Importance: Intravitreous injections of antivascular endothelial growth factor agents are effective for treating diabetic macular edema (DME) involving the center of the macula (center-involved DME [CI-DME]) with visual acuity impairment (20/32 or worse). The best approach to treating patients with CI-DME and good visual acuity (20/25 or better) is unknown. Objective: To compare vision loss at 2 years among eyes initially managed with aflibercept, laser photocoagulation, or observation. Design, Setting, and Participants: Randomized clinical trial conducted at 91 US and Canadian sites among 702 adults with type 1 or type 2 diabetes. Participants had 1 study eye with CI-DME and visual acuity of 20/25 or better. The first participant was randomized on November 8, 2013, and the final date of follow-up was September 11, 2018. Interventions: Eyes were randomly assigned to 2.0 mg of intravitreous aflibercept (n = 226) as frequently as every 4 weeks, focal/grid laser photocoagulation (n = 240), or observation (n = 236). Aflibercept was required for eyes in the laser photocoagulation or observation groups that had decreased visual acuity from baseline by at least 10 letters (≥ 2 lines on an eye chart) at any visit or by 5 to 9 letters (1-2 lines) at 2 consecutive visits. Main Outcomes and Measures: The primary outcome was at least a 5-letter visual acuity decrease from baseline at 2 years. Antiplatelet Trialists' Collaboration adverse events (defined as myocardial infarction, stroke, or vascular or unknown death) were reported. Results: Among 702 randomized participants (mean age, 59 years; 38% female [n=264]), 625 of 681 (92% excluding deaths) completed the 2-year visit. For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/326) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208) in the aflibercept, laser photocoagulation, and observation groups, respectively (aflibercept vs laser photocoagulation risk difference, -2% [95% CI, -9% to 5%]; relative risk, 0.88 [95% CI, 0.57-1.35; P = .79]; aflibercept vs observation risk difference, -3% [95% CI, -11% to 4%]; relative risk, 0.83 [95% CI, 0.55-1.27; P = .79]; laser photocoagulation vs observation risk difference, -1% [95% CI, -9% to 6%]; relative risk, 0.95 [95% CI, 0.64-1.41; P = .79]). Antiplatelet Trialists' Collaboration vascular events occurred in 15 (7%), 13 (5%), and 8 (3%) participants in the aflibercept, laser photocoagulation, and observation groups. Conclusions and Relevance: Among eyes with CI-DME and good visual acuity, there was no significant difference in vision loss at 2 years whether eyes were initially managed with aflibercept or with laser photocoagulation or observation and given aflibercept only if visual acuity worsened. Observation without treatment unless visual acuity worsens may be a reasonable strategy for CI-DME. Trial Registration: ClinicalTrials.gov Identifier: NCT01909791.
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.
PURPOSE: Severe corneal disease contributes significantly to the global burden of blindness. Corneal allograft surgery remains the most commonly used treatment, but does not succeed long term in every patient, and the odds of success fall with each repeated graft. The Boston keratoprosthesis type I has emerged as an alternative to repeat corneal allograft. However, cost limits its use in resource-poor settings, where most corneal blind individuals reside. METHODS: All aspects of the Boston keratoprosthesis design process were examined to determine areas of potential modification and simplification, with dual goals to reduce cost and improve the cosmetic appearance of the device in situ. RESULTS: Minor modifications in component design simplified keratoprosthesis manufacturing. Proportional machinist time could be further reduced by adopting a single axial length for aphakic eyes, and a single back plate diameter. The cosmetic appearance was improved by changing the shape of the back plate holes from round to radial, with a petaloid appearance, and by anodization of back plate titanium to impute a more natural color. CONCLUSIONS: We have developed a modified Boston keratoprosthesis type I, which we call the "Lucia." The Lucia retains the 2 piece design and ease of assembly of the predicate device, but would allow for manufacturing at a reduced cost. Its appearance should prove more acceptable to implanted patients. Successful keratoprosthesis outcomes require daily medications for the life of the patient and rigorous, frequent, postoperative care. Effective implementation of the device in resource-poor settings will require further innovations in eye care delivery.
