Autoregulated splicing of TRA2ß programs T cell fate in response to antigen-receptor stimulation.

T cell receptor (TCR) sensitivity to peptide-major histocompatibility complex (MHC) dictates T cell fate. Canonical models of TCR sensitivity cannot be fully explained by transcriptional regulation. In this work, we identify a posttranscriptional regulatory mechanism of TCR sensitivity that guides alternative splicing of TCR signaling transcripts through an evolutionarily ultraconserved poison exon (PE) in the RNA-binding protein (RBP) TRA2ß in mouse and human. TRA2ß-PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. Tra2ß-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, Tra2ß-PE reinclusion allowed T cell survival. Finally, we found that TRA2ß-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that TRA2ß-PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.

"Blue Scrub Lid Retraction": Changes in Eyelid Position on the Day of Surgery.

PURPOSE: The aim of this study is to test the hypothesis that margin-reflex distance 1 (MRD1) on the day of surgery will be higher than the MRD1 measured at the in-clinic consult visit among patients undergoing blepharoptosis repair due to an increased sympathetic drive. METHODS: Patients evaluated for involutional blepharoptosis repair were prospectively enrolled over a 12-month period in this single-center, self-controlled study. Three investigators independently determined MRD1 using cropped photos taken of patients at the in-clinic consult visit and on the day of surgery. A difference in height was tested for by using the 2-tailed Wilcoxon signed rank test. RESULTS: Evaluated in this study were 76 eyelids from 38 patients. Over 3-quarters of study participants had a higher MRD1 in the right and OSs on the day of surgery than at their in-clinic consultation visit (p < 0.001). The mean increase in MRD1 for the right eyelid and left eyelid was 1.0 mm (range: 0-3.15 mm) and 1.1 mm (range: 0-2.7 mm), respectively. CONCLUSIONS: In patients with involutional blepharoptosis, we conclude that MRD1 is higher on the day of surgery as compared with the in-clinic consult visit. This may be secondary to the stress of surgery and an associated increase in sympathetic drive. In some cases, this change in eyelid position led to resolution of apparent involutional ptosis altogether. Caution should be used when considering deferral of ptosis repair on the basis of exam findings present on the day of surgery.

UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors.

The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines and identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator of RLR transcription. UBR5 deficiency reduces antiviral immune responses to RNA viruses, while increases viral replication in primary cells and mice. Ubr5 knockout mice are more susceptible to lethal RNA virus infection than wild type littermates. Mechanistically, UBR5 mediates the Lysine 63-linked ubiquitination of Tripartite Motif Protein 28 (TRIM28), an epigenetic repressor of RLRs. This modification prevents intramolecular SUMOylation of TRIM28, thus disengages the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.

Predictors of Ophthalmology Resident Performance From Medical Student Application Materials.

OBJECTIVE: To determine whether elements in ophthalmology residency applications are predictors of future resident performance. DESIGN: This multi-institutional, cross-sectional, observational study retrospectively reviewed the residency application materials of ophthalmology residents who graduated from residency from 2006 through 2018. Resident performance was scored by 2 faculty reviewers in 4 domains (clinical, surgical, academic, and global performance). Correlation between specific elements of the residency application and resident performance was assessed by Spearman correlation coefficients (univariate) and linear regression (multivariate) for continuous variables and logistic regression (multivariate) for categorical variables. SETTING: Seven ophthalmology residency programs in the US. PARTICIPANTS: Ophthalmology residents who graduated from their residency program. RESULTS: High-performing residents were a diverse group, in terms of sex, ethnicity, visa status, and educational background. Residents with United States Medical Licensing Examination Step 1 scores higher than the national average for that year had significantly higher scores in all 4 performance domains than those who scored at or below the mean (all domains P < 0.05). Residents who had honors in at least 4 core clerkships and who were members of Alpha Omega Alpha Medical Honor Society also had higher scores in all 4 performance domains (all domains P ≤ 0.04). Step 1 score (ρ=0.26, P < 0.001) and the difference between Step 1 score and the national average for that year (ρ=0.19, P = 0.009) positively correlated with total resident performance scores. Residents who passed the American Board of Ophthalmology Written Qualifying Examination or Oral Examination on their first attempt had significantly higher Step 1/2 scores (P ≤ 0.005), Ophthalmology Knowledge Assessment Program scores (P = 0.001), and resident performance scores (P ≤ 0.004). CONCLUSIONS: In this new landscape of increasing numbers of applicants to residency programs and changing of the Step 1 score to pass/fail, our findings may help guide selection committees as they holistically review applicants to select exceptional future residents in ophthalmology.

