The Clinical Findings, Pathogenic Variants, and Gene Therapy Qualifications Found in a Leber Congenital Amaurosis Phenotypic Spectrum Patient Cohort.

This retrospective study examines the clinical characteristics and underlying genetic variants that exist in a Leber congenital amaurosis (LCA) patient cohort evaluated at the inherited retinal disease (IRD) clinic at the University of Minnesota (UMN)/M Health System. Our LCA cohort consisted of 33 non-syndromic patients and one patient with Joubert syndrome. We report their relevant history, clinical findings, and genetic testing results. We monitored disease presentation utilizing ocular coherence tomography (OCT) and fundus autofluorescence (FAF). Electroretinogram testing (ERG) was performed in patients when clinically indicated. Next-generation sequencing (NGS) and genetic counseling was offered to all evaluated patients. Advanced photoreceptor loss was noted in 85.7% of the subjects. All patients who underwent FAF had findings of either a ring of macular hypo/hyper AF or peripheral hypo-AF. All patients had abnormal ERG findings. A diagnostic genetic test result was identified in 74.2% of the patients via NGS single-gene testing or panel testing. Two patients in our cohort qualified for Luxturna® and both received treatment at the time of this study. These data will help IRD specialists to understand the genetic variants and clinical presentations that characterize our patient population in the Midwest region of the United States.

CHOROIDAL NEVUS ASSOCIATED WITH VITELLIFORM DEPOSITION IN A PATIENT WITH AUTOSOMAL DOMINANT BEST DYSTROPHY.

BACKGROUND/PURPOSE: To describe the clinical, optical coherence tomography (OCT), fundus autofluorescence and ultrasound findings of a patient with a choroidal nevus actively exuding vitelliform material in the setting of autosomal dominant Best dystrophy (BD). METHODS: The patient's clinical course was followed over time with ophthalmic examinations and multimodal imaging. RESULTS: A 71-year-old male patient with BD was referred for evaluation of a choroidal nevus in the right eye. Dilated fundoscopic examination showed a small pigmented choroidal nevus in the temporal periphery. Over a 3-year period, the nevus developed progressive deposition of vitelliform material along its inferior border. Meanwhile, OCT and fundus photography showed only slight growth. Ultrasound showed no change in height; basal measurements were confounded by the increased vitelliform deposits. Genetic testing confirmed a heterozygous mutation in the BEST1 gene and electrophysiology was consistent with BD. CONCLUSIONS: Dysfunction of the retinal pigment epithelium associated with BD may cause novel presentations of other conditions such as choroidal nevi. The implication for malignant transformation of a choroidal nevus associated with vitelliform deposit accumulation in this context is unknown.

An EMS Response to Refugees Arriving at an International Airport: A Report From the Field.

Following Afghanistan's fall in August 2021, many refugees were settled in the United States as part of Operation Allies Welcome. They were flown from Kabul to the Middle East and Europe before continuing to the U.S. By late September Philadelphia was the sole destination. From there refugees were transported to Safe Haven military bases around the country. Philadelphia International Airport became the site of a months-long operation involving city, state, federal, and private agencies engaged in processing, medical screening, and COVID-testing of arriving refugees. The Philadelphia Fire Department played an integral role. Minor medical conditions were treated onsite. Higher acuity patients were transported to nearby hospitals. The goal was to maintain flow of refugees to their next destination while addressing acute medical issues. Between August 28, 2021, and March 1, 2022, the airport processed 29,713 refugees. Philadelphia's experience may serve as a guide for planning future such refugee operations.

Multimodal Retinal Imaging Findings in Hardikar Syndrome.

PURPOSE: To describe the syndromic, clinical, and retinal findings of a patient with an extremely-rare genetic condition known as Hardikar Syndrome (HS) with presentation of optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein angiographic (FA), and indocyanine green angiographic (ICG) findings. METHODS: Clinical course was detailed and followed over time with examinations and multimodal imaging. PATIENT AND RESULTS: A 17-year-old patient with HS was referred for possible retinitis pigmentosa. Dilated fundoscopic examination revealed large, multifocal cauliform patches of chorioretinal retinal pigment epithelium (RPE) changes with RPE drop-out involving the macula and periphery in both eyes. Additionally, an inactive choroidal neovascular membrane (CNVM) was present in the left eye. Multimodal imaging with OCT, FAF, FA and ICG correlated with the clinical findings of focal patches of chorioretinal degeneration in both eyes. Additionally, an anomalous finding of the superior retinal arterial vessels filling in tandem with the choroidal was present in the left eye. The patient's clinical findings were consistent with HS, and genetic testing with whole exome sequencing revealed a pathogenic mutation in the MED12 gene, confirming diagnosis. DISCUSSION AND CONCLUSIONS: HS is associated with RPE degeneration, creating focal patches of pigmentary chorioretinal atrophic lesions. Vision loss can occur due to the development of CNVMs. We recommend close evaluation and follow-up for HS patients with multimodal retinal imaging.