PURPOSE: The most commonly applied prosthetic devices for corneal blindness in the setting of severe cicatricial keratoconjunctivitis are the Boston keratoprosthesis type II and the modified osteo-odonto-keratoprosthesis, with these requiring either normal eyelid skin or a healthy cuspid tooth, respectively. For patients with neither attribute, we developed a new keratoprosthesis device combining positive aspects of both Boston keratoprosthesis type II and modified osteo-odonto-keratoprosthesis, which we have named the "Lux." METHODS: Short-term postoperative outcomes for the Lux keratoprosthesis, best-corrected visual acuity (BCVA), device retention, and complications, were examined in a retrospective case series of 9 eyes of 9 patients implanted at 4 centers. RESULTS: Seven of 9 (77.8%) eyes had cicatricial corneal blindness due to autoimmune disease and 2 (22.2%) from severe burns. Preoperative BCVA was ≤hand motions in all patients. Three (33.3%) had previously received at least 1 keratoprosthesis in the affected eye, and 4 (44.4%) had previously undergone ≥1 therapeutic keratoplasty. One patient had 19 previous eye surgeries. The mean duration of postoperative follow-up was 18.7 months (range 7-28 months). BCVA of ≥20/200 was achieved in all 9 patients, with 2 (22.2%) reaching 20/20 at the last examination, and all 9 (100%) of the devices were retained. One recipient developed a retinal detachment 2 months after implantation. Two (22.2%) patients required placement of a glaucoma drainage device. CONCLUSIONS: The Lux keratoprosthesis was developed for patients with severe cicatricial keratoconjunctivitis who were otherwise not candidates for existing keratoprosthesis designs. Short-term outcomes after implantation of the Lux keratoprosthesis were encouraging.
Training the modern ophthalmic surgeon is a challenging process. Microsurgical education can benefit from innovative methods to practice surgery in low-risk simulations, assess and refine skills in the operating room through video content analytics, and learn at a distance from experienced surgeons. Developments in emerging technologies may allow us to pursue novel forms of instruction and build on current educational models. Artificial intelligence, which has already seen numerous applications in ophthalmology, may be used to facilitate surgical tracking and evaluation. Within immersive technology, growth in the space of virtual reality head-mounted displays has created intriguing possibilities for operating room simulation and observation. Here, we explore the applications of these technologies and comment on their future in ophthalmic surgical education.
There are various treatments for cystoid macular edema (CME) secondary to retinitis pigmentosa (RP); however, the evidence for these treatments has not been previously systematically reviewed. Our review that includes 23 studies shows that oral carbonic anhydrase inhibitors (CAI) (including acetazolamide, methazolamide) and topical CAI (dorzolamide and brinzolamide) are effective first line treatments. In patients unresponsive to CAI treatment, intravitreal steroids (triamcinolone acetonide and sustained-release dexamethasone implant), oral corticosteroid (Deflazacort), intravitreal anti-vascular endothelial growth factor agents (ranibizumab and bevacizumab), grid laser photocoagulation, pars plana vitrectomy, or ketorolac were also effective in improving CME secondary to RP. Oral acetazolamide has the strongest clinical basis for treatment and was superior to topical dorzolamide. Rebound of CME was commonly seen in the long term, regardless of the choice of treatment. Oral acetazolamide should be the first line treatment in CME secondary to RP. Topical dorzolamide is an appropriate alternative in patients intolerant to adverse effects of oral acetazolamide. More studies are required to investigate the management of rebound CME.
CONTEXT: A heterozygous de novo c.1228G>A mutation (E410K) in the TUBB3 gene encoding the neuronal-specific β-tubulin isotype 3 (TUBB3) causes the TUBB3 E410K syndrome characterized by congenital fibrosis of the extraocular muscles (CFEOM), facial weakness, intellectual and social disabilities, and Kallmann syndrome (anosmia with hypogonadotropic hypogonadism). All TUBB3 E410K subjects reported to date are sporadic cases. OBJECTIVE: This study aimed to report the clinical, genetic, and molecular features of a familial presentation of the TUBB3 E410K syndrome. DESIGN: Case report of a mother and three affected children with clinical features of the TUBB3 E410K syndrome. SETTING: Academic Medical Center. MAIN OUTCOME MEASURES: Genetic analysis of the TUBB3 gene and clinical evaluation of endocrine and nonendocrine phenotypes. RESULTS: A de novo TUBB3 c.1228G>A mutation arose in a female proband who displayed CFEOM, facial weakness, intellectual and social disabilities, and anosmia. However, she underwent normal sexual development at puberty and had three spontaneous pregnancies with subsequent autosomal-dominant inheritance of the mutation by her three boys. All sons displayed nonendocrine features of the TUBB3 E410K syndrome similar to their mother but, in addition, had variable features suggestive of additional endocrine abnormalities. CONCLUSIONS: This first report of an autosomal-dominant inheritance of the TUBB3 c.1228G>A mutation in a family provides new insights into the spectrum and variability of endocrine phenotypes associated with the TUBB3 E410K syndrome. These observations emphasize the need for appropriate clinical evaluation and complicate genetic counseling of patients and families with this syndrome.
