Orbitocranial Penetration of Ball Bearing Gun Trauma: A Prospective Human Cadaveric Study.

Objective We completed a prospective human cadaveric study to determine the ability of a ball bearing (BB) pellet to penetrate the orbit and/or surrounding structures. Methods A single trained sergeant officer discharged an alloy steel air rifle to eight cadaver orbits from four adult human cadaver heads. Five BB pellets each were aimed at three locations (caruncle, upper eyelid, or lower eyelid) at 10 cm and 1 m, and then less specifically, at the orbital region for 3- and 5-m distances. Computed tomography (CT) of the cadaver heads was performed. Final locations of BB pellets are divided into three categories: intracranial, surrounding orbital structures including the pterygopalatine fossa and infratemporal fossa, and orbit. Results Of 40 BB pellets, 37 penetrated soft tissue and were visualized on CT: 19 (51%) rested in the intracranial space, 17 (46%) in surrounding orbital structures, and 1 (3%) within the orbit. The deepest position of a pellet was in the parietal lobe, and most superficial location anterior to the frontal bone. Pellets discharged from 1 m were more likely to rest in the intracranial space compared with those from 10 cm ( p < 0.001), 3 m ( p = 0.011), and 5 m ( p = 0.004). The distance of discharge was associated with final pellet location ( p = 0.001). Conclusion BB guns should be considered dangerous and potentially deadly when aimed at the orbit. Although the thick calvarium can protect the intracranial space from BB penetration, the orbit may be a vulnerable entry point with relatively low resistance, allowing penetration of the intracranial and periorbital spaces.

Orbital indeterminate cell histiocytosis.

An 8-year-old female presented to the oculoplastics clinic with 3 months of left upper eyelid fullness and edema. Examination showed a mass in the left anterior superior orbit with erythema. Imaging demonstrated a well-circumscribed superolateral orbital mass that was T1 hypointense and T2 hypo-to-iso intense with contrast enhancement. An incisional biopsy was performed via an upper lid crease incision. Histopathology showed aggregates of histiocytic cells with fibrosis and infiltration of eosinophils. Immunohistochemistry revealed positive CD68 and CD163 staining and negative langerin staining, confirming the diagnosis of indeterminate cell histiocytosis. There was no systemic involvement or associated dermatologic findings. Repeat exam 3 months later showed no change in the size of the lesion and the patient was referred to hematology-oncology for treatment. On most recent exam, the patient had no new symptoms or side effects following 3 months of oral hydroxyurea (25 mg/kg/day). Repeat orbital imaging showed no progression of the lesion and the patient will be monitored closely. Here, we report a rare case of isolated orbital indeterminate cell histiocytosis in a young child.

Variable domain mutational analysis to probe the molecular mechanisms of high viscosity of an IgG1 antibody.

Subcutaneous injection is the preferred route of administration for many antibody therapeutics for reasons that include its speed and convenience. However, the small volume limit (typically ≤2 mL) for subcutaneous delivery often necessitates antibody formulations at high concentrations (commonly ≥100 mg/mL), which may lead to physicochemical problems. For example, antibodies with large hydrophobic or charged patches can be prone to self-interaction giving rise to high viscosity. Here, we combined X-ray crystallography with computational modeling to predict regions of an anti-glucagon receptor (GCGR) IgG1 antibody prone to self-interaction. An extensive mutational analysis was undertaken of the complementarity-determining region residues residing in hydrophobic surface patches predicted by spatial aggregation propensity, in conjunction with residue-level solvent accessibility, averaged over conformational ensembles from molecular dynamics simulations. Dynamic light scattering (DLS) was used as a medium throughput screen for self-interaction of ~ 200 anti-GCGR IgG1 variants. A negative correlation was found between the viscosity determined at high concentration (180 mg/mL) and the DLS interaction parameter measured at low concentration (2-10 mg/mL). Additionally, anti-GCGR variants were readily identified with reduced viscosity and antigen-binding affinity within a few fold of the parent antibody, with no identified impact on overall developability. The methods described here may be useful in the optimization of other antibodies to facilitate their therapeutic administration at high concentration.

