Benefits of Early vs Late Initiation of IVIG in the Treatment of Anti-HMGCR Immune-Mediated Necrotizing Myopathy.

BACKGROUND/OBJECTIVE: No clinical trials have been conducted to establish optimal and effective treatment in Immune-Mediated Necrotizing Myopathy (IMNM), which can have a refractory course with increased morbidity from permanent muscle damage especially in cases with delay in diagnosis and treatment. A subset of autoimmune necrotizing myopathy is associated with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Treatment involves withdrawing statins and using a combination of immunosuppressant and immunomodulatory treatment. Our study aims to provide longitudinally collected data on outcomes of early versus late initiation of intravenous immunoglobulin (IVIG) using our myositis center cohort of patients with Anti-HMGCR IMNM. METHODS: We conducted a retrospective chart review of 31 adult patients of the Oregon Health & Science University (OHSU) Myositis Center who were diagnosed with anti HMGCR-IMNM from September 2016 through October 2022 and reviewed physical exam, serologic lab data and their treatment including prednisone use as well as treatment response at the 0-months (the evaluation immediately prior to IVIG initiation), 3-months, 6-months and 12-months on treatment. We divided this cohort into those who received IVIG at or prior to 6 months after receiving the diagnosis of Anti-HMGCR IMNM and refer this as the "Non-Delayed" cohort, and those who received IVIG after 6 months following their diagnosis, which we referred to as "Delayed" cohort. Diagnosis of Anti-HMGCR IMNM was defined as per the 2016 ENMC criteria as having all 3 of: elevated serum CK, proximal muscle weakness, and anti-HMGCR antibodies. We evaluated the response to treatment by using a limited total improvement score (TIS) as per 2016 ACR/EULAR myositis response criteria. RESULTS: Amongst the 31 total patients, 19 were included within the Non-Delayed cohort, and 12 within the Delayed cohort. The two cohorts had a comparable amount of time between onset of symptoms and diagnosis; however, the Delayed cohort had a significantly longer time between diagnosis and IVIG treatment (p-value <0.001). At disease onset, cohorts had a comparable serum CK (p-value >0.999), but Delayed patients had an expected lower serum CK (p-value 0.016) at the 0-month time point. At the 0-month time point, 9 (47%) of the Non-Delayed patients required the use of a walker or wheelchair, while 8 (66%) of the Delayed cohort did. Non-Delayed patients demonstrated significant improvement in MMT8 at the 12-months intervals (p-value <0.001). Average serum CK values of all patients measured at the 3-month, 6-month, and 12-month did not significantly differ between the Non-Delayed and Delayed group. TIS improved more in the Non-Delayed group than in the Delayed group (p-value 0.002 at 3-months, 0.019 at 6-months and 0.001 at 12-months). Seven patients in the delayed group had permanent residual muscle weakness requiring walker or wheelchair use at 12-months while none of the patients in the Non-Delayed group did. CONCLUSION: Though our results have limitations, they contribute to a growing body of evidence which suggests that IVIG may prove to be a valuable addition to an early and aggressive induction regimen in patients afflicted by anti HMGCR IMNM. Delayed in IVIG treatment may lead to the development of permanent residual weakness and long-term disability.

A Hybrid Deep Learning Classification of Perimetric Glaucoma Using Peripapillary Nerve Fiber Layer Reflectance and Other OCT Parameters from Three Anatomy Regions.

Précis: A hybrid deep-learning model combines NFL reflectance and other OCT parameters to improve glaucoma diagnosis. Objective: To investigate if a deep learning model could be used combine nerve fiber layer (NFL) reflectance and other OCT parameters for glaucoma diagnosis. Patients and Methods: This is a prospective observational study where of 106 normal subjects and 164 perimetric glaucoma (PG) patients. Peripapillary NFL reflectance map, NFL thickness map, optic head analysis of disc, and macular ganglion cell complex thickness were obtained using spectral domain OCT. A hybrid deep learning model combined a fully connected network (FCN) and a convolution neural network (CNN) to develop to combine those OCT maps and parameters to distinguish normal and PG eyes. Two deep learning models were compared based on whether the NFL reflectance map was used as part of the input or not. Results: The hybrid deep learning model with reflectance achieved 0.909 sensitivity at 99% specificity and 0.926 at 95%. The overall accuracy was 0.948 with 0.893 sensitivity and 1.000 specificity, and the AROC was 0.979, which is significantly better than the logistic regression models (p < 0.001). The second best model is the hybrid deep learning model w/o reflectance, which also had significantly higher AROC than logistic regression models (p < 0.001). Logistic regression with reflectance model had slightly higher AROC or sensitivity than the other logistic regression model without reflectance (p = 0.024). Conclusions: Hybrid deep learning model significantly improved the diagnostic accuracy, without or without NFL reflectance. Hybrid deep learning model, combining reflectance/NFL thickness/GCC thickness/ONH parameter, may be a practical model for glaucoma screen purposes.