Purpose: To review preclinical and clinical advances in gene therapy, with a focus on gene editing technologies, and application to inherited retinal disease.Methods: A narrative overview of the literature, summarizing the state-of-the-art in clinical gene therapy for inherited retinal disease, as well as the science and application of new gene editing technology.Results: The last three years has seen the first FDA approval of an in vivo gene replacement therapy for a hereditary blinding eye disease and, recently, the first clinical application of an in vivo gene editing technique. Limitations and challenges in this evolving field are highlighted, as well as new technologies developed to address the multitude of molecular mechanisms of disease.Conclusion: Genetic therapy for the treatment of inherited retinal disease is a rapidly expanding area of ophthalmology. New technologies have revolutionized the field of genome engineering and rekindled an interest in precision medicines for these conditions.
PURPOSE: To evaluate the associations between optic disc (OD)-related anatomical parameters (interartery angle [IAA] between superior and inferior temporal retinal arteries, OD tilt [TL], rotation [ROT], and torsion [TO], OD surface curvature [CUR], and central retinal vessel trunk entry point location [CRVTL] on OD) and the spherical equivalent of refractive error (SE), and to assess the impact of glaucoma severity on these relationships. METHODS: Cirrus optical coherence tomography (OCT) fundus images and 24-2 visual fields of 438 patients were included. Ellipses were fitted to OD borders. IAA was calculated between marked retinal artery locations on a circle around OD. Blood vessel entry point on OD was marked to locate CRVTL. TL was measured as the angle between the lines fitted to OD clinical boundary and the Bruch's membrane edges on the horizontal B-scans. Ellipse rotation relative to the vertical axis defined ROT. Angle between the long axis of OD and the interartery line defined TO. CUR was determined by the inner limiting membrane on the horizontal B-scans. Linear regression models evaluated by Bayes Factors (BF) were used to determine the covariance structure between the parameters and SE as well as possible impacts of mean deviation (MD). RESULTS: Our results showed that CRVTL had the strongest relationship with SE, followed by ROT, TL, and IAA (BFs: 3.59 × 10(7), 2645, 1126, and 248, respectively). MD did not significantly modulate the relationship between ONH parameters and SE. CONCLUSION: Our results suggest that SE should be considered when interpreting the OD and its circumpapillary region for diagnostic purposes. TRANSLATIONAL RELEVANCE: The reported relationships between OD-related parameters and ametropia may help to decrease false-positive clinical diagnoses of optic neuropathies.
PURPOSE OF THE STUDY: The purpose of the study was to determine whether there are different patterns of retinal nerve fiber layer (RNFL) thinning as measured by spectral domain optical coherence tomography (SD-OCT) for 4 subtypes of open angle glaucoma (OAG): primary OAG (POAG), normal tension glaucoma (NTG), pseudoexfoliation glaucoma (PXG), and pigmentary glaucoma (PDG) and to compare them with normal controls. MATERIALS AND METHODS: SD-OCT RNFL thickness values were measured for 4 quadrants and for 4 sectors (ie, superior-nasal, superior-temporal, inferior-nasal, and inferior-temporal). Differences in RNFL thickness values between groups were analyzed using analysis of variance. Paired t tests were used for quadrant comparisons. RESULTS: Two hundred eighty-five participants (102 POAG patients, 33 with NTG, 48 with PXG, 13 with PDG, and 89 normal patients) were included in this study. All 4 subtypes of OAG showed significant RNFL thinning in the superior, inferior, and nasal quadrants as well as the superior-temporal and inferior-temporal sectors (all P-values <0.0001) compared with normals. POAG and NTG patients had greater RNFL thinning inferiorly and inferior-temporally than superiorly (P-values: 0.002 to 0.018 and 0.006, respectively) compared with PXG patients. In contrast, PDG patients had greater RNFL thinning superiorly and superior-nasally than inferiorly compared with other OAG subtypes (ie, POAG, NTG, PXG groups, with P-values: 0.009, 0.003, 0.009, respectively). Of the 4 OAG subtypes, PXG patients exhibited the greatest degree of inter-eye RNFL asymmetry. CONCLUSIONS: This study suggests that SD-OCT may be able to detect significant differences in patterns of RNFL thinning for different subtypes of OAG.
