PURPOSE: To assess the relationship between baseline age-related macular degeneration (AMD) and disease stage, as well as optical coherence tomography (OCT) features seen in AMD, with three-year changes in dark adaptation (DA). METHODS: Prospective longitudinal study including patients with AMD and a comparison group (n=42 eyes, 27 patients). At baseline and three years, we obtained color fundus photographs, spectral-domain OCT and rod-mediated dark adaptation (20 minutes protocol). Multilevel mixed effect models were used for analyses, with changes in rod intercept time (RIT) at three years as the primary outcome. As some eyes (n=11) reached the DA testing ceiling value at baseline, we used three-year changes in area under the DA curve (AUDAC) as an additional outcome. RESULTS: Baseline AMD, AMD stage and hyperreflective foci on OCT were associated with larger changes in RIT at three years. When change in AUDAC was used as an outcome in addition to these features, the presence of retinal atrophy and drusenoid pigment epithelial detachment (PED) had significant associations. New subretinal drusenoid deposits at three years was also associated with more pronounced changes in RIT and AUDAC. CONCLUSIONS: Specific OCT features are associated with DA impairments over time, which supports that structural changes predict functional loss over three years.
INTRODUCTION: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW. METHODS: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography. RESULTS: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement. DISCUSSION: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.
BACKGROUND: Community-genotype methicillin-resistant Staphylococcus aureus (CG-MRSA) emerged in the 1990s as a global community pathogen primarily involved in skin and soft tissue infections (SSTIs) and pneumonia. To date, the CG-MRSA SSTI burden in Latin America (LA) has not been assessed. OBJECTIVE: The main objective of this study was to report the rate and genotypes of community-genotype methicillin-resistant Staphylococcus aureus (CG-MRSA) causing community-onset skin and soft tissue infections (CO-SSTIs) in LA over the last two decades. In addition, this research determined relevant data related to SSTIs due to CG-MRSA, including risk factors, other invasive diseases, and mortality. DATA SOURCES: Relevant literature was searched and extracted from five major databases: Embase, PubMed, LILACS, SciELO, and Web of Science. METHODS: A systematic review was performed, and a narrative review was constructed. RESULTS: An analysis of 11 studies identified epidemiological data across LA, with Argentina presenting the highest percentage of SSTIs caused by CG-MRSA (88%). Other countries had rates of CG-MRSA infection ranging from 0 to 51%. Brazil had one of the lowest rates of CG-MRSA SSTI (4.5-25%). In Argentina, being younger than 50 years of age and having purulent lesions were predictive factors for CG-MRSA CO-SSTIs. In addition, the predominant genetic lineages in LA belonged to sequence types 8, 30, and 5 (ST8, ST30, and ST5). CONCLUSION: There are significant regional differences in the rates of CG-MRSA causing CO-SSTIs. It is not possible to conclude whether or not CG-MRSA CO-SSTIs resulted in more severe SSTI presentations or in a higher mortality rate.
PURPOSES: To evaluate the effect of YAG laser peripheral iridotomy (LPI) on corneal endothelial cell density (ECD) and morphology in primary angle closure suspects (PACS) over 72 months. METHODS: The Zhongshan Angle Closure Prevention Trial is a single-centre randomised controlled trial. Subjects with bilateral PACS received YAG LPI prophylactic treatment in one eye randomly, while the fellow eye served as control. Central corneal ECD and morphology were assessed using non-contact specular microscopy (SP-2000P, Topcon) at baseline, 6, 18, 36, 54 and 72 months postoperatively. Mixed model analysis was conducted to compare the difference between treated and fellow eyes. RESULTS: A total of 875 participants were included, with a mean age of 59.3±5.0 years and 83.5% female. The ECD declined significantly (p<0.001) over time in both treated and fellow eyes, but the treated eyes showed more progressive cell loss with increasing time (p<0.001). The difference in ECD loss between LPI-treated and fellow eyes was not significant at each follow-up until 72 months (4.9% in LPI eyes vs 4.2% in non-LPI eyes, p=0.003). Mean cell areas increased significantly over time in both treated and fellow eyes (p<0.001), but no longitudinal change was observed for hexagonality. In LPI-treated eyes, no significant correlation was found between age, gender, ocular biometrics, intraocular pressure and laser settings with endothelium change, except for time effect (p<0.01). CONCLUSION: ECD decreases over time primarily due to ageing effect. YAG LPI does not appear to cause clinically significant corneal endothelial damage over 72 months after treatment. TRIAL REGISTRATION NUMBER: ISRCTN45213099.