Early diagnosis and treatment by newborn screening (NBS) or family history is associated with improved visual outcomes for long-chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD) chorioretinopathy.

Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.

Bias Reduction Practices in Underrepresented Groups in Ophthalmology Resident Recruitment.

Importance: Best recruitment practices for increasing diversity are well established, but the adoption and impact of these practices in ophthalmology residency recruitment are unknown. Objective: To describe the adoption of bias reduction practices in groups underrepresented in ophthalmology (URiO) residency recruitment and determine which practices are effective for increasing URiO residents. Design, Setting, and Participants: This cross-sectional survey study used an 18-item questionnaire included in the online survey of the Association of University Professors in Ophthalmology (AUPO) Residency Program Directors. Data collection occurred from July 2022 to December 2022. The data were initially analyzed on January 16, 2023. Participants included residency program directors (PDs) in the AUPO PD listserv database. Main Outcomes and Measures: Descriptive analysis of resident selection committee approaches, evaluation of applicant traits, and use of bias reduction tools. Primary outcome was diversity assessed by presence of at least 1 resident in the last 5 classes who identified as URiO, including those underrepresented in medicine (URiM), lesbian, gay, bisexual, transgender, queer, intersex, and asexual plus, or another disadvantaged background (eg, low socioeconomic status). Multivariate analyses of recruitment practices were conducted to determine which practices were associated with increased URiO and URiM. Results: Among 106 PDs, 65 completed the survey (61.3%). Thirty-nine PDs used an interview rubric (60.0%), 28 used interview standardization (43.0%), 56 provided at least 1 bias reduction tool to their selection committee (86.2%), and 44 used postinterview metrics to assess diversity, equity, and inclusion efforts (67.7%). Application filters, interview standardization, and postinterview metrics were not associated with increased URiO. Multivariate logistic regression analysis showed larger residency class (odds ratio [OR], 1.34; 95% CI, 1.09-1.65; P = .01) and use of multiple selection committee bias reduction tools (OR, 1.47; 95% CI, 1.13-1.92; P = .01) were positively associated with increased URiO, whereas use of interview rubrics (OR, 0.72; 95% CI, 0.59-0.87; P = .001) and placing higher importance of applicant interest in a program (OR, 0.83; 95% CI, 0.75-0.92; P = .02) were negatively associated. URiM analyses showed similar associations. Conclusions and Relevance: Ophthalmology residency interviews are variably standardized. In this study, providing multiple bias reduction tools to selection committees was associated with increased URiO and URiM residents. Prioritizing applicant interest in a program may reduce resident diversity. Interview rubrics, while intended to reduce bias, may inadvertently increase inequity.

Stratification of Fusobacterium nucleatum by local health status in the oral cavity defines its subspecies disease association.

The ubiquitous inflammophilic oral pathobiont Fusobacterium nucleatum (Fn) is widely recognized for its strong association with inflammatory dysbiotic diseases and cancer. Fn is subdivided into four subspecies, which are historically considered functionally interchangeable in the oral cavity. To test this assumption, we analyzed patient-matched dental plaque and odontogenic abscess clinical specimens and examined whether an inflammatory environment selects for/against particular Fn subspecies. Dental plaque harbored a greater diversity of fusobacteria, with Fn. polymorphum dominating, whereas odontogenic abscesses were exceptionally biased for the largely uncharacterized organism Fn. animalis. Comparative genomic analyses revealed significant genotypic distinctions among Fn subspecies that correlate with their preferred ecological niches and support a taxonomic reassignment of each as a distinct Fusobacterium species. Despite originating as a low-abundance organism in dental plaque, Fn. animalis typically outcompetes other oral fusobacteria within the inflammatory abscess environment, which may explain its prevalence in other oral and extraoral diseases.

