MIWI N-terminal arginines orchestrate generation of functional pachytene piRNAs and spermiogenesis.

N-terminal arginine (NTR) methylation is a conserved feature of PIWI proteins, which are central components of the PIWI-interacting RNA (piRNA) pathway. The significance and precise function of PIWI NTR methylation in mammals remains unknown. In mice, PIWI NTRs bind Tudor domain containing proteins (TDRDs) that have essential roles in piRNA biogenesis and the formation of the chromatoid body. Using mouse MIWI (PIWIL1) as paradigm, we demonstrate that the NTRs are essential for spermatogenesis through the regulation of transposons and gene expression. The loss of TDRD5 and TDRKH interaction with MIWI results in attenuation of piRNA amplification. We find that piRNA amplification is necessary for transposon control and for sustaining piRNA levels including select, nonconserved, pachytene piRNAs that target specific mRNAs required for spermatogenesis. Our findings support the notion that the vast majority of pachytene piRNAs are dispensable, acting as self-serving genetic elements that rely for propagation on MIWI piRNA amplification. MIWI-NTRs also mediate interactions with TDRD6 that are necessary for chromatoid body compaction. Furthermore, MIWI-NTRs promote stabilization of spermiogenic transcripts that drive nuclear compaction, which is essential for sperm formation. In summary, the NTRs underpin the diversification of MIWI protein function.

Choroidal Morphology and Photoreceptor Activity Are Related and Affected by Myopia Development.

Purpose: The choroid is critical for the regulation of eye growth and is involved in the pathogenesis of myopia-associated ocular complications. This study explores the relationship among choroidal biometry, photoreceptor activity, and myopic growth in marmosets (Callithrix jacchus) with lens-induced myopia. Methods: A total of 34 common marmosets aged 92 to 273 days old were included in this study. Axial myopia was induced in 17 marmosets using negative soft contact lenses and 17 marmosets served as untreated controls. Cycloplegic refraction (RE) and vitreous chamber depth (VCD) were measured using autorefraction and A-scan ultrasonography, respectively. Choroidal scans were obtained using spectral-domain optical coherence tomography and binarized to calculate subfoveal choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), stromal area (SA), choroidal vascularity index (CVI), and LA/SA. To assess photoreceptor activity, the a-wave of the full-field electroretinogram was measured. Regression models were used to investigate the relationship between outcome measures. Results: Eyes induced with axial myopia (RE = -7.14 ± 4.03 diopters [D], VCD = 6.86 ± 0.39 mm) showed significant reductions (4.92-21.24%) in all choroidal parameters (ChT, TCA, LA, SA, CVI, and LA/SA) compared to controls (RE = -1.25 ± 0.60 D, VCD = 6.58 ± 0.26 mm, all P < 0.05), which changed as a function of refraction and vitreous elongation, and were associated with a decrease in the a-wave amplitude. Further, multiple regression showed that a combination of ChT and CVI could well predict RE and VCD. Conclusions: This study reports the existence of significant alterations in choroidal morphology in non-human primate eyes induced with myopia. The changes in choroidal anatomy were associated with reduced light-adapted a-wave amplitude. These findings may represent early markers for reduced visual performance and chorioretinal complications known to occur in eyes with large degrees of myopia.

JAK/STAT Signaling Predominates in Human and Murine Fungal Post-infectious Inflammatory Response Syndrome.

Post-infection inflammatory syndromes have been increasingly recognized as a cause of host damage in a variety of infectious diseases including tuberculosis, bacterial meningitis, and COVID-19. Recently, a post-infectious inflammatory response syndrome (PIIRS) was described in non-HIV-infected cryptococcal fungal meningoencephalitis (CM) as a major cause of mortality. Inflammatory syndromes are particularly severe in neurological infections due to the skull's rigid structure which limits unchecked tissue expansion from inflammatory-induced edema. In the present studies, neurologic transcriptional pathway analysis utilizing a murine PIIRS model demonstrated a predominance of Janus kinase/signal transducer and activator of transcription (JAK/STAT) activation. JAK/STAT inhibitor treatment resulted in improvements in CNS damage markers, reductions in intrathecal CD44hiCD62lo CD4+ effector CD4+ T-cells and MHC II+ inflammatory myeloid cells, and weight gains in mice, the latter after treatment with antifungals. Based on these data, pathway-driven steroid-sparing human treatment for steroid-refractory PIIRS was initiated using short courses of the JAK/STAT inhibitor ruxolitinib. These were well tolerated and reduced activated HLA-DR+ CD4+ and CD8+ cells and inflammatory monocytes as well as improved brain imaging. Together, these findings support the role of JAK/STAT in PIIRS as well as further study of JAK/STAT inhibitors as potential adjunctive therapy for PIRS and other neural inflammatory syndromes.