BACKGROUND: Pragmatic and comparative effectiveness randomized controlled trials (RCTs) aim to be highly generalizable studies, with broad applicability and flexibility in methods. These trials also address recruitment issues by minimizing exclusions. The trials may also appeal to potential subjects because of lower risk and lower burdens of participation. We sought to examine rates of refusal and uses of waivers of informed consent in pragmatic and comparative effectiveness RCTs. METHODS: A systematic review of pragmatic and comparative effectiveness RCTs performed wholely or in part in the United States and first published in 2014 and 2017. RESULTS: 103 studies involving 105 discrete populations were included for review. Refusal data was collected for 71 RCTs. Overall, studies reported an average rate of 31.9% of potential subjects refused participation; on an individual basis, 38.4% of people asked to take part refused at some point during recruitment. 23 trials (22%) were performed, at least in part, with a waiver of informed consent, 7 (30%) of which provided any form of notice to subjects. CONCLUSIONS: Overall refusal rates for pragmatic and comparative effectiveness RCTs appear roughly the same as other types of research, with studies reporting about a third of people solicited for participation refuse. Moreover, informed consent was waived in 22% (95% Binomial exact Confidence Interval 13.9-30.5%) of the trials, and further study is needed to understand when waivers are justified and when notice should be provided.
The vertebrate retina is generated by retinal progenitor cells (RPCs), which produce >100 cell types. Although some RPCs produce many cell types, other RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). We used genome-wide assays of chromatin structure to compare the profiles of a restricted cone/HC RPC and those of other RPCs in chicks. These data nominated regions of regulatory activity, which were tested in tissue, leading to the identification of many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. Two transcription factors, Otx2 and Oc1, were found to bind to many of these CRMs, including those near genes important for cone development and function, and their binding sites were required for activity. We also found that Otx2 has a predicted autoregulatory CRM. These results suggest that Otx2, Oc1 and possibly other Onecut proteins have a broad role in coordinating cone development and function. The many newly discovered CRMs for cones are potentially useful reagents for gene therapy of cone diseases.
: Ultra-widefield (UWF) imaging of the myopic eye. : Myopes, and particularly high and pathologic myopes, present a unique challenge in fundoscopic imaging. Critical pathology is often located in the anteriormost portion of the retina, variations in posterior segment contour are difficult to capture in two-dimensional images, and extremes in axial length make simply focusing imaging devices difficult. We review the evolution of modalities for ophthalmic imaging (color fundus photography [CFP], optical coherence topography [OCT], angiography, artificial intelligence [AI]) to present day UWF technology and its impact on our understanding of myopia. Advances in UWF technology address many of the challenges in fundoscopic imaging of myopes, providing new insights into the structure and function of the myopic eye. UWF CFP improves our ability to detect and document anterior segment pathology prevalent in approximately half of all high myopes. UWF OCT better captures the staphylomatous contour of the myopic eye, providing enhanced visualization of the vitreoretinal interface and progressive development of myopic traction maculopathy. UWF angiography highlights the posterior vortex veins, thin choriocapillaris, far peripheral avascularity, and peripheral retinal capillary microaneurysms more prevalent in the myopic eye. Researchers have demonstrated the ability of AI algorithms to predict refractive error, and great potential remains in the use of AI technology for the screening and prevention of myopic disease. We note significant progress in our ability to capture anterior pathology and improved image quality of the posterior segment of high and pathologic myopes. The next jump forward for UWF imaging will be the ability to capture a high quality ora to ora multimodal fundoscopic image in a single scan that will allow for sensitive AI-assisted screening of myopic disease.