Outcomes of Patients With Thyroid Eye Disease Partially Treated With Teprotumumab.

PURPOSE: In response to the coronavirus (COVID-19) pandemic, teprotumumab production was temporarily halted with resources diverted toward vaccine production. Many patients who initiated treatment with teprotumumab for thyroid eye disease were forced to deviate from the standard protocol. This study investigates the response of teprotumumab when patients receive fewer than the standard 8-dose regimen. METHODS: This observational cross-sectional cohort study included patients from 15 institutions with active or minimal to no clinical activity thyroid eye disease treated with the standard teprotumumab infusion protocol. Patients were included if they had completed at least 1 teprotumumab infusion and had not yet completed all 8 planned infusions. Data were collected before teprotumumab initiation, within 3 weeks of last dose before interruption, and at the visit before teprotumumab reinitiation. The primary outcome measure was reduction in proptosis more than 2 mm. Secondary outcome measures included change in clinical activity score (CAS), extraocular motility restriction, margin reflex distance-1 (MRD1), and reported adverse events. RESULTS: The study included 74 patients. Mean age was 57.8 years, and 77% were female. There were 62 active and 12 minimal to no clinical activity patients. Patients completed an average of 4.2 teprotumumab infusions before interruption. A significant mean reduction in proptosis (-2.9 mm in active and -2.8 mm in minimal to no clinical activity patients, P < 0.01) was noted and maintained during interruption. For active patients, a 3.4-point reduction in CAS ( P < 0.01) and reduction in ocular motility restriction ( P < 0.01) were maintained during interruption. CONCLUSIONS: Patients partially treated with teprotumumab achieve significant reduction in proptosis, CAS, and extraocular muscle restriction and maintain these improvements through the period of interruption.

Optimizing 3D Rotational Angiography for Congenital Cardiac Catheterization.

The aim of the study was to determine the variables associated with high-quality (HQ) versus low-quality (LQ) three-dimensional rotational angiography (3DRA) and create guides for optimization of approach to 3DRA in congenital cardiac catheterization (CCC). CCC has adopted 3DRA as a mainstay, but there has not been systematic analysis of approach to and factors associated with HQ 3DRA. This was a single-center, retrospective study of 3DRAs using Canon Infinix-I platform. Reconstructions were graded by 3 interventionalists. Quality was dichotomized into HQ and LQ. Univariable analyses and multivariable logistic regression models were performed. From 8/2016 to 12/2018, 208 3DRAs were performed in 195 CCCs; median age 7 years (2, 16), weight 23 kg (12, 57). The majority of 3DRAs were performed in patients with biventricular physiology (N = 137, 66%) and in pulsatile sites (N = 144, 69%). HQ 3DRA (N = 182, 88%) was associated with greater total injection volume [2.20 mL/kg (1.44, 3.29) vs. 1.62 mL/kg (1.10, 1.98), p = 0.005] and more dilute contrast solution [60% (50, 100) vs. 100% (60, 100), p = 0.007], but not with contrast volume administered (p = 0.2) on univariable analysis. On multivariable logistic regression, HQ 3DRA was significantly associated with patient weight [OR 0.97 (95% CI (0.94, 0.99), p = 0.018], total injection volume [OR 1.04 (95% CI 1.01, 1.07) p = 0.011], and percent contrast solution [OR 0.97 (95% CI 0.95, 1.00), p = 0.022]. These data resulted in creation of scatter plots and a novel 3DRA Nomogram for estimating the probability of HQ 3DRA. This is the first study to create evidence-based contrast dose guides and nomogram for 3DRA in CCC. HQ 3DRA was associated with lower weight, higher total injection volumes, and more dilute contrast solution.