Long-term visual acuity outcomes following cataract surgery in eyes with ocular inflammatory disease.

PURPOSE: To evaluate the long-term visual acuity (VA) outcome of cataract surgery in inflammatory eye disease. SETTING: Tertiary care academic centres. DESIGN: Multicentre retrospective cohort study. METHODS: A total of 1741 patients with non-infectious inflammatory eye disease (2382 eyes) who underwent cataract surgery while under tertiary uveitis management were included. Standardised chart review was used to gather clinical data. Multivariable logistic regression models with adjustment for intereye correlations were performed to evaluate the prognostic factors for VA outcomes. Main outcome measure was VA after cataract surgery. RESULTS: Uveitic eyes independent of anatomical location showed improved VA from baseline (mean 20/200) to within 3 months (mean 20/63) of cataract surgery and maintained through at least 5 years of follow-up (mean 20/63). Eyes that achieved 20/40 or better VA at 1 year were more likely to have scleritis (OR=1.34, p<0.0001) or anterior uveitis (OR=2.2, p<0.0001), VA 20/50 to 20/80 (OR 4.76 as compared with worse than 20/200, p<0.0001) preoperatively, inactive uveitis (OR=1.49, p=0.03), have undergone phacoemulsification (OR=1.45 as compared with extracapsular cataract extraction, p=0.04) or have had intraocular lens placement (OR=2.13, p=0.01). Adults had better VA immediately after surgery, with only 39% (57/146) paediatric eyes at 20/40 or better at 1 year. CONCLUSIONS: Our results suggest that adult and paediatric eyes with uveitis typically have improved VA following cataract surgery and remain stable thereafter for at least 5 years.

Usability and feasibility of a take-home methadone web-application for opioid treatment program patients: A Small Business Innovation Research mixed methods study.

BACKGROUND: Most patients in opioid treatment programs (OTPs) attend daily for observed dosing. A Stage IA (create and adapt) and a Stage IB (feasibility and pilot) mixed method studies tested a web-application (app) designed to facilitate access to take-home methadone. METHODS: A Stage IA, intervention development study, used qualitative interviews to assess the usability (ease of use) and feasibility (ability to implement) of a take-home methadone app. The Stage IA market research was a two-week test with 96 patient participants from four OTPs. Qualitative interviews were completed with 20 systematically selected individuals who used the take-home app and 20 OTP clinicians (five each from the four OTPs). The Stage IB Small Business Innovation Research (SBIR) study (24 patients and 8 clinicians in a single OTP) included quantitative assessments of the app's usability, acceptability, appropriateness, and feasibility. Thematic analysis coded participant and staff assessments of the take-home app. RESULTS: Stage IA patients (mean age = 41 years; 52 % men, 57 % White) and IB patients (mean age = 38 years, 54 % men, 79 % White) described the app as "easy to use." Compared to unsupervised take-homes, some patients preferred using the take-home app. In Stage IB, patients rated the app highly on standardized measures of usability, acceptability, appropriateness, and feasibility. Clinician ratings were more ambivalent. Patients rated in-clinic dosing as more disruptive than unsupervised take-homes and take-homes using the app. DISCUSSION: A Stage IA study informed the development and maturation of a Stage IB feasibility pilot study. Overall, the take-home app's usability, acceptability, appropriateness, and feasibility were rated positively. Clinical staff ratings were less positive, but individuals commented that using the app a) enhanced patient quality of life, b) provided new tools for counselors, and c) offered competitive advantages. The SBIR award enhanced market research with more complete and systematic data collection and analysis.

The prevalence of Fusobacterium nucleatum subspecies in the oral cavity stratifies by local health status.