Clinical Characteristics and Genetic Variants of a Large Cohort of Patients with Retinitis Pigmentosa Using Multimodal Imaging and Next Generation Sequencing.

This retrospective study identifies patients with RP at the Inherited Retinal Disease Clinic at the University of Minnesota (UMN)/M Health System who had genetic testing via next generation sequencing. A database was curated to record history and examination, genetic findings, and ocular imaging. Causative pathogenic and likely pathogenic variants were recorded. Disease status was further characterized by ocular coherence tomography (OCT) and fundus autofluorescence (AF). Our study cohort included a total of 199 patients evaluated between 1 May 2015-5 August 2022. The cohort included 151 patients with non-syndromic RP and 48 with syndromic RP. Presenting symptoms included nyctalopia (85.4%) photosensitivity/hemeralopia (60.5%), and decreased color vision (55.8%). On average, 38.9% had visual acuity of worse than 20/80. Ellipsoid zone band width on OCT scan of less than 1500 µm was noted in 73.6%. Ninety-nine percent had fundus autofluorescence (AF) findings of a hypo- or hyper-fluorescent ring within the macula and/or peripheral hypo-AF. Of the 127 subjects who underwent genetic testing, a diagnostic pathogenic and/or likely pathogenic variant was identified in 67 (52.8%) patients-33.3% of syndromic RP and 66.6% of non-syndromic RP patients had a diagnostic gene variant identified. It was found that 23.6% of the cohort had negative genetic testing results or only variants of uncertain significance identified, which were deemed as non-diagnostic. We concluded that patients with RP often present with advanced disease. In our population, next generation sequencing panels identified a genotype consistent with the exam in just over half the patients. Additional work will be needed to identify the underlying genetic etiology for the remainder.

A case of descending necrotizing mediastinitis complicated by internal jugular thrombosis in a setting of MRSA bacteremia.

BACKGROUND: Acute Descending Necrotizing Mediastinitis is a rare but serious illness that carries a high mortality rate. It is not commonly part of the Emergency Physician's differential diagnoses for the chief complaint of chest pain when there has been no recent instrumentation to the area. Because the disease is so uncommon, there is a relative paucity of reports of the illness. CASE REPORT: We report the case of a 58-year-old male with a past medical history of HIV and history of intravenous drug use (IVDU) who presented to the Emergency Department with anterior chest pain for several days in addition to 3 days of fever and chills. The patient's presentation raised concern for intrathoracic infection and the diagnosis of Descending Necrotizing Mediastinitis complicated by internal jugular thrombosis was confirmed by contrast enhanced computed tomography and sonography.

Sustained Control of Serpiginous Choroiditis with the Fluocinolone Acetonide 0.18 mg Intravitreal Implant.

Purpose: To describe an alternative treatment for a patient with serpiginous choroiditis (SC) who was not tolerant to systemic therapies. Methods: Case report of a patient with serpiginous choroiditis with their clinical course followed with ophthalmic examinations and multimodal imaging overtime. Patients and Results. A 57-year-old female with serpiginous choroiditis was treated for seven years with numerous therapies including systemic steroids, immunosuppressive agents, and repeated dexamethasone intravitreal implants. The patient was intolerant of systemic therapies and would flare if dexamethasone injections were performed less frequently than every 8 weeks, making a viable long-term treatment plan problematic. Following one injection of the fluocinolone acetonide 0.18 mg intravitreal implant, she has experienced sustained control for 20 months. Discussion and Conclusions. Real-world treatment of SC is complex as long-term control is necessary, and associated side effects of the therapies provided may limit sustained use. The fluocinolone acetonide implant lasts 36 months and may be an alternative long-term management option, especially in the setting of systemic medication intolerance for some patients with SC.

Accuracy of Emergency Department Chest Pain Patients' Reporting of Coronary Disease History.

Introduction: History is an important component of emergency department risk stratification for chest pain patients. We hypothesized that a significant portion of patients would not be able to accurately report their history of coronary artery disease (CAD) and diagnostic testing. Methods: We prospectively enrolled a convenience sample of a cohort of adult ED patients with a chief complaint of chest pain. They completed a structured survey that included questions regarding prior testing for CAD and cardiac history. Study authors performed a structured chart review within the electronic medical record for our 6-hospital system. