Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling.

BACKGROUND: RERE is a highly conserved transcriptional co-regulator that is associated with a human neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH, OMIM: 616975). RESULTS: We show that the zebrafish rerea mutant (babyface) robustly recapitulates optic fissure closure defects resulting from loss of RERE function, as observed in humans. These defects result from expansion of proximal retinal optic stalk (OS) and reduced expression of some of the ventral retinal fate genes due to deregulated protein signaling. Using zebrafish and cell-based assays, we determined that NEDBEH-associated human RERE variants function as hypomorphs in their ability to repress shh signaling and some exhibit abnormal nuclear localization. Inhibiting shh signaling by the protein inhibitor HPI-1 rescues coloboma, confirming our observation that coloboma in rerea mutants is indeed due to deregulation of shh signaling. CONCLUSIONS: Zebrafish rerea mutants exhibit OS and optic fissure closure defects. The optic fissure closure defect was rescued by an shh signaling inhibitor, suggesting that this defect could arise due to deregulated shh signaling.

Comparison of Myopia Progression among Myopic Children with Intermittent Exotropia and No Strabismus.

SIGNIFICANCE: Myopia is a highly prevalent condition in the pediatric population that is commonly comorbid with intermittent exotropia. Our study found a trend toward significance in the reduction of myopia progression with strabismus correction surgery. Further investigations characterizing the interaction between myopia and strabismus may help inform future management guidelines. PURPOSE: This study describes and compares myopic progression in the pediatric population with and without intermittent exotropia and its interaction with corrective strabismus surgery. METHODS: This study analyzed a retrospective cohort of 1239 pediatric myopic patients who were evaluated by pediatric ophthalmologists and optometrists at a tertiary care center from 2012 to 2020. The main outcome measures were the trends in refractive error over time in those with and without intermittent exotropia as well as trends in those who did and did not undergo strabismus surgery. RESULTS: A total of 275 patients (22%) were identified to have intermittent exotropia, and 12 (4.4%) from this group underwent surgical correction in the study period. No statistically significant difference was identified in myopic progression between those with intermittent exotropia and those without strabismus, and no difference was found in mean annual spherical equivalent change between intermittent exotropia patients who did not undergo surgery compared with those who did. CONCLUSIONS: Pediatric myopic patients generally experience progression in the condition for several years independent of concurrent intermittent exotropia. Corrective strabismus surgery was not found to alter the natural history of myopia in children, although a reduction in myopic progression in surgically treated patients trended toward significance. Increases in the prevalence of different treatment strategies will necessitate further studies to determine best practices for this population.

Characterization of ophthalmic presentations to emergency departments in the United States: 2010-2018.

BACKGROUND: Both traumatic and nontraumatic ocular issues often present to the emergency department. Understanding the epidemiology of ocular presentations to the emergency department not only informs current resource allocation, but also provides opportunities to evaluate the efficacy of prior healthcare access interventions. PURPOSE: To characterize emergency department utilization in the United States for ophthalmic encounters between 2010 and 2018. METHODS: Cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey database, a nationally representative sample of United States emergency department visits. 4284 deidentified emergency department patient encounters with an ICD-10 ophthalmic diagnosis from 2010 to 2018 were analyzed. The main outcome measures were the composition and characteristics of ophthalmic emergency department encounters over time. MAIN FINDINGS: 4284 ophthalmic visits were identified which represented an estimated 23.1 million visits (95% CI, 20.8 million-25.5 million). 31.6% (95% CI, 29.6-33.8) of ophthalmic visits were traumatic. Conjunctivitis was the most common non-traumatic diagnosis (32.8%, 95% CI, 30.7-35.0), while superficial injury of the cornea was the most common traumatic diagnosis (13.9%, 95% CI, 12.5-15.3). A greater proportion of emergency department visits involving the sclera and cornea were made by men (58.7%, 95% CI, 53.7%-63.6%; P = 0.02), whereas more women visited for visual disturbances (57.8%, 95% CI, 51.3%-64.4%; P = 0.01). Longitudinal trends of ophthalmic visits revealed an increase in public insurance payers in 2014, which corresponds to Medicaid expansion and implementation of mandated coverage for pediatric vision care. After stratification, this increase continued to be present in nontraumatic visits, but not traumatic ones. CONCLUSIONS: Ophthalmic emergency department visits in the United States between 2010 and 2018 were typically for non-traumatic eye issues. Diagnoses varied greatly by patient demographics, such as age and gender. Understanding these variations is valuable for preparing emergency departments for ocular presentations and providing guidance for future practice.