MIWI arginines orchestrate generation of functional pachytene piRNAs and spermiogenesis.

N-terminal arginine (NTR) methylation is a conserved feature of PIWI proteins, which are central components of the PIWI-interacting RNA (piRNA) pathway. The significance and precise function of PIWI NTR methylation in mammals remains unknown. In mice, PIWI NTRs bind Tudor domain containing proteins (TDRDs) that have essential roles in piRNA biogenesis and the formation of the chromatoid body. Using mouse MIWI (PIWIL1) as paradigm, we demonstrate that the NTRs are essential for spermatogenesis through the regulation of transposons and gene expression. Surprisingly, the loss of TDRD5 and TDRKH interaction with MIWI results in defective piRNA amplification, rather than an expected failure of piRNA biogenesis. We find that piRNA amplification is necessary for both transposon control and for sustaining levels of select, nonconserved, pachytene piRNAs that target specific mRNAs required for spermatogenesis. Our findings support the notion that the vast majority of pachytene piRNAs are dispensable, acting as autonomous genetic elements that rely for propagation on MIWI piRNA amplification. MIWI-NTRs also mediate interactions with TDRD6 that are necessary for chromatoid body compaction. Furthermore, MIWI-NTRs promote stabilization of spermiogenic transcripts that drive nuclear compaction, which is essential for sperm formation. In summary, the NTRs underpin the diversification of MIWI protein function.

Non-Invasive Hybrid Ultrasound Stimulation of Visual Cortex In Vivo.

The optic nerve is the second cranial nerve (CN II) that connects and transmits visual information between the retina and the brain. Severe damage to the optic nerve often leads to distorted vision, vision loss, and even blindness. Such damage can be caused by various types of degenerative diseases, such as glaucoma and traumatic optic neuropathy, and result in an impaired visual pathway. To date, researchers have not found a viable therapeutic method to restore the impaired visual pathway; however, in this paper, a newly synthesized model is proposed to bypass the damaged portion of the visual pathway and set up a direct connection between a stimulated visual input and the visual cortex (VC) using Low-frequency Ring-transducer Ultrasound Stimulation (LRUS). In this study, by utilizing and integrating various advanced ultrasonic and neurological technologies, the following advantages are achieved by the proposed LRUS model: 1. This is a non-invasive procedure that uses enhanced sound field intensity to overcome the loss of ultrasound signal due to the blockage of the skull. 2. The simulated visual signal generated by LRUS in the visual-cortex-elicited neuronal response in the visual cortex is comparable to light stimulation of the retina. The result was confirmed by a combination of real-time electrophysiology and fiber photometry. 3. VC showed a faster response rate under LRUS than light stimulation through the retina. These results suggest a potential non-invasive therapeutic method for restoring vision in optic-nerve-impaired patients using ultrasound stimulation (US).

Spatiotemporal local and abscopal cell death and immune responses to histotripsy focused ultrasound tumor ablation.

Introduction: Histotripsy is a novel focused ultrasound tumor ablation modality with potent immunostimulatory effects. Methods: To measure the spatiotemporal kinetics of local andabscopal responses to histotripsy, C57BL/6 mice bearing bilateral flank B16 melanoma or Hepa1-6 hepatocellular carcinoma tumors were treated with unilateral sham or partial histotripsy. Treated and contralateral untreated (abscopal) tumors were analyzed using multicolor immunofluorescence, digital spatial profiling, RNA sequencing (RNASeq), and flow cytometry. Results: Unilateral histotripsy triggered abscopal tumor growth inhibition. Within the ablation zone, early high mobility group box protein 1 (HMGB1) release and necroptosis were accompanied by immunogenic cell death transcriptional responses in tumor cells and innate immune activation transcriptional responses in infiltrating myeloid and natural killer (NK) cells. Delayed CD8+ T cell intratumoral infiltration was spatiotemporally aligned with cancer cell features of ferroptosis; this effect was enhanced by CTLA-4 blockade and recapitulated in vitro when tumor-draining lymph node CD8+ T cells were co-cultured with tumor cells. Inoculation with cell-free tumor fractions generated by histotripsy but not radiation or freeze/thaw conferred partial protection from tumor challenge. Discussion: We propose that histotripsy may evoke local necroptotic immunogenic cell death, priming systemic adaptive immune responses and abscopal ferroptotic cancer cell death.