A Case of the Blues-Colored Pencil Orbitopathy in an 18-Month-Old Boy.

Orbital penetrating injuries from pencils are rare. This report describes a case of penetrating orbital injury in a young child with a retained blue-colored pencil core foreign body, which led to rapid onset of orbital abscess requiring surgical drainage. Intraoperatively, orbital tissues were stained a bright-blue color. Histopathological study of specimen also highlighted bright blue aggregates of foreign material infiltrating the orbital tissues. Cultures grew Streptococcus mitis and Exophiala jeanselmei , which are rare causes of orbital abscess. Unique properties of retained colored pencil core as compared to graphite pencil core are herein discussed. Due to differences in composition, colored pencil core foreign bodies may require more timely surgical intervention compared to noncolored graphite pencil core.

A scoping review of operative and non-invasive management in the treatment of non-unions.

INTRODUCTION: Non-union occurs when a fracture fails to adequately heal, and requires additional intervention to achieve union. The purpose of this scoping review is to provide a high-level overview of the existing non-union management literature. This review aims to highlight the current literature on non-union management, as well as identify key areas that require future research to provide a better understanding of potential non-union management strategies. METHODS: This study utilized the scoping review framework from Arksey and O'Malley All relevant literature on non-union management was systematically searched for within the OVID Medline, OVID Embase, and Web of Science databases. As a scoping review, this study aimed to identify the high-level trends in non-union literature. This was assessed through a visual and numerical summary of the general themes in non-union literature, as well as the timeline in which these trends have occurred. RESULTS: The literature search identified 8081 articles, of which 2210 articles were included. There is a large body of evidence for various surgical treatment options for non-union. The literature suggests healing rates between 80 and 100 percent for commonly utilized surgical procedures, such as plating with bone graft for long bones. Despite these beneficial healing rates, the requirement of a surgery creates a large socioeconomic burden. The possibility for bone growth stimulator (BGS) options to achieve non-union healing rates in a similar realm as surgical options suggests that the use of a BGS may be a beneficial option prior to surgical intervention, as this would potentially reduce the number of patients who would otherwise require surgery. CONCLUSION: A large body of evidence exists on non-union management, which is largely comprised of case series and reports. The most commonly assessed non-unions include the tibia, wrist, and femur. Bone grafting, plating, and nailing are the most investigated treatment options. BGS are a non-operative treatment options for non-union that provide similar healing rates to surgical options in certain indications within initial observational data. BGS are a potential option for non-operative management of non-unions to reduce socioeconomic burdens of surgical intervention, with a need for further high-quality investigation in this therapeutic area.

Delayed-Onset Inflammatory Optic Nerve Sheath Mass and Perineuritis Following Cessation of Ipilimumab and Nivolumab Therapy.

A 65-year-old male presented with headaches and painless episodes of unilateral vision loss. He had a history of renal cell carcinoma, in remission following surgery and immunotherapy with ipilimumab and nivolumab, discontinued 2 years and 3 months before presentation, respectively. MRI revealed an optic nerve sheath mass and perineuritis. After 1 month of corticosteroid therapy, there was a robust clinical and radiographic response, which relapsed dramatically following cessation. An optic nerve sheath biopsy showed chronic mild inflammation, and extensive work-up for alternative etiologies of orbital inflammation was negative. Following a prolonged taper of corticosteroids, he demonstrated complete response. In the setting of ocular immune privilege, ophthalmic immune-related adverse events (irAE) are rare, although multifarious. While on-treatment irAE are well-characterized, posttreatment irAE have become increasingly recognized across multiple organ systems. We report a case of a delayed-onset inflammatory optic nerve sheath mass and perineuritis after cessation of immunotherapy.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Immunoglobulin G4 Involvement in Lacrimal Sac Squamous Cell Carcinoma.