OBJECTIVES/HYPOTHESIS: Most patients who undergo endoscopic dacryocystorhinostomy (DCR) have a diagnosis of idiopathic nasolacrimal duct obstruction. The purpose of this study was to examine the impact of routine biopsy of the lacrimal sac performed at time of DCR on subsequent patient diagnosis and treatment. STUDY DESIGN: Retrospective review. METHODS: The histopathology of nasolacrimal specimens (n = 769), obtained from 654 consecutive patients undergoing endoscopic DCR by a single surgeon over a 30-year period, were reviewed. Specific focus included the identification of unanticipated pathologic findings as they related to pertinent patient demographics, clinical presentation, radiologic findings, and intraoperative observations. RESULTS: The study population was 69.6% female, with an average age of 56.1 ± 18.2 years. Pathological findings of tissue from the nasolacrimal sac, which was routinely sampled in all cases, showed inflammation (n = 566 [73.6%]), normal histology (n = 147 [19.1%]), granulomas (n = 8 [1.0%]), and neoplastic process (n = 7 [0.9%]). Patient history, preoperative CT scan, and/or intraoperative findings alerted the surgeon to the possibility of an unusual diagnosis in 12 of the 15 patients. An unsuspected neoplastic or granulomatous cause of lacrimal obstruction was identified on intraoperative biopsy in three patients (0.46%). CONCLUSIONS: Although neoplastic and granulomatous diseases are relatively rare causes of lacrimal obstruction necessitating DCR surgery, they may be identified by through patient evaluation in most cases and by routine intraoperative biopsy of the lacrimal sac in all cases. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:584-589, 2020.
BACKGROUND: Retinovascular changes are reported on fundus imaging in schizophrenia (SZ). This is the first study to use swept-source optical coherence tomography angiography (OCT-A) to comprehensively examine retinal microvascular changes in SZ. METHODS: This study included 30 patients with SZ/schizoaffective disorder (8 early and 15 chronic) and 22 healthy controls (HCs). All assessments were performed at Beth Israel Deaconess Medical Center and Massachusetts Eye and Ear. All participants underwent swept-source OCT-A of right (oculus dextrus [OD]) and left (oculus sinister [OS]) eye, clinical, and cognitive assessments. Macular OCT-A images (6 × 6 mm) were collected with the DRI Topcon Triton for superficial, deep, and choriocapillaris vascular regions. Microvasculature was quantified using vessel density (VD), skeletonized vessel density (SVD), fractal dimension (FD), and vessel diameter index (VDI). RESULTS: Twenty-one HCs and 26 SZ subjects were included. Compared to HCs, SZ patients demonstrated higher overall OD superficial SVD, OD choriocapillaris VD, and OD choriocapillaris SVD, which were primarily observed in the central, central and outer superior, and central and outer inferior/superior, respectively. Early-course SZ subjects had significantly higher OD superficial VD, OD choriocapillaris SVD, and OD choriocapillaris FD compared to matched HCs. Higher bilateral (OU) superficial VD correlated with lower Positive and Negative Syndrome Scale (PANSS) positive scores, and higher OU deep VDI was associated with higher PANSS negative scores. CONCLUSIONS AND RELEVANCE: These results suggest the presence of microvascular dysfunction associated with early-stage SZ. Clinical associations with microvascular alterations further implicate this hypothesis, with higher measures being associated with worse symptom severity and functioning in early stages and with lower symptom severity and better functioning in later stages.
The cerebral cortex needs to maintain information for long time periods while at the same time being capable of learning and adapting to changes. The degree of stability of physiological signals in the human brain in response to external stimuli over temporal scales spanning hours to days remains unclear. Here, we quantitatively assessed the stability across sessions of visually selective intracranial field potentials (IFPs) elicited by brief flashes of visual stimuli presented to 27 subjects. The interval between sessions ranged from hours to multiple days. We considered electrodes that showed robust visual selectivity to different shapes; these electrodes were typically located in the inferior occipital gyrus, the inferior temporal cortex, and the fusiform gyrus. We found that IFP responses showed a strong degree of stability across sessions. This stability was evident in averaged responses as well as single-trial decoding analyses, at the image exemplar level as well as at the category level, across different parts of visual cortex, and for three different visual recognition tasks. These results establish a quantitative evaluation of the degree of stationarity of visually selective IFP responses within and across sessions and provide a baseline for studies of cortical plasticity and for the development of brain-machine interfaces.
Sensory signals must be interpreted in the context of goals and tasks. To detect a target in an image, the brain compares input signals and goals to elicit the correct behavior. We examined how target detection modulates visual recognition signals by recording intracranial field potential responses from 776 electrodes in 10 epileptic human subjects. We observed reliable differences in the physiological responses to stimuli when a cued target was present versus absent. Goal-related modulation was particularly strong in the inferior temporal and fusiform gyri, two areas important for object recognition. Target modulation started after 250 ms post stimulus, considerably after the onset of visual recognition signals. While broadband signals exhibited increased or decreased power, gamma frequency power showed predominantly increases during target presence. These observations support models where task goals interact with sensory inputs via top-down signals that influence the highest echelons of visual processing after the onset of selective responses.
Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.