Tattoo-Induced Exacerbations of Systemic Disease and Uveitis.

Purpose: To examine an underreported and underdiagnosed phenomenon with implications for the pathophysiological mechanisms of tattoo-induced uveitis. Methods: Two cases highlighting the clinical presentation of tattoo-related uveitis were evaluated. Results: A 28-year-old man with biopsy-proven sarcoidosis and ocular manifestations presented with worsening retinal vasculitis after acquiring a red-ink tattoo. Each subsequent flare followed acquisition of a new tattoo. A 31-year-old woman without systemic sarcoidosis presented with multiple episodes of bilateral intermediate uveitis and macular edema concurrent with inflammatory granulomas to recently acquired black-ink tattoos. A skin biopsy in both patients showed cutaneous noncaseating granulomas. Conclusions: These cases add to those reported in the literature and emphasize the importance of understanding the modifiable factors of inflammatory ocular disease. Future study is necessary to understand the mechanisms of tattoo-related uveitis.

Emergency department evaluation of nurse triage questions about safe-at-home and abuse or neglect in traumatic ocular injuries.

OBJECTIVES: Approximately 10 million Americans experience acts of physical violence by an intimate partner (IPV). Ocular injuries can present as a symptom of IPV in the emergency department, but IPV remains underreported in the literature. Understanding the incidence and trends in IPV-associated ocular injuries in the emergency department could increase the detection of at-risk patients otherwise overlooked. DESIGN: Retrospective chart review. PARTICIPANTS: Emergency department patients evaluated for traumatic ocular injuries between January 2018 and April 2023 at a large tertiary care health system. METHODS: The study population was identified by ICD-10 code and their responses to being screened at triage for home safety and any nursing concerns for abuse or neglect. Patient screening consisted of a 2-part questionnaire inquiring first about whether the patient feels safe at home ("Yes" or "No") and second regarding nurses' concerns for abuse, neglect, domestic violence, sexual assault, or human trafficking. RESULTS: There were 2,653,993 emergency department visits and 16,737 traumatic ocular injuries in the study period. Of them, 1.1% of patients (154 of 14,457) responded "No" to feeling safe at home. In only 0.6% of patients (82 of 14,457), a nursing concern was documented. Patients responding "No" to feeling safe at home presented with more severe ocular injuries such as maxillary fractures. On regression analysis, married, divorced, and widowed patients as well as patients on private insurance were less likely to report feeling unsafe at home than single patients on public insurance (p < 0.05). CONCLUSION: Traumatic ocular injuries in emergency departments should raise concerns about IPV. Opportunity exists to improve education, screening, and management of these patients.

Lack of association between Lp(a) and retinal vein occlusion in a single institution and US national database.

OBJECTIVE: This study examines associations between lipoprotein(a) (Lp[a]), a low-density-like lipoprotein, and renal vein occlusion (RVO) in US cohorts to characterize its prognostic role in the setting of RVO. DESIGN: A two-phase retrospective cohort study. METHODS: In the first phase, patients with RVO and a Lp(a) quantitative laboratory value at a single tertiary centre were reviewed. Lp(a) status was assessed in association with age of RVO diagnosis, visual acuity, time to development of RVO, and central subfield thickness. In the second phase, the TriNetX US Collaborative Network, a large national database, also was queried for the presence of high or low Lp(a) values and diagnoses of RVO. RESULTS: The single tertiary care centre identified 45 patients with RVO and a laboratory value of Lp(a), finding no significant associations with respect to Lp(a) status and age of RVO onset, time from the laboratory draw to the development of RVO, visual acuity, and central subfield thickness (p > 0.05 for all). The TriNetX national database identified 35,687 patients with a high Lp(a) value (>30 mg/dL or 61 nmol/L) and 51,692 with a low Lp(a) value. An elevated Lp(a) value was not associated with higher odds of central (odds ratio [OR] = 1.15; 95% CI, 0.88-1.50) or branch RVO (OR = 1.01; 95% CI, 0.76-1.36). CONCLUSION: Taken together, this analysis suggests a lack of association between Lp(a) value and risk of RVO. This study highlights the benefit of large national databases in the validation of laboratory value predictors identified through small-cohort observational studies.

Optimizing evaluation in pediatric and young adult patients with Marfan syndrome: Novel longitudinal metrics to track growth of aortic structures.

