 0.001). Similar but marginal interactions were observed for the BMI-GRS (P for interaction = 0.045). Our data indicate that the genetic susceptibility to weight gain may be diminished by increasing physical activity.
Penicillin-binding proteins (PBPs) are enzymes involved in the assembly of the bacterial cell wall, a major target for antibiotics. These proteins are classified by mass into high-molecular-weight PBPs, which are transpeptidases that form peptidoglycan cross-links, and low-molecular-weight PBPs, which are typically hydrolases. We report a functionally unique family of low-molecular-weight PBPs that act as transpeptidases rather than hydrolases, but they do not cross-link peptidoglycan. We show that these PBPs can exchange d-amino acids bearing chemical tags or affinity handles into peptidoglycan precursors, including Lipid II, enabling biochemical studies of proteins involved in cell wall assembly. We report that, in two organisms, the PBPs incorporate lysine into cellular peptidoglycan and that, further, the PBPs have the unprecedented ability to transfer the primary ε-amine of lysine to peptidoglycan.
Genetic and genomic studies, including genome-wide association studies (GWAS) have accelerated the discovery of genes contributing to glaucoma, the leading cause of irreversible blindness world-wide. Glaucoma can occur at all ages, with Mendelian inheritance typical for rare early onset disease (before age 40) and complex inheritance evident in common adult-onset forms of disease. Recent studies have suggested possible therapeutic targets for some patients with early-onset glaucoma based on the molecular and cellular events caused by MYOC, OPTN and TBK1 mutations. Diagnostic genetic tests using early-onset glaucoma genes are also proving useful for pre-symptomatic disease detection and genetic counseling. Recent GWAS completed for three types of common adult-onset glaucoma have identified novel loci for POAG (primary-open-angle glaucoma) (ABCA1, AFAP1, GMDS, PMM2, TGFBR3, FNDC3B, ARHGEF12, GAS7, FOXC1, ATXN2, TXNRD2); PACG (primary angle-closure glaucoma (EPDR1, CHAT, GLIS3, FERMT2, DPM2-FAM102); and exfoliation syndrome (XFS) glaucoma (CACNA1A). In total sixteen genomic regions have been associated with POAG (including the normal tension glaucoma (NTG) subgroup), 8 with PACG and 2 with XFS. These studies are defining important biological pathways and processes that contribute to disease pathogenesis.