A Mechanistic Model of Aqueous Humor Flow to Study Effects of Angle Closure on Intraocular Pressure.

Purpose: To study the relationship between the circumferential extent of angle closure and elevation in intraocular pressure (IOP) using a novel mechanistic model of aqueous humor (AH) flow. Methods: AH flow through conventional and unconventional outflow pathways was modeled using the unified Stokes and Darcy equations, which were solved using the finite element method. The severity and circumferential extent of angle closure were modeled by lowering the permeability of the outflow pathways. The IOP predicted by the model was compared with biometric and IOP data from the Chinese American Eye Study, wherein the circumferential extent of angle closure was determined using anterior segment OCT measurements of angle opening distance. Results: The mechanistic model predicted an initial linear rise in IOP with increasing extent of angle closure which became nonlinear when the extent of closure exceeded around one-half of the circumference. The nonlinear rise in IOP was associated with a nonlinear increase in AH outflow velocity in the open regions of the angle. These predictions were consistent with the nonlinear relationship between angle closure and IOP observed in the clinical data. Conclusions: IOP increases rapidly when the circumferential extent of angle closure exceeds 180°. Residual AH outflow may explain why not all angle closure eyes develop elevated IOP when angle closure is extensive. Translational Relevance: This study provides insight into the extent of angle closure that is clinically relevant and confers increased risk of elevated IOP. The proposed model can be utilized to study other mechanisms of impaired aqueous outflow.

Rates and Patterns of Diagnostic Conversion from Anatomical Narrow Angle to Primary Angle-Closure Glaucoma in the United States.

PURPOSE: To assess rates of diagnostic conversion from anatomical narrow angle (ANA) to primary angle-closure glaucoma (PACG) in the United States and identify factors associated with diagnostic conversion. DESIGN: Retrospective case-control study. PARTICIPANTS: Patients diagnosed with ANA between the years 2007 and 2019 were identified based on International Classification of Diseases (ICD) codes in the Optum Clinformatics Data Mart Database. Inclusion was limited to newly diagnosed ANA, defined as the following: (1) continuous enrollment during a 2-year look back period and 6-year study period from index (first) date of ANA diagnosis; (2) diagnosis by an ophthalmologist or optometrist and record of gonioscopy; and (3) no history of intraocular pressure (IOP)-lowering drops, laser peripheral iridotomy (LPI), or intraocular surgery. METHODS: Cox proportional hazards models were developed to assess factors associated with diagnostic conversion, defined as a change in ICD code from ANA to PACG. MAIN OUTCOME MEASURES: New diagnosis of PACG within the 6-year study period recorded after an index diagnosis of ANA. RESULTS: Among 3985 patients meeting inclusion criteria, 459 (11.52%) had detected diagnostic conversion to PACG within the study period. The conversion rate was stable at 3.54% per year after the first 6 months of ANA diagnosis. In the Cox proportional hazards model, age > 70 years and early (within 6 months of ANA diagnosis) need for LPI or IOP-lowering drops were positively associated with diagnostic conversion (hazard ratio [HR] > 1.59; P < 0.02). Cataract surgery at any time and late (after 6 months of ANA diagnosis) need for IOP-lowering drops appeared protective against diagnostic conversion (HR < 0.46; P < 0.004). CONCLUSIONS: Annual risk of diagnostic conversion from ANA to PACG is relatively low overall; elderly patients are at higher risk whereas patients receiving cataract surgery are at lower risk. The utility of long-term monitoring seems low for most patients with ANA, highlighting the need for improved clinical methods to identify patients at higher risk for PACG. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Effectiveness of Glaucoma Screening and Factors Associated with Follow-up Adherence among Glaucoma Suspects in a Safety-Net Teleretinal Screening Program.