BACKGROUND/AIMS: To determine whether timing of ophthalmic screening influences prevalence of neonatal fundus haemorrhages. We compared the prevalence of fundus haemorrhages in two populations: term newborns screened early (less than 72 hours) and preterm newborns screened late (4-11 weeks). Additionally, we reviewed the literature on timing and prevalence of newborn haemorrhages. METHODS: Retrospective observational cohort study. Infants who underwent wide-angle ophthalmic digital imaging over one overlapping year in the Newborn Eye Screen Testing (NEST) or Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) programme were included. The PubMed database was filtered to include English-language articles dating back to 1950. Nine articles were selected for review based on inclusion of the prevalence of newborn fundus haemorrhages at multiple time points. RESULTS: A total of 202 patients received early imaging in the NEST cohort and 73 patients received late imaging in the SUNDROP cohort. In the NEST cohort, 20.2% of newborns had haemorrhages. In contrast, we found haemorrhages in only one case or 1.4% of the SUNDROP cohort. Using prevalence data from nine additional studies, we developed a predicted probabilities model of newborn haemorrhages. Per this model, the probability of seeing a haemorrhage if you screen an infant at 1 hour is 18.8%, at 2 weeks is 2.9% and at 1 month is 0.28%. CONCLUSION: We found a significant difference in the prevalence of fundus haemorrhages between the early-screened NEST cohort and the late-screened, preterm SUNDROP cohort. Likely, this difference is due to the transient nature of most newborn haemorrhages.
PURPOSE: Flanged intrascleral haptic fixation (FISHF) is a useful method to secure intraocular lenses (IOLs) in eyes without capsular support. Biomechanical studies were conducted to support the use of this technique. DESIGN: Laboratory investigation METHODS: Haptics of 3-piece IOLs were passed through cadaveric human sclera using 30-gauge and 27-gauge needles. Flanges were created by melting 1.0 mm from the haptic ends using cautery. The forces required to remove the flanged haptic from the sclera and disinsert the haptic from the optic were measured using a mechanical tester and a custom-fabricated mount. RESULTS: The mean FISHF dislocation force using 30-gauge needles was greatest with the CT Lucia 602 (2.04 ± 0.24 N) compared to the LI61AO (0.93 ± 0.41 N; p=0.001), ZA9003 (0.70 ± 0.34 N; p=<0.001), and MA60AC (0.27 ± 0.19 N; p<0.001). Using 27-gauge needles with the CT Lucia resulted in a lower dislocation force (0.56 ± 0.36 N, p<0.001). The FISHF dislocation force was correlated with the flange-to-needle diameter ratio (r=0.975). The FISHF dislocation forces of the CT Lucia and LI61AO using 30-gauge needles were not significantly different from their haptic-optic disinsertion forces (p=0.79 and 0.27 respectively). There was no difference in flange diameter between 1.0 mm and 2.0 mm haptic melt lengths across the IOLs (p=0.15-0.85). CONCLUSIONS: This data strongly supports the biomechanical stability of FISHF with the polyvinylidene fluoride haptics of the CT Lucia using small diameter instruments for intrascleral tunnel creation. 1.0 mm of haptic may be the optimal melt length.
PURPOSE: To report a case of microsporidia (Encephalitozoon hellem) keratoconjunctivitis acquired through avian transmission in an immunocompetent adult, diagnosed by metagenomic deep sequencing (MDS), and confirmed by polymerase chain reaction. METHODS: A case report. RESULTS: An 18-year-old woman was referred with unilateral keratoconjunctivitis unresponsive to topical and systemic therapy after exposure to birdcage debris. Slit-lamp examination of the left eye revealed a follicular papillary reaction of the palpebral conjunctiva and multiple corneal punctate epithelial opacities that stained minimally with fluorescein. In vivo confocal microscopy revealed bright double-walled structures and smaller bright round structures in the superficial epithelial debris and epithelium. Molecular diagnosis with MDS of E. hellem was confirmed by polymerase chain reaction. Clinical resolution and normalization of in vivo confocal microscopy was observed after a 6-week course of topical azithromycin. The patient elected a 3-week course of topical voriconazole 1% for definitive antimicrosporidial treatment, with no evidence of persistent infection 1 month later. CONCLUSIONS: Microsporidial (E. hellem) keratoconjunctivitis can occur through avian transmission in immunocompetent hosts. Topical azithromycin may be effective against this pathogen. MDS has utility in the diagnosis of atypical keratoconjunctivitis.