Dedifferentiated liposarcoma of the orbit.

Purpose: To present a rare case of dedifferentiated liposarcoma of the orbit. Observations: A 61-year-old male complained of left-sided proptosis, diplopia, and limited ocular motility for two years. Biopsy results at that time were suggestive of an atypical lipomatous neoplasm. Ten years later, he presented with increase in size of the mass and worsening of his symptoms. Imaging showed a multi-lobulated mass in the left orbit involving the intraconal, medial, and anterior orbit. Decompression and orbitotomy with biopsy were performed to debulk the mass. Pathology showed a low-grade well-differentiated liposarcoma and the patient was monitored thereafter annually. Eight years later, he complained of persistent proptosis and mass effect from the tumor resulting in ptosis and diplopia and underwent orbital exenteration. Histopathological analysis of the exenterated orbit revealed a focal area of dedifferentiated liposarcoma. Conclusions and importance: Dedifferentiation of an orbital mass can occur as a late complication years after the diagnosis of well-differentiated liposarcoma. Compared to the previously published cases of orbital liposarcoma, this presentation shows a prolonged timeline prior to dedifferentiation (18 years after initial diagnosis). Symptoms of growth or invasive features could indicate dedifferentiation and should warrant a biopsy.

Prevalence, Clinical and Imaging Characteristics of Superior Ophthalmic Vein Periphlebitis in Thyroid Eye Disease.

INTRODUCTION: To determine the prevalence, clinical features, and radiographic findings of superior ophthalmic vein periphlebitis (SOVP) in thyroid eye disease (TED). METHODS: Patients with a clinical diagnosis of thyroid eye disease and contrast-enhanced imaging were included. Imaging was reviewed for the presence of SOVP, and patients with SOVP were compared to those without. A random eye was determined to be the affected eye in patients without SOVP. RESULTS: A total of 212 patients met the inclusion criteria. Unilateral SOVP was identified in 4.7% of cases. There was no significant difference in age (p = 0.22), gender (p = 0.09), or disease duration (p = 0.14) between patients with and without SOVP. There was a significant (p < 0.05) difference in stage classification and clinical activity core between the groups. The affected eye in patients with SOVP had significantly (p < 0.05) greater margin reflex distance 1, degree of relative proptosis, horizontal motility restriction, and vertical motility restriction than in patients without SOVP. There was no significant difference in horizontal strabismus (p = 1.0), vertical strabismus (p = 0.87), or relative intraocular pressure (p = 0.77). On imaging, the maximal diameter of the SR and IR were found to be significantly (p < 0.05) larger in the affected eye of patients with periphlebitis; however, there was no difference in measured diameter of the medial rectus and (p = 0.30) or lateral rectus (p = 0.78). CONCLUSIONS: SOVP is an under-reported imaging finding of thyroid eye disease. It is associated with significantly greater margin reflex distance 1, relative proptosis, and motility restriction on exam as well as larger superior rectus and inferior rectus diameter on imaging. These patients tend to present in the active stage of disease with greater clinical activity score.

Recent Fluctuations in Public Searches for Cosmetic Procedures as Shown by Google Trends.

PURPOSE: The goal of this study is to understand the dynamic trends of 20 cosmetic procedures in the United States using Google Trends. METHODS: This was a descriptive cross-sectional study using Google Trends to measure changes in search volumes for 20 cosmetic procedures from a 5-year period (2018 to 2023) in the United States. Outcome measures included total and weekly changes in relative search volumes and variance levels for the following 20 search terms related to cosmetic surgeries: blepharoplasty, botox, breast augmentation, breast lift, brow lift, buccal fat removal, chemical peel, dermal filler, face lift, hair removal, hair transplant, lip filler, liposuction, masseter botox, microneedling, otoplasty, photofacial, rhinoplasty, tear trough filler, and tummy tuck. Search terms were divided into 3 categories, a) those with a change of public interest over a single week of 25% or less, b) 26%-50%, and c) greater than 50%. RESULTS: There was an overall 5-year increase of public interest in all but 5 search terms: breast augmentation, breast lift, liposuction, photofacial, and tummy tuck. Within a single week, lip filler, masseter botox, buccal fat removal, and tear trough filler exhibited greater than 50% change in public interest, while public interest in microneedling, hair removal, rhinoplasty, tummy tuck, liposuction, breast lift, and augmentation were more stable with less than 26% change. CONCLUSIONS: While certain procedures may experience rapid accelerations in public interest, not all procedures will consistently increase in popularity. Physicians must recognize the shifting popularity of cosmetic procedures to provide informed cosmetic care to patients.