PURPOSE: To evaluate rates and risk factors associated with follow-up adherence to in-person glaucoma evaluations and confirmed glaucoma diagnosis in glaucoma suspects identified through teleretinal diabetic retinopathy screening (TDRS). DESIGN: Retrospective cohort study SUBJECTS: Patients with diabetes identified through teleretinal screening to have large or asymmetric cup-to-disc ratios in a Los Angeles County safety-net primary care-based TDRS program. METHODS: Retrospective chart review was performed to obtain demographic and clinical information for patients with cup-to-disc ratios concerning for glaucoma on TDRS. Patients who completed an in-person follow-up appointment within 1 year of teleretinal screening were adherent. Factors associated with follow-up adherence and diagnosis of glaucoma were analyzed with chi-square and independent t tests along with multivariable logistic regressions. MAIN OUTCOME MEASURES: The proportion of patients with suspected glaucoma who adhered with in-person follow-up examination, proportion of patients with confirmed glaucoma diagnosis, and factors associated with follow-up adherence and glaucoma diagnosis. RESULTS: Eight-hundred seventeen patients with optic discs suspicious for glaucoma were included. Five-hundred thirty-four (65.4%) patients successfully completed an in-person glaucoma evaluation. Among these patients, 62.9% and 24.5% received a diagnosis of glaucoma suspect and glaucomatous optic neuropathy, respectively. Compared with patients aged < 50 years, patients aged 50 to 64 years had 1.57 times higher odds of being adherent with in-person visits (P = 0.036), whereas no difference was seen in those aged ≥ 65 years. For every $10 000 increase in the zip code median income, patients had 11% lower odds of being adherent (P = 0.031). Compared with Latino patients, Black patients had 3.52 times (P < 0.001) higher odds of having confirmed glaucoma. CONCLUSION: The majority of patients referred as glaucoma suspects on TDRS completed a follow-up examination, and nearly a quarter of those examined received a confirmed glaucoma diagnosis. Patients aged ≥ 50 and < 65 years along with those from lower-income neighborhoods were more likely to follow up for an in-person evaluation. Compared with Latino patients, Black patients had a higher risk for a confirmed glaucoma diagnosis. This demonstrates the effectiveness of glaucoma detection in a large-scale TDRS program for a safety-net patient population. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Misdiagnosis of Orbital Foreign Body as Glaucoma Drainage Device.

BACKGROUND: Sight-threatening complications from retained orbital and intraocular foreign bodies are frequently reported in literature. Delays in diagnosis can result in severe complications, including choroidal neovascularization, infection, and irreversible vision loss. Therefore, it is imperative that emergency physicians consider the possibility of orbital and intraocular foreign bodies when evaluating patients with acute facial trauma. CASE REPORT: A 91-year-old woman with a history of laser-treated glaucoma and cataracts presented to an outside emergency department after a ground-level fall. A maxillofacial noncontrast computed tomography scan showed no facial fractures or hemorrhage, but a 41 mm × 4 mm foreign body within the intraconal compartment of the right orbit was identified. The object was presumed to be an implanted glaucoma drainage device, and the patient was discharged without antibiotics. One day after discharge, the patient developed right periorbital swelling and erythema with increasing purulent discharge and skin thickening, ultimately requiring transfer to our facility for management of complex right orbital cellulitis, orbital compartment syndrome, and surgical foreign body removal. Despite globe exploration and surgical intervention, the patient developed a frozen globe with no light perception in the right eye. Why Should an Emergency Physician Be Aware of This? Subtle ophthalmologic emergencies such as sight-threatening foreign bodies can be challenging to diagnose on imaging, particularly with the advent of implantable ocular technology. When an orbital foreign body is discovered in the context of facial trauma, early ophthalmology consultation should be considered.

Restoration of Vision in Severe, Cicatricial, Ocular Surface Disease With the Boston Keratoprosthesis Type II.