: To determine the response to the second TNF-α inhibitor (adalimumab and infliximab) after failing the first agent in idiopathic inflammatory retinal vascular leakage.: This was a retrospective observational case series. Patients with the diagnosis of idiopathic inflammatory retinal vascular leakage who had received both infliximab and adalimumab were included in the study.: Twelve and 15 patients received adalimumab (Group one) and infliximab (Group two) as the first treatment, respectively. The remission rates between Group one (58.3%) and Group two (66.7%) were not statistically significant. ( = .4) As the second agent, adalimumab was more effective in younger patients (27.5 ± 20.6) compared to older patients (48.75 ± 10.2). ( = .03). Moreover, patients with lower vision responded marginally better to infliximab as the second treatment ( = .06).: Either TNF-α inhibitor, adalimumab and infliximab, can be employed in the treatment of the patients with idiopathic inflammatory retinal vascular leakage who fail one of these agents.
In some patients, migraine attacks are associated with symptoms of allodynia which can be localized (cephalic) or generalized (extracephalic). Using functional neuroimaging and cutaneous thermal stimulation, we aimed to investigate the differences in brain activation of patients with episodic migraine (n = 19) based on their allodynic status defined by changes between ictal and interictal pain tolerance threshold for each subject at the time of imaging. In this prospective imaging study, differences were found in brain activity between the ictal and interictal visits in the brainstem/pons, thalamus, insula, cerebellum and cingulate cortex. Significant differences were also observed in the pattern of activation along the trigeminal pathway to noxious heat stimuli in no allodynia vs. generalized allodynia in the thalamus and the trigeminal nucleus but there were no activation differences in the trigeminal ganglion. The functional magnetic resonance imaging (fMRI) findings provide direct evidence for the view that in migraine patients who are allodynic during the ictal phase of their attacks, the spinal trigeminal nucleus and posterior thalamus become hyper-responsive (sensitized)-to the extent that they mediate cephalic and extracephalic allodynia, respectively. In addition, descending analgesic systems seem as "switched off" in generalized allodynia.
BACKGROUND/AIM: To investigate the prevalence, causes and risk factors of visual impairment (VI) among the elderly in 'home for the aged' in Hyderabad, India. METHODS: Individuals aged ≥60 years were recruited from 41 'homes for the aged'. All participants had complete eye examinations including presenting visual acuity, refraction, slit-lamp examination, intraocular pressure measurement and fundus imaging by trained clinicians. VI was defined as presenting visual acuity worse than 6/18 in the better eye. Multivariate logistic regression was used to determine the risk factors associated with VI. RESULTS: 1512 elderly residents from 41 homes for the aged were enumerated, of whom 1182 (78.1%) were examined. The mean age of examined participants was 75.0 years (SD 8.8 years; range: 60-108 years); 35.4% of those examined were men. The prevalence of VI was 30.1% (95% CI 27.5 to 32.8). The leading cause of VI was cataract (46.3%, n=165), followed by uncorrected refractive error (27.0%, n=96), posterior capsular opacification (14.9%, n=53) and posterior segment disease (6.5%, n=23). Overall, 88.2% of the VI was either treatable or correctable. In multiple logistic regression, those aged 80 years and older (OR: 1.7, p<0.01), living in 'free' homes (OR: 1.5, p<0.01) and who were immobile/bedridden (OR: 3.02, p<0.01) had significantly higher odds of VI. Gender was not associated with VI. CONCLUSIONS: VI was common and largely avoidable in residents of 'homes for the aged' in Hyderabad, India. Screening for vision loss in 'homes for aged' and the provision of appropriate services should become routine practice to achieve the goal of healthy ageing in India.