Discovery of Selective Tertiary Amide Inhibitors of Cyclin-Dependent Kinase 2 (CDK2).

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and are frequently altered in cancer cells, thereby leading to uncontrolled proliferation. In this context, CDK2 has emerged as an appealing target for anticancer drug development. Herein, we describe the discovery of a series of selective small molecule inhibitors of CDK2 beginning with historical compounds from our ERK2 program (e.g., compound 6). Structure-based drug design led to the potent and selective tool compound 32, where excellent selectivity against ERK2 and CDK4 was achieved by filling the lipophilic DFG-1 pocket and targeting interactions with CDK2-specific lower hinge binding residues, respectively. Compound 32 demonstrated 112% tumor growth inhibition in mice bearing OVCAR3 tumors with 50 mg/kg bis in die (BID) oral dosing.

Purtscher-like retinopathy in a 19-year-old with maturity-onset diabetes of the young: a case report.

BACKGROUND: We report the first case of Purtscher-like retinopathy in a patient with 17q12 deletion-associated maturity-onset diabetes of the young. CASE PRESENTATION: A 19-year-old diabetic Hispanic male with history of cataracts and toe amputations presented with sudden onset of painless bilateral vision loss for 1 week with no associated trauma. Visual acuity was counting fingers at six feet in both eyes. Dilated retinal examination revealed bilateral peripapillary cotton wool spots and intraretinal hemorrhages, and significant subretinal and intraretinal fluid on optical coherence tomography. Fluorescein angiography revealed arteriolar staining and leakage around the disc with areas of capillary nonperfusion, supporting the diagnosis of Purtscher-like retinopathy. Systemic workup revealed multiple diabetic complications including chronic osteomyelitis of multiple toes, nonhealing diabetic foot ulcers, neurogenic bladder and bowel, and bilateral lower-extremity muscular neuropathies. Genetic evaluation revealed a 17q12 deletion, which is associated with maturity-onset diabetes of the young 5. On follow-up examination, he received a single intravitreal antivascular endothelial growth factor injection in the left eye (off label) for persistent macular edema. Although his retinal edema improved, his visual acuity remained poor. CONCLUSIONS: The presentation of our patient's multiple diabetic complications along visual symptoms suggests Purtscher-like retinopathy can be a sequela of uncontrolled diabetes. Purtscher-like retinopathy is a rare but possible consideration in diabetic patients who present with acute-onset vision loss.

Frosted Branch Angiitis in the Setting of Active COVID-19 Infection and Underlying Mixed Connective Tissue Disease.

Frosted branch angiitis (FBA) is an uncommon form of retinal vasculitis and is typically associated with vision loss. We report a unique case of FBA that manifested in the setting of an active COVID-19 infection in a patient with Mixed Connective Tissue Disease (MCTD). A 34-year-old female with a history of MCTD, including overlapping findings of dermatomyositis, systemic lupus erythematosus, and rheumatoid arthritis, on immunosuppressive medications, presented for left-sided vision loss. She was also found to have an active COVID-19 infection with symptoms including sore throat and dry cough. The patient's visual acuity was counting fingers in her affected eye with a fundus exam revealing diffuse retinal hemorrhages, retinal whitening, cystoid macular edema, and perivascular sheathing of tertiary arterioles and venules, characteristic of FBA. Labs showed mildly elevated inflammatory markers. She exhibited no other signs or symptoms concerning systemic rheumatologic flare. There was no evidence of COVID-19 on viral PCR testing of intraocular fluid but given her positive nasopharyngeal PCR, COVID-induced retinal vasculitis with FBA remained high on the differential. The patient's retinal vasculitis later improved with heightened immunosuppressive therapy including high-dose intravenous corticosteroids. Clinicians should be aware of the possibility of COVID-related FBA, particularly in patients with an underlying predisposition to autoimmune inflammation. Our experience with this patient highlights the utility of high-dose systemic immunosuppressive therapy in treating such inflammatory occlusive retinal vasculitis. Further studies are needed to characterize retinal manifestations of COVID-19 in the setting of autoimmune disease.