PURPOSE: To assess clinical outcomes of patients with severe, cicatricial ocular surface disease (OSD) implanted with the currently marketed design of the Boston keratoprosthesis type II (BK2). DESIGN: Retrospective cohort study. METHODS: Records of consecutive patients undergoing BK2 implantation from June 2009 to March 2021 were assessed for postoperative visual acuity, postoperative complications, device replacement, and additional surgeries. RESULTS: Fifty-six eyes of 53 patients with a mean follow-up of 45.8 months (range, 0.2-134.7 months) were included. Stevens-Johnson syndrome/toxic epidermal necrolysis was the most common indication (49.1%), followed by mucous membrane pemphigoid (39.6%) and other OSD (11.3%). Visual acuity improved from logMAR 2.2 ± 0.5 preoperatively to 1.5 ± 1.2 at final follow-up. Of 56 eyes, 50 saw ≥20/200 at some point postoperatively. Of the eyes with a follow-up of more than 5 years, 50.0% retained a visual acuity of ≥20/200 at their final follow-up. The most common complications over the entire postoperative course (mean ∼4 years) were de novo or worsening glaucoma (41.1%), choroidal effusions (30.3%), retinal detachment (25.0%), and end-stage glaucoma (25.0%). In a univariate analysis, patients who experienced irreversible loss of ≥20/200 visual acuity were more likely to have been previously implanted with an older design of BK2, less likely to be on preoperative systemic immunosuppressive therapy, and less likely to have undergone concurrent glaucoma tube implantation, compared to patients who retained ≥20/200 acuity (P < .04 for all). CONCLUSIONS: Advances in device design and postoperative care have made implantation of BK2 a viable option for corneal blindness in the setting of severe cicatricial OSD.

Repeatability and Reproducibility of 4.5 by 4.5 mm Peripapillary Optical Coherence Tomography Angiography Scans in Glaucoma and Non-Glaucoma Eyes.

PRCIS: Peripapillary vessel parameters from optical coherence tomography angiography (OCTA) 4.5×4.5 mm scans in nonglaucomatous and glaucomatous eyes showed high repeatability and reproducibility, with higher reliability for commercially developed OCTA parameters compared with custom OCTA parameters. PURPOSE: The purpose of this study was to assess intrasession repeatability versus intersession reproducibility of peripapillary vessel parameters from 4.5×4.5 mm OCTA scans in nonglaucomatous eyes and glaucomatous eyes. MATERIALS AND METHODS: In a longitudinal study, peripapillary OCTA scans were quantified using research-oriented custom quantification software that calculated vessel area density (VAD) and flux and clinic-oriented commercially developed software (Cirrus 11.0) that calculated perfusion density (PD) and flux index (FI). Intrasession repeatability and intersession reproducibility were evaluated using within-eye coefficient of variation (CV W ) and intraclass correlation coefficient (ICC). RESULTS: With 127 nonglaucomatous eyes, intrasession CV W for VAD, PD, flux, and FI were 1.900%, 1.174%, 2.787%, and 1.425%, respectively. The intersession CV W were 2.039%, 1.606%, 4.053%, and 2.798%, respectively. Intrasession ICC ranged from 0.903 to 0.956, and intersession ICC ranged from 0.850 to 0.896. Among 144 glaucomatous eyes, intrasession CV W for VAD, PD, flux, and FI were: 3.841%, 1.493%, 5.009%, and 2.432%, respectively. The intersession CV W were 4.991%, 2.155%, 6.360%, and 3.458%, respectively. Intrasession ICC ranged from 0.956 to 0.969, and intersession ICC ranged from 0.918 to 0.964. CONCLUSIONS: Among nonglaucomatous and glaucomatous eyes, the majority of peripapillary OCTA vessel parameters from 4.5×4.5 mm scans had greater intrasession repeatability than intersession reproducibility. There was a greater agreement for the commercially developed quantification parameters than for their custom quantification counterparts.

Phenyl Sulfones: A Route to a Diverse Family of Trisubstituted Cyclohexenes from Three Independent Nucleophilic Additions.

A novel process is described for the synthesis of di- and trisubstituted cyclohexenes from an arene. These compounds are prepared from three independent nucleophilic addition reactions to a phenyl sulfone (PhSO2R; R = Me, Ph, and NC4H8) dihapto-coordinated to the tungsten complex {WTp(NO)(PMe3)}(Tp = trispyrazolylborate). Such a coordination renders the dearomatized aryl ring susceptible to protonation at a carbon ortho to the sulfone group. The resulting arenium species readily reacts with the first nucleophile to form a dihapto-coordinated sulfonylated diene complex. This complex can again be protonated, and the subsequent nucleophilic addition forms a trisubstituted cyclohexene species bearing a sulfonyl group at an allylic position. Loss of the sulfinate anion forms a π-allyl species, to which a third nucleophile can be added. The trisubstituted cyclohexene can then be oxidatively decomplexed, either before or after substitution of the sulfonyl group. Nucleophiles employed include masked enolates, cyanide, amines, amides, and hydride, with all three additions occurring to the same face of the ring, anti to the metal. Of the 12 novel functionalized cyclohexenes prepared as examples of this methodology, nine compounds meet five independent criteria for evaluating drug likeliness. Structural assignments are supported with nine crystal structures, density functional theory studies, and full 2D NMR analysis.