Mucins are a family of high molecular weight, heavily-glycosylated proteins produced by wet epithelial tissues, including the ocular surface epithelia. Densely-packed O-linked glycan chains added post-translationally confer the biophysical properties of hydration, lubrication, anti-adhesion and repulsion. Membrane-associated mucins (MAMs) are the distinguishing components of the mucosal glycocalyx. At the ocular surface, MAMs maintain wetness, lubricate the blink, stabilize the tear film, and create a physical barrier to the outside world. In addition, it is increasingly appreciated that MAMs function as cell surface receptors that transduce information from the outside to the inside of the cell. Recently, our team published a comprehensive review/perspectives article for molecular scientists on ocular surface MAMs, including previously unpublished data and analyses on two new genes MUC21 and MUC22, new MAM functions and new biological roles, comparing human and mouse (PMID: 31493487). The current article is a refocus for the audience of The Ocular Surface. First, we update the gene and protein information in a more concise form, and include a new section on glycosylation. Next, we discuss biological roles, with some new sections and further updating from our previous review. Finally, we provide a new chapter on MAM involvement in ocular surface disease. We end this with discussion of an emerging mechanism responsible for damage to the epithelia and their mucosal glycocalyces: the unfolded protein response (UPR). The UPR offers a novel target for therapeutic intervention.
Importance: The role of anti-vascular endothelial growth factor injections for the management of nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) has not been clearly established. Objective: To determine the efficacy of intravitreous aflibercept injections compared with sham treatment in preventing potentially vision-threatening complications in eyes with moderate to severe NPDR. Design, Setting, and Participants: Data for this study were collected between January 15, 2016, and May 28, 2020, from the ongoing DRCR Retina Network Protocol W randomized clinical trial, conducted at 64 US and Canadian sites among 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study severity level, 43-53), without CI-DME. Analyses followed the intent-to-treat principle. Interventions: Eyes were randomly assigned to 2.0 mg of aflibercept injections (n = 200) or sham (n = 199) given at baseline; 1, 2, and 4 months; and every 4 months through 2 years. Between 2 and 4 years, treatment was deferred if the eye had mild NPDR or better. Aflibercept was administered in both groups if CI-DME with vision loss (≥10 letters at 1 visit or 5-9 letters at 2 consecutive visits) or high-risk proliferative diabetic retinopathy (PDR) developed. Main Outcomes and Measures: Development of CI-DME with vision loss or PDR through May 2020, when the last 2-year visit was completed. Results: Among the 328 participants (57.6% men [230 of 399 eyes]; mean [SD] age, 56  years), the 2-year cumulative probability of developing CI-DME with vision loss or PDR was 16.3% with aflibercept vs 43.5% with sham. The overall hazard ratio for either outcome was 0.32 (97.5% CI, 0.21-0.50; P < .001), favoring aflibercept. The 2-year cumulative probability of developing PDR was 13.5% in the aflibercept group vs 33.2% in the sham group, and the 2-year cumulative probability of developing CI-DME with vision loss was 4.1% in the aflibercept group vs 14.8% in the sham group. The mean (SD) change in visual acuity from baseline to 2 years was -0.9 (5.8) letters with aflibercept and -2.0 (6.1) letters with sham (adjusted mean difference, 0.5 letters [97.5% CI, -1.0 to 1.9 letters]; P = .47). Conclusions and Relevance: In this randomized clinical trial, among eyes with moderate to severe NPDR, the proportion of eyes that developed PDR or vision-reducing CI-DME was lower with periodic aflibercept compared with sham treatment. However, through 2 years, preventive treatment did not confer visual acuity benefit compared with observation plus treatment with aflibercept only after development of PDR or vision-reducing CI-DME. The 4-year results will be important to assess longer-term visual acuity outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02634333.