Emotional memories are enhanced when reactivated in slow wave sleep, but impaired when reactivated in REM.

Sleep supports memory consolidation. However, it is not completely clear how different sleep stages contribute to this process. While rapid eye movement sleep (REM) has traditionally been implicated in the processing of emotionally charged material, recent studies indicate a role for slow wave sleep (SWS) in strengthening emotional memories. Here, to directly examine which sleep stage is primarily involved in emotional memory consolidation, we used targeted memory reactivation (TMR) in REM and SWS during a daytime nap. Contrary to our hypothesis, reactivation of emotional stimuli during REM led to impaired memory. Consistent with this, REM% was correlated with worse recall in the group that took a nap without TMR. Meanwhile, cueing benefit in SWS was strongly correlated with the product of times spent in REM and SWS (SWS-REM product), and reactivation significantly enhanced memory in those with high SWS-REM product. Surprisingly, SWS-REM product was associated with better memory for reactivated items and poorer memory for non-reactivated items, suggesting that sleep both preserved and eliminated emotional memories, depending on whether they were reactivated. Notably, the emotional valence of cued items modulated both sleep spindles and delta/theta power. Finally, we found that emotional memories benefited from TMR more than did neutral ones. Our results suggest that emotional memories decay during REM, unless they are reactivated during prior SWS. Furthermore, we show that active forgetting complements memory consolidation, and both take place across SWS and REM. In addition, our findings expand upon recent evidence indicating a link between sleep spindles and emotional processing.

Dendritic Melanocytic Hyperplasia in Pterygia: A Potential Source of Diagnostic Confusion with Primary Acquired Melanosis.

Introduction: The aim of this study was to report the nearly ubiquitous prevalence of melanocytic hyperplasia in benign pterygia/pingueculae and establish that the entity is insufficiently recognized. Methods: This is a retrospective immunohistochemical pathology case series of 30 consecutive pterygia/pingueculae samples selected from an ophthalmic pathology database at a single institution. Histopathologic and immunohistochemistry analyses with anti-SOX-10 and anti-MART-1 antibodies were used for identifying melanocytes. The number of squamous cells intervening between melanocytes was determined. Results: The frequency of dendritic melanocytes was found to meet the criteria for dendritic melanocytic hyperplasia in 29 of 30 pterygia/pingueculae samples using specific antibodies. Melanocytes were found in several patterns: diffuse (28%), multifocal (28%), and focal (44%). In each case, the melanocytes were distributed as single melanocytes at the base; clusters of melanocytes were seen in 17% of samples. There were an average of about two intervening epithelial cells between melanocytes at the base. Conclusion: When diagnosed with immunohistochemistry, dendritic melanocytic hyperplasia is nearly ubiquitous in pterygia and pingueculae. Melanocytic hyperplasia may have a distribution that includes nests and single melanocytes above the basal layer, which can be confused with forms of primary acquired melanosis. It is important for pathologists to recognize these lesions as a distinct benign clinicopathologic entity.

Low-grade fibromyxoid sarcoma of the orbit.

A 70-year-old male presented with diplopia and painless proptosis of the left eye for 5 months. Examination showed 6 mm of axial proptosis and restriction of supraduction, abduction and adduction, and mild limitation of infraduction of the left eye. Magnetic resonance imaging demonstrated a large, moderately well-circumscribed intraconal mass in the left lateral orbit, and excisional biopsy was performed. Histopathologic features of mixed fibrous and myxoid areas in a whorl-like pattern and immunohistochemical staining for MUC4 confirmed the diagnosis of low-grade fibromyxoid sarcoma (LGFMS). Next-generation sequencing revealed genetic fusion of EWSR1-CREB3L1. LGFMS is an extremely rare neoplasm with only two prior documented cases of orbital involvement. Here, we report the third case of orbital LGFMS.