Lacrimal sac squamous cell carcinoma is a rare but life-threatening disease that is often a delayed diagnosis secondary to difficulty in differentiating from other causes of dacrocystitis and acquired nasolacrimal duct obstruction. Chronic inflammation, including that of an underlying autoimmune disease, prior instrumentation, and poor wound healing, may be risk factors in the development to lacrimal sac squamous cell carcinoma. The authors present the first case of lacrimal sac squamous cell carcinoma associated with antineutrophil cytoplasmic antibody-associated vasculitis and immunoglobulin G4 positivity. Rather than an overlap syndrome between antineutrophil cytoplasmic antibody-associated vasculitis and immunoglobulin G4-related disease, high immunoglobulin G4 positivity may be considered an inflammatory marker of disease severity in the setting of antineutrophil cytoplasmic antibody-associated vasculitis and underlying malignancy. Inflammation-mediated tumorangiogenesis should be considered in the development of malignancy and red flags of chronic uncontrolled inflammation should warrant a lower threshold for further workup.

Predictive Modeling of New-Onset Postoperative Diplopia Following Orbital Decompression for Thyroid Eye Disease.

PURPOSE: To identify risk factors for the development of new-onset, postoperative diplopia following orbital decompression surgery based on patient demographics, clinical exam characteristics, radiographic parameters, and surgical techniques. METHODS: We conducted a multi-center retrospective chart review of patients who underwent orbital decompression for thyroid eye disease (TED). Patient demographics, including age, gender, smoking history, preoperative exophthalmometry, clinical activity score (CAS), use of peribulbar and/or systemic steroids, and type of orbital decompression were reviewed. Postoperative diplopia was determined at a minimum of 3 months postoperatively and before any further surgeries. Cross-sectional area ratios of each extraocular muscle to orbit and total fat to orbit were calculated from coronal imaging in a standard fashion. All measurements were carried out using PACS imaging software. Multivariable logistic regression modeling was performed using Stata 14.2 (StataCorp, College Station, TX). RESULTS: A total of 331 patients without preoperative diplopia were identified. At 3 months postoperatively, 249 patients had no diplopia whereas 82 patients developed diplopia. The average postoperative follow-up was 22 months (range 3-156) months. Significant preoperative clinical risk factors for postoperative diplopia included older age at surgery, proptosis, use of peribulbar or systemic steroids, elevated clinical activity score, and presence of preoperative compressive optic neuropathy. Imaging findings of enlarged cross-sectional areas of each rectus muscle to the overall orbital area also conferred a significant risk of postoperative diplopia. Regarding surgical factors, postoperative diplopia was more common among those undergoing medial wall decompression, bilateral orbital surgery, and balanced decompression, whereas endoscopic medial wall decompression was found to be relatively protective. CONCLUSIONS: This study identifies risk factors associated with the development of diplopia following orbital decompression using multivariable data. This study demonstrates that several characteristics including age, clinical activity score, the cross-sectional muscle to orbit ratios, in addition to the type of orbital decompression surgery, are predictive factors for the development of new-onset postoperative diplopia.

Insights Into Ferroptosis: Targeting Glycolysis to Treat Graves' Orbitopathy.