OBJECTIVE: Surveillance metrics in pediatric and young adult Marfan syndrome (pMFS) are challenging. We evaluated the utility of aortic root cross-sectional area/height index (CSA/Ht) on echocardiogram among pMFS patients as a risk stratification and surgical triage metric. METHODS: Genotype or phenotype positive pMFS patients aged 25 years or younger seen at our center from 2001 to 2020 were identified. Time-related transition to surgery was modeled using parametric methods. Predictive utility of CSA/Ht compared with aortic root diameter (ARd) and root Z score (ARz) were modeled using nonlinear multivariable parametric and nonparametric longitudinal regression models. RESULTS: Seventy-nine patients (43% female) presented at median age of 5.8 years (15th-85th percentile, 0.75-17 years) with median follow-up of 4.4 years (range, 0-18.5 years). Baseline echocardiography data were: CSA/Ht, 3.9 ± 1.4 cm2/m; ARd, 2.4 ± 0.89 cm; and ARz, 2.4 ± 1.7. CSA/Ht tracked ARd better compared with ARz (r = 0.91 vs 0.24). Eighteen patients underwent surgery. Surgical procedures included at least 2 components in 17 (aortic, mitral, tricuspid, aortic root, and arch procedures) and isolated mitral valve procedures in 1 patient. Time-related transition to surgery showed a prominent early phase to 1 year post presentation, followed by a slowly increasing late phase. CSA/Ht had a more linear correlation versus ARz during periods of rapid somatic growth in surgical patients. Surgical repair occurred at CSA/Ht between 5 and 7 cm2/m. CONCLUSIONS: CSA/Ht tracked ARd well over time. CSA/Ht between 5 and 7 cm2/m might be a promising metric for surgical triage in pMFS patients. CSA/Ht surgical threshold values in pMFS patients occurred at lower than current accepted "surgical" threshold values for CSA/Ht in adult Marfan syndrome patients.

Dietary restriction transforms the mammalian protein persulfidome in a tissue-specific and cystathionine γ-lyase-dependent manner.

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

Asymmetric memory for harming versus being harmed.

Most people have been both the victim and the perpetrator of a moral transgression at some point in their lives; this article asks whether one set of moral experiences is easier to remember than the other, and why. In Study 1, we documented this basic asymmetry, finding that individuals recalled more instances in which they were the victim of a moral transgression than instances in which they were the perpetrator. In Study 2, we found that this asymmetry in memory arises because experiences of being the victim are perceived more negatively than experiences of being the perpetrator. In Studies 3 and 4, we demonstrated the critical role of intent in this asymmetry, finding that victim memories emphasize perpetrator intent to a greater degree than do perpetrator memories (Study 3), and that the memory asymmetry disappeared when individuals recalled unintentional moral violations (Study 4). Finally, in Study 5, we ruled out a potential alternative mechanism for these effects-that of self-protective motivation on the part of perpetrators. We found that the threat associated with the moral violation moderated victim (but not perpetrator) memories, a finding that is inconsistent with a motivational account for perpetrator memories. This research demonstrates that perceived agency shapes emotional experience and autobiographical memory and speaks to the importance of studying morality as it occurs in everyday contexts. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease.

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.

Phenotypic Approaches to Identify Inhibitors of B Cell Activation.

An EPIC label-free phenotypic platform was developed to explore B cell receptor (BCR) and CD40R-mediated B cell activation. The phenotypic assay measured the association of RL non-Hodgkin's lymphoma B cells expressing lymphocyte function-associated antigen 1 (LFA-1) to intercellular adhesion molecule 1 (ICAM-1)-coated EPIC plates. Anti-IgM (immunoglobulin M) mediated BCR activation elicited a response that was blocked by LFA-1/ICAM-1 specific inhibitors and a panel of Bruton's tyrosine kinase (BTK) inhibitors. LFA-1/ICAM-1 association was further increased on coapplication of anti-IgM and mega CD40L when compared to individual application of either. Anti-IgM, mega CD40L, or the combination of both displayed distinct kinetic profiles that were inhibited by treatment with a BTK inhibitor. We also established a FLIPR-based assay to measure B cell activation in Ramos Burkitt's lymphoma B cells and an RL cell line. Anti-IgM-mediated BCR activation elicited a robust calcium response that was inhibited by a panel of BTK inhibitors. Conversely, CD40R activation did not elicit a calcium response in the FLIPR assay. Compared to the FLIPR, the EPIC assay has the propensity to identify inhibitors of both BCR and CD40R-mediated B cell activation and may provide more pharmacological depth or novel mechanisms of action for inhibition of B cell activation.