Assessment of KRAS G12C Target Engagement by a Covalent Inhibitor in Tumor Biopsies Using an Ultra-Sensitive Immunoaffinity 2D-LC-MS/MS Approach.

KRAS is one of the most frequently mutated oncogenes, with KRAS G12C recently becoming an actionable target for small molecule intervention. GDC-6036 is an investigational KRAS G12C inhibitor that acts by irreversibly binding to the switch II pocket of KRAS G12C when in the inactive GDP-bound state, thereby blocking GTP binding and activation. Assessing target engagement is an essential component of clinical drug development, helping to demonstrate mechanistic activity, guide dose selection, understand pharmacodynamics as it relates to clinical response, and explore resistance. Here, we report the development of an ultra-sensitive approach for assessing KRAS G12C engagement. Immunoaffinity enrichment with a commercially available anti-RAS antibody was combined with a targeted 2D-LC-MS/MS technique to quantify both free and GDC-6036-bound KRAS G12C proteins. A KRAS G12C-positive non-small cell lung cancer xenograft model was dosed with GDC-6036 to assess the feasibility of this assay for analyzing small core needle biopsies. As predicted, dose-dependent KRAS G12C engagement was observed. To date, a sensitivity of 0.08 fmol/µg of total protein has been achieved for both free and GDC-6036-bound KRAS G12C with as little as 4 µg of total protein extracted from human tumor samples. This sub-fmol/µg level of sensitivity provides a powerful potential approach to assess covalent inhibitor target engagement at the site of action using core needle tumor biopsies from clinical studies.

Conformation-locking antibodies for the discovery and characterization of KRAS inhibitors.

Small molecules that stabilize inactive protein conformations are an underutilized strategy for drugging dynamic or otherwise intractable proteins. To facilitate the discovery and characterization of such inhibitors, we created a screening platform to identify conformation-locking antibodies for molecular probes (CLAMPs) that distinguish and induce rare protein conformational states. Applying the approach to KRAS, we discovered CLAMPs that recognize the open conformation of KRASG12C stabilized by covalent inhibitors. One CLAMP enables the visualization of KRASG12C covalent modification in vivo and can be used to investigate response heterogeneity to KRASG12C inhibitors in patient tumors. A second CLAMP enhances the affinity of weak ligands binding to the KRASG12C switch II region (SWII) by stabilizing a specific conformation of KRASG12C, thereby enabling the discovery of such ligands that could serve as leads for the development of drugs in a high-throughput screen. We show that combining the complementary properties of antibodies and small molecules facilitates the study and drugging of dynamic proteins.

Dual Specific Phosphatase 14 Deletion Rescues Retinal Ganglion Cells and Optic Nerve Axons after Experimental Anterior Ischemic Optic Neuropathy.

PURPOSE: Understanding molecular changes is essential for designing effective treatments for nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults older than 50 years. We investigated changes in the mitogen-activated protein kinase (MAPK) pathway after experimental AION and focused on dual specificity phosphatase 14 (Dusp14), an atypical MAPK phosphatase that is downstream of Krüppel-like transcription factor (KLF) 9-mediated inhibition of retinal ganglion cell (RGC) survival and axonal regeneration. MATERIALS AND METHODS: We induced severe AION in a photochemical thrombosis model in adult C57BL/6 wild-type and Dusp14 knockout mice. For comparison, some studies were performed using an optic nerve crush model. We assessed changes in MAPK pathway molecules using Western blot and immunohistochemistry, measured retinal thickness using optical coherence tomography (OCT), and quantified RGCs and axons using histologic methods. RESULTS: Three days after severe AION, there was no change in the retinal protein levels of MAPK ERK1/2, phosphorylated-ERK1/2 (pERK1/2), downstream effector Elk-1 and phosphatase Dusp14 on Western blot. Western blot analysis of purified RGCs after a more severe model using optic nerve crush also showed no change in Dusp14 protein expression. Because of the known importance of the Dusp14 and MAPK pathway in RGCs, we examined changes after AION in Dusp14 knockout mice. Three days after AION, Dusp14 knockout mice had significantly increased pERK1/2+, Brn3A+ RGCs on immunohistochemistry. Three weeks after AION, Dusp14 knockout mice had significantly greater preservation of retinal thickness, increased number of Brn3A+ RGCs on whole mount preparation, and increased number of optic nerve axons compared with wild-type mice. CONCLUSIONS: Genetic deletion of Dusp14, a MAPK phosphatase important in KFL9-mediated inhibition of RGC survival, led to increased activation of MAPK ERK1/2 and greater RGC and axonal survival after experimental AION. Inhibiting Dusp14 or activating the MAPK pathway should be examined further as a potential therapeutic approach to treatment of AION.Abbreviations: AION: anterior ischemic optic neuropathy; Dusp14: dual specific phosphatase 14; ERK1/2: extracellular signal-regulated kinases 1/2; Elk-1: ETS Like-1 protein; GCC: ganglion cell complex; GCL: ganglion cell layer; inner nuclear layer; KO: knockout; MAPK: mitogen-activated phosphokinase; OCT: optical coherence tomography; RGC: retinal ganglion cell; RNFL: retinal nerve fiber layer.