CONTEXT: Oxidative stress plays an indispensable role in pathogenesis of Graves' orbitopathy (GO). Ferroptosis is a newly discovered form of cell death resulting from lipid peroxidation. Little is known about the role of ferroptosis in GO. OBJECTIVE: We aimed to identify the divergent role of ferroptosis in the GO and control orbital fibroblasts (OFs). METHODS: Orbital fat/connective tissues and serum immunoglobulins (Igs) were collected from GO and control subjects. Cell viability and lipid peroxidation were measured to evaluate ferroptosis sensitivity. Pyruvate dehydrogenase kinase 2 (PDK2) level and oxygen consumption rate were quantified to assess glycolysis status. RESULTS: Primary OFs were cultured from orbital tissues. Ferroptosis was induced by cystine deprivation and/or erastin treatment. The GO OFs possessed stronger resistance to ferroptosis than the control OFs. Selenium, a potential ferroptosis inhibitor, protected the control OFs from ferroptosis. Both transcriptomic and proteomic analyses indicated glycolytic shift in the GO OFs. Metabolic profiling, PDK2 quantification, and oxygen consumption assay confirmed enhanced glycolysis in the GO OFs. Inhibition of glycolysis by PDK2 knockdown and dichloroacetic acid (DCA) promoted ferroptosis sensitivity in the GO OFs. The ferroptosis-sensitizing effects of DCA were also observed when the GO OFs were treated with GO-Igs. IGF1R overexpression in the GO OFs contributed to glycolysis shift. IGF1R inhibitory antibodies facilitated ferroptosis induction in the GO OFs, but the effects were less remarkable under GO-Igs treatment. CONCLUSION: These study findings establish that glycolysis facilitates ferroptosis resistance in the GO OFs, providing insights into the therapeutic role of glycolysis for GO treatment.

Orbital volume changes during growth and development in human children assessed using cone beam computed tomography.

OBJECTIVES: To measure growth-related changes in orbital volume from childhood to the late teenage years using cone-beam computed tomography (CBCT) scans. METHODS: This retrospective cohort study involved 65 (24 male, 41 female) healthy Caucasian children (ages 6-18 years) with existing serial craniofacial CBCT scans. CBCT scans were available for 292 orbits. Each orbit was transformed into a closed space with well-defined boundaries, and orbital volume was measured using manual segmentation. A novel statistical analysis was applied to extract the maximum amount of longitudinal information from the data. Intra- and inter-operator correlation coefficients were calculated from replications performed on a random subset of 10% of the sample. RESULTS: Orbital volume increased at a rate of 1-2% annually until the late teenage years. Intra- and inter-operator agreement between repeated measurements were >90%. CONCLUSIONS: Orbital volume increases by 1-2% per year throughout childhood continuing until the late teenage years. This annual increase is large enough to be clinically relevant as it may lead to less-than-optimal long term surgical outcomes when reconstructive surgery for the pediatric anophthalmic socket is required.

Differential roles of RIG-I like receptors in SARS-CoV-2 infection.

Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) sense viral RNA and activate antiviral immune responses. Herein we investigate their functions in human epithelial cells, the primary and initial target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A deficiency in MDA5, RIG-I or mitochondrial antiviral signaling protein (MAVS) enhanced viral replication. The expression of the type I/III interferon (IFN) during infection was impaired in MDA5-/- and MAVS-/-, but not in RIG-I-/-, when compared to wild type (WT) cells. The mRNA level of full-length angiotensin-converting enzyme 2 (ACE2), the cellular entry receptor for SARS-CoV-2, was ~ 2.5-fold higher in RIG-I-/- than WT cells. These data demonstrate MDA5 as the predominant SARS-CoV-2 sensor, IFN-independent induction of ACE2 and anti-SARS-CoV-2 role of RIG-I in epithelial cells.

An Essential Role of UBXN3B in B Lymphopoiesis.

Hematopoiesis is finely regulated to enable timely production of the right numbers and types of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential role of UBXN3B in maintenance of hematopoietic homeostasis and restriction of immunopathogenesis during respiratory viral infection. Ubxn3b deficient ( Ubxn3b -/- ) mice are highly vulnerable to SARS-CoV-2 and influenza A infection, characterized by more severe lung immunopathology, lower virus-specific IgG, significantly fewer B cells, but more myeloid cells than Ubxn3b +/+ littermates. This aberrant immune compartmentalization is recapitulated in uninfected Ubxn3b -/- mice. Mechanistically, UBXN3B controls precursor B-I (pre-BI) transition to pre-BII and subsequent proliferation in a cell-intrinsic manner, by maintaining BLNK protein stability and pre-BCR signaling. These results reveal an essential role of UBXN3B for the early stage of B cell development.