The ubiquitous inflammophilic pathobiont Fusobacterium nucleatum is widely recognized for its strong association with a variety of human dysbiotic diseases such as periodontitis and oral/extraoral abscesses, as well as multiple types of cancer. F. nucleatum is currently subdivided into four subspecies: F. nucleatum subspecies nucleatum (Fn. nucleatum), animalis (Fn. animalis), polymorphum (Fn. polymorphum), and vincentii/fusiforme (Fn. vincentii). Although these subspecies have been historically considered as functionally interchangeable in the oral cavity, direct clinical evidence is largely lacking for this assertion. Consequently, we assembled a collection of oral clinical specimens to determine whether F. nucleatum subspecies prevalence in the oral cavity stratifies by local oral health status. Patient-matched clinical specimens of both disease-free dental plaque and odontogenic abscess were analyzed with newly developed culture-dependent and culture-independent approaches using 44 and 60 oral biofilm/tooth abscess paired specimens, respectively. Most oral cavities were found to simultaneously harbor multiple F. nucleatum subspecies, with a greater diversity present within dental plaque compared to abscesses. In dental plaque, Fn. polymorphum is clearly the dominant organism, but this changes dramatically within odontogenic abscesses where Fn. animalis is heavily favored over all other fusobacteria. Surprisingly, the most commonly studied F. nucleatum subspecies, Fn. nucleatum, is only a minor constituent in the oral cavity. To gain further insights into the genetic basis for these phenotypes, we subsequently performed pangenome, phylogenetic, and functional enrichment analyses of oral fusobacterial genomes using the Anvi'o platform, which revealed significant genotypic distinctions among F. nucleatum subspecies. Accordingly, our results strongly support a taxonomic reassignment of each F. nucleatum subspecies into distinct Fusobacterium species. Of these, Fn. animalis should be considered as the most clinically relevant at sites of active inflammation, despite being among the least characterized oral fusobacteria.

Sector-Based Regression Strategies to Reduce Refractive Error-Associated Glaucoma Diagnostic Bias When Using OCT and OCT Angiography.

Purpose: This cross-sectional study aimed to investigate the sectoral variance of optical coherence tomography (OCT) and OCT angiography (OCTA) glaucoma diagnostic parameters across eyes with varying degrees of refractive error. Methods: Healthy participants, including individuals with axial ametropia, enrolled in the Hong Kong FAMILY cohort were imaged using the Avanti/AngioVue OCT/OCTA system. The OCT and OCTA parameters obtained include peripapillary nerve fiber layer thickness (NFLT), peripapillary nerve fiber layer plexus capillary density (NFLP-CD), and macular ganglion cell complex thickness (GCCT). Sectoral measurements of NFLT, NFLP-CD, and GCCT were based on sectors and hemispheres. Results: A total of 1339 eyes from 791 participants were stratified based on spherical equivalent refraction: high myopia (<-6 D), low myopia (-6 D to -1 D), emmetropia (-1 D to 1 D), and hyperopia (>1 D). Multivariable broken stick regression models, accounting for age, sex, and signal strength, showed that all NFLT sectors except temporally, the inferior GCCT hemisphere, and half of the NFLP-CD sectors were more affected by ametropia-related covariates than the corresponding global parameters. As expected, the false-positive rates in those sectors were elevated. Finally, sector-specific axial length (AL) and spherical equivalent (SE) adjustments helped reduce the elevated false-positive rates. Conclusions: The effect of optical magnification is even more prominent among sectors than the global parameters. AL- and SE-based adjustments should be individualized to each sector to mitigate this magnification bias effectively. Translational Relevance: Identifying sectoral differences among diagnostic parameters and adopting these sector-based adjustments into commercial OCT systems will hopefully reduce false-positive rates related to refractive error.

Optic Nerve Head Gene Transcription Sequelae to a Single Elevated IOP Exposure Provides Insights Into Known Responses to Chronically Elevated IOP.