The efficacy of 'high in' warning labels, health star and traffic light front-of-package labelling: an online randomised control trial.

OBJECTIVE: To examine the impact of front-of-package (FOP) labels on perceived healthfulness, purchasing intentions and understanding of common FOP systems. DESIGN: A parallel, open-label design randomised participants to different FOP labelling conditions: 'high in' warning labels (WL), multiple traffic light labelling (TLL), health star ratings (HSR) (all displayed per serving) or control with no interpretive FOP labelling. Participants completed a brief educational session via a smartphone application and two experimental tasks. In Task 1, participants viewed healthy or unhealthy versions of four products and rated healthiness and purchasing intention on a seven-point Likert-type scale. In Task 2, participants ranked three sets of five products from healthiest to least healthy. SETTING: Online commercial panel. PARTICIPANTS: Canadian residents ≥ 18 years who were involved in household grocery shopping, owned a smartphone and met minimum screen requirements. RESULTS: Data from 1997 participants (n 500/condition) were analysed. Task 1: across most product categories, the TLL and HSR increased perceived healthiness of healthier products. All FOP systems decreased perceived healthiness of less healthy products. Similar, albeit dampened, effects were seen regarding purchasing intentions. Task 2: participants performed best in the HSR, followed by the TLL, WL and control conditions. Lower health literacy was associated with higher perceived healthiness and purchasing intentions and poorer ranking task performance across all conditions. CONCLUSIONS: All FOP labelling systems, after a brief educational session, improved task performance across a wide spectrum of foods. This effect differed depending on the nutritional quality of the products and the information communicated on labels.Trial Registration: NCT03290118.

Consumers' Implicit and Explicit Recall, Understanding and Perceptions of Products with Nutrition-Related Messages: An Online Survey.

This study aimed to assess consumers' implicit and explicit recall, understanding and perceptions of products with a nutrition claim and a symbol depicting 'health,' and to determine whether these perceptions differed among Nutrition Facts table (NFt) users vs. nonusers. In an online survey, participants (n = 1997) were randomized to one of eight conditions in a 2 × 2 × 2 factorial design, consisting of a label with a claim (present/absent) a heart-shaped symbol depicting 'health' (present/absent) for a healthier or less healthy soup. Participants were shown a label for 10 s and asked whether they recalled seeing a claim. If participants answered yes, they were then asked to describe their response using open-ended questions. Participants also rated the product's perceived nutritional quality and purchase intentions using seven-point Likert scales. In the claim condition, most participants (75%) were able to recall the presence of a claim, while 12% incorrectly mentioned the presence of a claim when there was none. Claims likely attracted consumers' attention and increased perceived nutritional quality, although with limited influence among NFt users (23%). The symbol depicting 'health' did not enhance perceived nutritional quality or purchase intentions. Although most participants (77%) made their decisions implicitly using the front of labels, those who used the NFt had a better understanding of the nutritional quality of products.