Development of Herpes Zoster Ophthalmicus in an Immunocompetent Pediatric Patient Following Facial Trauma.

Herpes zoster ophthalmicus (HZO) is a neuro-oculo-dermic infection caused by reactivation of latent varicella zoster virus in the dorsal root ganglia of the ophthalmic division of the trigeminal nerve. Although a rare diagnosis in an otherwise healthy, vaccinated pediatric patient, this entity may occur with increasing frequency among those with preceding trauma, particularly in the month prior to presentation. Herein, we highlight a case of HZO in a vaccinated, immunocompetent adolescent in the setting of recent facial trauma.

Transport of patients with giant disfiguring cranial tumors from Africa to the US for collaborative multidisciplinary treatment.

BACKGROUND: Giant disfiguring cranial tumors are exceptionally rare and develop over the course of many years, typically in patients who lack access to medical care. Here, we describe four patients who were flown to our center for treatment by a multidisciplinary surgical team, who had previously been turned down for treatment at multiple international centers in Africa, Europe, and the United States (US) due to complexity and financial concerns. The case series describes socioeconomic implications and the feasibility of offering such care to patients from outside the US. CASE DESCRIPTIONS: Four patients with giant skull disfiguring tumors were flown internationally and treated by a surgical team consisting of a complex cranial neurosurgeon, a craniofacial reconstructive plastic surgeon, and an oculoplastic surgeon. All patients underwent aggressive surgical therapy with the aim of complete tumor removal and simultaneous cranial reconstruction. A patient with osteogenic sarcoma underwent two additional resections in 3 years, with delayed reconstruction. They returned home but ultimately succumbed to the disease. A patient with ossifying fibroma required two follow-up procedures for cosmetic reconstruction and sought asylum in the US, where they remain today. Two additional patients, one with a giant plexiform neurofibroma and one with a cerebellopontine angle meningioma, achieved good results and returned to Africa 1 month and 3 weeks after surgery, respectively. CONCLUSION: Resection of giant disfiguring cranial tumors and reconstruction of the impacted region requires an experienced multidisciplinary team. These cases can be managed by transporting such patients from areas without access to medical care to specialized centers able to provide excellent care.

Low-intensity pulsed ultrasound (LIPUS) for stimulation of bone healing - A narrative review.

The use of low intensity pulsed ultrasound (LIPUS) to accelerate the fracture repair process in humans was first reported by Xavier & Duarte in 1983 [1]. This success led to clinical trials and the 1994 approval of LIPUS in the United States for the accelerated healing of certain fresh fractures. LIPUS was approved in the US for the treatment of established non-unions in 2000, and is also approved around the world. In this article, we present relevant literature on the effect of LIPUS on bone healing in patients with acute fractures and non-unions and provide a molecular explanation for the effects of LIPUS on bone healing. Data on LIPUS accelerated fracture repair is controversial with many controlled studies showing a positive effect. However, the largest trial in acute tibial fractures stabilized with an intramedullary nail failed to show significant differences in accelerated healing and in functional outcomes. Uncontrolled data from prospective case series suggest a positive effect of LIPUS in non united fractures with healing rates of around 85%. Evaluation of results from studies, both positive and negative, has enabled an understanding that the patient population with potentially the greatest benefit from receiving LIPUS are those at-risk for fracture healing, e.g. diabetic & elderly patients. The elucidation of a pathway to activate the Rac-1 pathway by LIPUS might explain this beneficial effect. Overall, there is a strong need for further clinical trials, particularly for acute fractures at risk of progressing to non-union and in established non-unions including a comparison to the current standard of care.