Purpose: To clarify the optic nerve head (ONH) gene expression responses associated with a single, axon-damaging exposure to elevated IOP in relation to the composite cellular events previously identified in models of chronically elevated IOP. Methods: Anesthetized rats were exposed unilaterally to an 8-hour pulse-train controlled elevation of IOP (PT-CEI) at 60 mm Hg, while others received normotensive CEI at 20 mm Hg. ONH RNA was harvested at 0 hours and 1, 2, 3, 7, and 10 days after either CEI and from naïve animals. RNA sequencing was performed to analyze ONH gene expression. DAVID Bioinformatics tools were used to identify significant functional annotation clusters. Gene function was compared between PT-CEI and two models of chronic ocular hypertension from the literature. Results: The number of significantly changed genes peaked immediately (n = 1354) after PT-CEI (0 hours). This was followed by a lull (<4 genes per time point) at 1 and 2 days after PT-CEI. Gene activity increased again at 3 days (136 genes) and persisted at 7 (78 genes) and 10 (339 genes) days. Significant gene functional categories included an immediate upregulation of Defense Response at 0 hours, followed by upregulation in Cell Cycle, a reduction in Axonal-related genes at 3 to 10 days, and upregulation of Immune Response-related genes at 10 days following PT-CEI. The most commonly upregulated gene expression across our PT-CEI study and two chronic models of ocular hypertension were cell cycle related. Conclusions: The PT-CEI model places in sequence ONH gene expression responses previously reported in models with chronically elevated IOP and may provide insights into their role in optic nerve damage.

Outcome assessment of orthodontic clear aligner vs fixed appliance treatment in adolescents with moderate to severe malocclusions.

OBJECTIVE: To compare the efficacy and efficiency of treatment with clear aligners (CAT) vs fixed appliances (FAT) in adolescents with Class I and II moderate to severe malocclusions. MATERIALS AND METHODS: One operator's (Garfinkle) cases from 2014 to 2019, started at age 12-18 years, with pre- and posttreatment records were identified and used according to an institutional review board-approved protocol. Records were measured by two calibrated, blinded investigators, aided by software (OrthoCAD [Cadent, Fairview, N.J.], Dolphin Imaging & Management Solutions [Chatsworth, Calif]). Discrepancy index (DI) and cast radiograph evaluation (CRE) scores, treatment duration, number of scheduled and emergency visits, and reported appliance and interarch elastic wear compliance were compared between groups using Wilcoxon rank sum and Fisher's exact tests. Cephalometric superimpositions were completed to evaluate craniofacial growth and dental changes. RESULTS: Records from 72 cases met the criteria and were included. For the 47 CAT and 25 FAT cases, mean DI (21 ± 5 and 24 ± 8, respectively; P = .20) and CRE (35 ± 10 and 34 ± 9, respectively; P = .90) scores were not significantly different. Other case attributes and reported appliance and interarch elastic wear compliance were also not significantly different. CAT vs FAT cases had significantly smaller treatment durations (24 ± 6 vs 27 ± 5 months; P = .01) and visit numbers (16 ± 5 vs 24 ± 4; P < .01), but emergency visit numbers were not significantly different (2 ± 2 vs 3 ± 2; P = .08). CONCLUSIONS: In adolescents with Class I and II malocclusions and moderate to severe DI scores, on average, CAT vs FAT cases were completed 3 months faster with eight fewer visits, but treatment efficacy was not significantly different.

A mixed methods study to uncover impediments to accurate diagnosis of nonradiographic axial spondyloarthritis in the USA.

INTRODUCTION/OBJECTIVES: Delayed diagnosis of axial spondyloarthritis (axSpA) is well documented; little is known about the diagnostic journey and impediments for US patients with nonradiographic axSpA (nr-axSpA). It is hypothesized that impediments are varied and exist at both the healthcare provider (HCP) and patient levels. This study aims to understand patient experiences and contributors to delayed nr-axSpA diagnosis in the USA. METHOD: Interviews of adults with rheumatologist-diagnosed nr-axSpA, recruited through Spondylitis Association of America outreach and patient panels, and of rheumatologists, explored the diagnostic journey and diagnostic barriers. Emerging themes were further explored in an online patient survey. A multiple logistic regression analysis evaluated the main outcome variable, factors affecting time to nr-axSpA diagnosis. RESULTS: Interviews were conducted with 25 patients and 16 rheumatologists. Survey responses from 186 eligible patients revealed median time from symptom onset to diagnosis of nr-axSpA was 3.25 years. Delayed diagnosis was significantly more likely for women and people in rural areas. Most patients consulted ≥4 different types of HCPs before a rheumatologist and ≥2 rheumatologists before diagnosis. Impediments to timely diagnosis included insidious chronic pain; episodic symptom patterns attributed to activity; symptoms other than chronic lumbosacral back pain requiring medical consultation; and unfamiliarity with and misperceptions about nr-axSpA among HCPs, radiologists, and rheumatologists. CONCLUSIONS: Delayed nr-axSpA diagnosis is common and reflects HCP knowledge gaps and frequent patient presentation with dominant nonaxial symptoms. Targeted HCP education, research into early disease patterns, and interventions sensitive to the broader spectrum of nr-axSpA manifestations are needed to improve timely diagnosis. Key Points • Patients with nr-axSpA often see multiple types of HCPs, and multiple rheumatologists, before receiving a diagnosis. • Both patients and HCPs are unfamiliar with nr-axSpA and its symptoms, lacking understanding that nr-axSpA can occur in young people, females, and those presenting with normal x-rays. • Disease recognition by nonrheumatology HCPs is key for early referral. • Education on cardinal features, epidemiology, burden, and benefits of timely nr-axSpA diagnosis is warranted for HCPs who commonly manage back pain.