Intrasession Repeatability and Intersession Reproducibility of Macular Vessel Parameters on Optical Coherence Tomography Angiography in Glaucomatous and Non-Glaucomatous Eyes.

PURPOSE: Using optical coherence tomography angiography (OCTA), this study compared intrasession repeatability versus intersession reproducibility of macular vessel parameters in glaucoma and non-glaucoma subjects. METHODS: 6 × 6 mm2 macular OCTA scans (Cirrus HD-OCT 5000) were acquired from glaucomatous and non-glaucomatous subjects as part of an observational, longitudinal study. Vessel area density (VAD) and vessel skeleton density (VSD) were calculated using research-based quantification software while perfusion density (PDZ) and vessel density (VDZ) were calculated using commercially developed software (Cirrus 11.0, Carl Zeiss Meditec). Intrasession repeatability and intersession reproducibility were determined using within-eye standard deviation (SW), within-eye coefficient of repeatability (CRW), within-eye coefficient of variation (CVW), and intraclass correlation coefficients (ICC). RESULTS: The intrasession repeatability and intersession reproducibility for macular OCTA parameters were similar to one another for both non-glaucomatous and glaucomatous eyes. Intrasession CVW from the non-glaucoma group (n = 73) was 1.097% for VAD, 1.007% for VSD, 2.980% for PDZ, and 2.714% for VDZ. Intersession CVW from the non-glaucoma group (n = 55) was 1.389% for VAD, 1.279% for VSD, 2.935% for PDZ, and 2.695% for VDZ. Intrasession CVW from the glaucoma group (n = 59) was 1.189% for VAD, 0.970% for VSD, 3.827% for PDZ, and 3.542% for VDZ. Intersession CVW from the glaucoma group (n = 45) was 1.412% for VAD, 1.132% for VSD, 3.915% for PDZ, and 3.654% for VDZ. Non-glaucomatous intrasession ICC ranged from 0.711 to 0.824, non-glaucomatous intersession ICC ranged from 0.649 to 0.762, glaucomatous intrasession ICC ranged from 0.710 to 0.853, and glaucomatous intersession ICC ranged from 0.661 to 0.827. CONCLUSIONS: Macular OCTA scans can be a useful tool in monitoring the longitudinal progression of glaucoma due to their high repeatability and reproducibility.

Racial and Sociodemographic Disparities in the Detection of Narrow Angles before Detection of Primary Angle-Closure Glaucoma in the United States.

PURPOSE: To assess the proportion of newly diagnosed cases of primary angle-closure glaucoma (PACG) with and without prior diagnosis of anatomical narrow angle (ANA) and to identify sociodemographic risk factors for late detection (PACG without prior ANA diagnosis). DESIGN: Retrospective cohort study. METHODS: One hundred two thousand six hundred seventeen patients with PACG were identified from the Optum Clinformatics Data Mart Database (2007-2019). Patients with newly diagnosed PACG met the following criteria: (1) diagnosis made by an ophthalmologist, (2) disease observable for at least 12 months before diagnosis, and (3) no history of treatment before diagnosis unless preceded by a diagnosis of ANA. Multivariate logistic regression modeling was performed to identify sociodemographic risk factors for late detection. MAIN OUTCOME MEASURES: Proportion of patients with newly diagnosed PACG without prior ANA diagnosis and sociodemographic factors associated with late detection. RESULTS: Thirty-one thousand forty-four patients were eligible. More than 70% of PACG cases were detected without prior ANA diagnosis, regardless of patient age, sex, or race. The odds of late detection were significantly higher (P < 0.001) among men (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.25-1.40), Black patients (OR, 1.25; 95% CI, 1.15-1.37), and patients 80 years of age or older (OR, 1.28; 95% CI, 1.11-1.47) or living in Southern (OR, 1.30; 95% CI, 1.22-1.40) or Pacific (OR, 1.27; 95% CI, 1.16-1.36) regions. Findings were similar for patients with PACG with a record of gonioscopy and treatment or with a 24-month lookback period. CONCLUSIONS: Most patients who receive a new diagnosis of PACG in the United States do not have a prior diagnosis of ANA. The elderly, men, and Black patients are at higher risk of late detection. A need exists for increased disease awareness among providers and more accessible tools to detect patients at risk of developing PACG.