Environmental influences on Streptococcus sanguinis membrane vesicle biogenesis.

Membrane vesicles are produced by Gram-negative and Gram-positive bacteria. While membrane vesicles are potent elicitors of eukaryotic cells and involved in cell-cell communication, information is scarce about their general biology in the context of community members and the environment. Streptococcus sanguinis, a Gram-positive oral commensal, is prevalent in the oral cavity and well-characterized for its ability to antagonize oral pathobionts. We have found that production and dissemination of membrane vesicles by S. sanguinis is dependent on environmental and community factors. Co-culture with interacting commensal Corynebacterium durum, as well as with the periodontal pathobiont Filifactor alocis had no effect on S. sanguinis vesicle number and size, whereas the periodontal pathobiont Porphyromonas gingivalis abolished S. sanguinis vesicle production. Using both correlation and differential expression analyses to examine the transcriptomic changes underlying vesicle production, we found that differential expression of genes encoding proteins related to the cytoplasmic membrane and peptidoglycan correlate with the abundance of membrane vesicles. Proteomic characterizations of the vesicle cargo identified a variety of proteins, including those predicted to influence host interactions or host immune responses. Cell culture studies of gingival epithelial cells demonstrated that both crude and highly purified membrane vesicles could induce the expression of IL-8, TNF-α, IL-1ß, and Gro-α within 6 hours of inoculation at levels comparable to whole cells. Our findings suggest that production of membrane vesicles by S. sanguinis is heavily influenced by community and environmental factors and plays an important role in communication with host cells.

Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis.

PURPOSE: The purpose of this study was to compare the histopathologic inflammation and fibrosis of orbital adipose tissue in orbital inflammatory disease (OID) specimens. METHODS: In this retrospective cohort study, inflammation, and fibrosis in orbital adipose tissue from patients with thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis, nonspecific orbital inflammation (NSOI), and healthy controls were scored by 2 masked ocular pathologists. Both categories were scored on a scale of 0 to 3 with scoring criteria based on the percentage of specimens containing inflammation or fibrosis, respectively. Tissue specimens were collected from oculoplastic surgeons at 8 international centers representing 4 countries. Seventy-four specimens were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 24 with NSOI, and 12 healthy controls. RESULTS: The mean inflammation and fibrosis scores for healthy controls were 0.0 and 1.1, respectively. Orbital inflammatory disease groups' inflammation (I) and fibrosis (F) scores, formatted [I, F] with respective p -values when compared to controls, were: TAO [0.2, 1.4] ( p = 1, 1), GPA [1.9, 2.6] ( p = 0.003, 0.009), sarcoidosis [2.4, 1.9] ( p = 0.001, 0.023), and NSOI [1.3, 1.8] ( p ≤ 0.001, 0.018). Sarcoidosis had the highest mean inflammation score. The pairwise analysis demonstrated that sarcoidosis had a significantly higher mean inflammation score than NSOI ( p = 0.036) and TAO ( p < 0.0001), but no difference when compared to GPA. GPA had the highest mean fibrosis score, with pairwise analysis demonstrating a significantly higher mean fibrosis score than TAO ( p = 0.048). CONCLUSIONS: Mean inflammation and fibrosis scores in TAO orbital adipose tissue samples did not differ from healthy controls. In contrast, the more "intense" inflammatory diseases such as GPA, sarcoidosis, and NSOI did demonstrate higher histopathologic inflammation and fibrosis. This has implications in prognosis, therapeutic selection, and response monitoring in orbital inflammatory disease.

Three-Year Safety Results of SAR422459 (EIAV-ABCA4) Gene Therapy in Patients With ABCA4-Associated Stargardt Disease: An Open-Label Dose-Escalation Phase I/IIa Clinical Trial, Cohorts 1-5.

PURPOSE: To report on the safety of the first 5 cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt dystrophy due to mutations in ABCA4. DESIGN: Nonrandomized multicenter phase I/IIa clinical trial. METHODS: Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at 3 dose levels and were followed for 3 years after treatment. MAIN OUTCOME MEASURES: The primary end point was ocular and systemic adverse events. The secondary end points were best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, multifocal ERG, color fundus photography, short-wavelength fundus autofluorescence, and spectral domain optical coherence tomography. RESULTS: The subretinal injections were well tolerated by all 22 patients across 3 dose levels. There was 1 case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In 1 patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared with the untreated eye. However, in 6 patients, hypoautofluorescent changes were worse in the treated eye than in the untreated eye. Of these, 1 patient had retinal pigment epithelium atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, or multifocal ERG attributable to the treatment. CONCLUSIONS: Subretinal treatment with EIAV-ABCA4 was well tolerated with only 1 case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of retinal pigment epithelium atrophy on fundus autofluorescence. There was a significant reduction in macular flecks in 1 treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.

ANKRD24 organizes TRIOBP to reinforce stereocilia insertion points.

The stereocilia rootlet is a key structure in vertebrate hair cells, anchoring stereocilia firmly into the cell's cuticular plate and protecting them from overstimulation. Using superresolution microscopy, we show that the ankyrin-repeat protein ANKRD24 concentrates at the stereocilia insertion point, forming a ring at the junction between the lower and upper rootlets. Annular ANKRD24 continues into the lower rootlet, where it surrounds and binds TRIOBP-5, which itself bundles rootlet F-actin. TRIOBP-5 is mislocalized in Ankrd24KO/KO hair cells, and ANKRD24 no longer localizes with rootlets in mice lacking TRIOBP-5; exogenous DsRed-TRIOBP-5 restores endogenous ANKRD24 to rootlets in these mice. Ankrd24KO/KO mice show progressive hearing loss and diminished recovery of auditory function after noise damage, as well as increased susceptibility to overstimulation of the hair bundle. We propose that ANKRD24 bridges the apical plasma membrane with the lower rootlet, maintaining a normal distribution of TRIOBP-5. Together with TRIOBP-5, ANKRD24 organizes rootlets to enable hearing with long-term resilience.

The Interplay Between COVID-19 and Spondyloarthritis or Its Treatment.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has created multiple uncertainties regarding rheumatic diseases or their treatment, with regard to the susceptibility to or severity of the viral disease. We aimed to address these questions as they relate to spondyloarthritis (SpA). METHODS: We created a longitudinal survey from April 10, 2020, to April 26, 2021. There were 4723 subjects with SpA and 450 household contacts who participated worldwide. Of these, 3064 respondents were from the US and 70.4% of them provided longitudinal data. To control for the duration of potential risk of COVID-19, the rate of contracting the disease was normalized for person-months of exposure. RESULTS: In an analysis of US subjects who provided longitudinal data, the incident rate ratio for the 159 (out of 2157) subjects who tested positive for COVID-19 was 1.16 compared to the US population as adjusted for age and sex (range 0.997-1.361, P = 0.06). A paired evaluation using patients and household members did not show a statistically significant effect to indicate a predisposition for developing COVID-19 as a result of SpA or its treatment. Our data failed to show that any class of medication commonly used to treat SpA significantly affected the risk of developing COVID-19 or increasing the severity of COVID-19. CONCLUSION: These data do not exclude a small increased risk of developing COVID-19 as a result of SpA, but the risk, if it exists, is low and not consistently demonstrated. The data should provide reassurance to patients and to rheumatologists about the risk that COVID-19 poses to patients with SpA.

Enrichment of IGF-1R and PPARγ signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis.