Wedge Defects on Optical Coherence Tomography Angiography of the Peripapillary Retina in Glaucoma: Prevalence and Associated Clinical Factors.

PRCIS: Among subjects with glaucoma, wedge-shaped defects on optical coherence tomography angiography (OCTA) were associated with disc hemorrhages (DH), paracentral visual field (VF) defects, increased cup-to-disc ratio (CDR), and thinner retinal nerve fiber layer (RNFL). PURPOSE: To examine determinants of wedge defects on peripapillary OCTA in glaucoma. MATERIALS AND METHODS: A total of 278 eyes of 186 subjects with mild to severe primary open-angle glaucoma underwent 6×6 spectral-domain OCTA imaging of the superficial peripapillary retina from 2016 to 2020 at an academic practice. Wedge defects were defined as focal microvasculature loss that extends outward from the optic nerve in an arcuate, wedge shape. Logistic regression models controlling for intereye correlation identified variables significantly associated with wedge defects. Eyes with profound microvasculature loss in both hemispheres were excluded. Candidate variables included: age, sex, race or ethnicity, diabetes, hypertension, follow-up duration, baseline untreated intraocular pressure, intraocular pressure at time of imaging, DH history, paracentral VF defects, CDR, central corneal thickness, spherical equivalent, VF mean deviation, RNFL thickness, and glaucoma stage. RESULTS: Of 278 eyes, 126 (45.3%) had wedge defects in at least 1 hemisphere. In our multivariable logistic regression model, wedge defects were associated with DH history [odds ratio (OR): 3.19, 95% confidence interval (CI): 1.05-9.69, P=0.041], paracentral VF defects [OR: 4.38 (95% CI: 2.11-9.11), P<0.0001], larger CDR [OR: 1.27 (95% CI: 1.03-1.56), P=0.024, per 0.1 increase], and thinner RNFL [OR: 1.71 (95% CI: 1.25-2.34), P=0.0009, per 10 µm decrease]. CONCLUSION: DH history and paracentral VF defects were independently associated with wedge defects on OCTA, which was present in 45.3% of primary open-angle glaucoma patients. These findings may provide insight into glaucoma pathogenesis.

Super-Resolution Ultrasound Localization Microscopy for Visualization of the Ocular Blood Flow.

OBJECTIVE: The ocular vascular system plays an important role in preserving the visual function. Alterations in either anatomy or hemodynamics of the eye may have adverse effects on vision. Thus, an imaging approach that can monitor alterations of ocular blood flow of the deep eye vasculature ranging from capillary-level vessels to large supporting vessels would be advantageous for detection of early stage retinal and optic nerve diseases. METHODS: We propose a super-resolution ultrasound localization microscopy (ULM) technique that can assess both the microvessel and flow velocity of the deep eye with high resolution. Ultrafast plane wave imaging was acquired using an L22-14v linear array on a high frequency Verasonics Vantage system. A robust microbubble localization and tracking technique was applied to reconstruct ULM images. The experiment was first performed on pre-designed flow phantoms in vitro and then tested on a New Zealand white rabbit eye in vivo calibrated to various intraocular pressures (IOP) - 10 mmHg, 30 mmHg and 50 mmHg. RESULTS: We demonstrated that retinal/choroidal vessels, central retinal artery, posterior ciliary artery, and vortex vein were all visible at high resolution. In addition, reduction of vascular density and flow velocity were observed with elevated IOPs. CONCLUSION: These results indicate that super-resolution ULM is able to image the deep ocular tissue while maintaining high resolution that is comparable with optical coherence tomography angiography. SIGNIFICANCE: Capability to detect subtle changes of blood flow may be clinically important in detecting and monitoring eye diseases such as glaucoma.

The role of RNA editing enzyme ADAR1 in human disease.