BACKGROUND: Orbital inflammatory disease (OID) encompasses a wide range of pathology including thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis and non-specific orbital inflammation (NSOI), accounting for up to 6% of orbital diseases. Understanding the underlying pathophysiology of OID can improve diagnosis and help target therapy. AIMS: To test the hypothesis that shared signalling pathways are activated in different forms of OID. METHODS: In this secondary analysis, pathway analysis was performed on the previously reported differentially expressed genes from orbital adipose tissue using patients with OID and healthy controls who were characterised by microarray. For the original publications, tissue specimens were collected from oculoplastic surgeons at 10 international centres representing four countries (USA, Canada, Australia and Saudi Arabia). Diagnoses were independently confirmed by two masked ocular pathologists (DJW, HEG). Gene expression profiling analysis was performed at the Oregon Health & Science University. Eighty-three participants were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 25 with NSOI and 20 healthy controls. RESULTS: Among the 83 subjects (mean (SD) age, 52.8 (18.3) years; 70% (n=58) female), those with OID demonstrated perturbation of the downstream gene expressions of the IGF-1R (MAPK/RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways), peroxisome proliferator-activated receptor-γ (PPARγ), adipocytokine and AMPK signalling pathways compared with healthy controls. Specifically, GPA samples differed from controls in gene expression within the insulin-like growth factor-1 receptor (IGF-1R, PI3K-Akt (p=0.001), RAS (p=0.005)), PPARγ (p=0.002), adipocytokine (p=0.004) or AMPK (p=<0.001) pathways. TAO, sarcoidosis and NSOI samples were also found to have statistically significant differential gene expression in these pathways. CONCLUSIONS: Although OID includes a heterogenous group of pathologies, TAO, GPA, sarcoidosis and NSOI share enrichment of common gene signalling pathways, namely IGF-1R, PPARγ, adipocytokine and AMPK. Pathway analyses of gene expression suggest that other forms of orbital inflammation in addition to TAO may benefit from blockade of IGF-1R signalling pathways.

Identification of Missense Extracellular Matrix Gene Variants in a Large Glaucoma Pedigree and Investigation of the N700S Thrombospondin-1 Variant in Normal and Glaucomatous Trabecular Meshwork Cells.

PURPOSE: Primary open-angle glaucoma (POAG) is a complex heterogeneous disease. While several POAG genes have been identified, a high proportion of estimated heritability remains unexplained. Elevated intraocular pressure (IOP) is a leading POAG risk factor and dysfunctional extracellular matrix (ECM) in the trabecular meshwork (TM) contributes to elevated IOP. In this study, we sought to identify missense variants in ECM genes that correlate with ocular hypertensive POAG. METHODS: Whole-genome sequencing was used to identify genetic variants in five members of a large POAG family (n = 68) with elevated IOP. The remaining family members were screened by Sanger sequencing. Unrelated normal (NTM) and glaucomatous (GTM) cells were sequenced for the identified variants. The ECM protein levels were determined by Western immunoblotting and confocal and electron microscopy investigated ECM ultrastructural organization. RESULTS: Three ECM gene variants were significantly associated with POAG or elevated IOP in a large POAG pedigree. These included rs2228262 (N700S; thrombospondin-1 (THBS1, TSP1)), rs112913396 (D563 G; collagen type VI, alpha 3 (COL6A3)) and rs34759087 (E987K; laminin subunit beta 2 (LAMB2)). Screening of unrelated TM cells (n = 27) showed higher prevalence of the THBS1 variant but not the LAMB2 variant, in GTM cells (39%) than NTM cells (11%). The rare COL6A3 variant was not detected. TSP1 protein was upregulated and COL6A3 was down-regulated in TM cells with N700S subject to mechanical stretch, an in vitro method that mimics elevated IOP. Immunofluorescence showed increased TSP1 immunostaining in cell strains with N700S compared to wild-type TM cells. Ultrastructural studies showed ECM disorganization and altered collagen type VI distribution in GTM versus NTM cells. CONCLUSIONS: Our results suggest that missense variants in ECM genes may not cause catastrophic changes to the TM, but over many years, subtle changes in ECM may accumulate and cause structural disorganization of the outflow resistance leading to elevated IOP in POAG patients.