Adenosine deaminase acting on RNA (ADAR) catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA), which can lead to the creation of missense mutations in coding sequences. Recent studies show that editing-dependent functions of ADAR1 protect dsRNA from dsRNA-sensing molecules and inhibit innate immunity and the interferon-mediated response. Deficiency in these ADAR1 functions underlie the pathogenesis of autoinflammatory diseases such as the type I interferonopathies Aicardi-Goutieres syndrome and dyschromatosis symmetrica hereditaria. ADAR1-mediated editing of endogenous coding and noncoding RNA as well as ADAR1 editing-independent interactions with DICER can also have oncogenic or tumor suppressive effects that affect tumor proliferation, invasion, and response to immunotherapy. The combination of proviral and antiviral roles played by ADAR1 in repressing the interferon response and editing viral RNAs alters viral morphogenesis and cell susceptibility to infection. This review analyzes the structure and function of ADAR1 with a focus on its position in human disease pathways and the mechanisms of its disease-associated effects. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Hemiretinal Asymmetry in Peripapillary Vessel Density in Healthy, Glaucoma Suspect, and Glaucoma Eyes.

PURPOSE: To investigate hemiretinal asymmetry in radial peripapillary capillary vessel area density (VAD) of healthy, glaucoma suspect, and glaucoma eyes of varying severity and its diagnostic utility for glaucoma. DESIGN: Population-based, cross-sectional study. METHODS: Optic disc scans (6 × 6 mm) were collected on optical coherence tomography angiography (OCTA) to obtain VAD and on optical coherence tomography (OCT) to measure circumpapillary retinal nerve fiber layer (RNFL) thickness. Hemiretinal difference in VAD (hdVAD) was defined as the absolute difference between superior and inferior hemiretinal VAD. Age-adjusted multivariable linear regression of hdVAD on glaucoma severity was performed. Areas under curves (AUCs) were calculated from predicted probabilities generated by multiple logistic regression of glaucoma severity on age-adjusted single and combined parameters. RESULTS: A total of 1,043 eyes of 1,043 participants (587 healthy, 270 suspect, 67 mild, 54 moderate, 65 severe glaucoma) were included. After age adjustment, mean hdVAD was similar between healthy and suspect (P = .225), higher in mild vs suspect (P < .001), and higher in moderate vs mild (P = .018), but lower in severe vs moderate (P = .001). AUCs of hdVAD were highest for discriminating mild (0.685) and moderate (0.681) glaucoma from healthy. Combining hdVAD and global RNFL (gRNFL) yielded the highest AUCs of all parameters for mild (0.818) and any POAG (0.859) and resulted in significantly better diagnostic accuracy than either hdVAD or gRNFL alone (P < .05 for all comparisons). CONCLUSIONS: hdVAD is higher in early glaucoma and may help with early detection when damage is focal, but its diagnostic ability appears less robust in advanced glaucoma when damage is diffuse.

The GSDMB rs7216389 SNP is associated with chronic rhinosinusitis in a multi-institutional cohort.

BACKGROUND: Chronic rhinosinusitis (CRS) is a multifactorial disease with a high co-occurrence with asthma. In this multicohort study, we tested whether single nucleotide polymorphisms (SNPs) associated with childhood asthma and rhinovirus (RV)-associated disease are related to an increased susceptibility to adult CRS in a multicohort retrospective case-control study. METHODS: Participants at two tertiary academic rhinology centers, University of Arizona (UofA) and University of Pennsylvania (UPenn) were recruited. Cases were defined as those with physician diagnosed CRS (UofA, n = 149; UPenn, n = 250), and healthy controls were those without CRS (UofA, n = 66; UPenn, n = 275). Genomic DNA was screened for the GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP. Gene dosage, or the number of combined risk alleles in a single subject was calculated. Meta-analysis of the association between GSDMB or CDHR3 genotypes and CRS was performed and additive gene dosage effect for each population calculated using p for trend. RESULTS: A meta-analysis revealed a combined increased risk for CRS in subjects with the GSDMB rs7216389 SNP (odds ratio [OR] 1.40; 95% confidence interval [CI], 1.16-1.76; p = 0.004). Both the UofA (OR 1.73; 95% CI, 1.23-2.43; p = 0.002) and UPenn (OR 1.27; 95% CI, 1.02-1.58; p = 0.035) populations showed a significant positive association between the number of combined risk alleles of GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP and risk for CRS. CONCLUSION: Carriers of the GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP are at increased susceptibility for CRS. These data suggest that therapeutic approaches to target aberrant responses to RV infection may play a role in the treatment of unified airway disease.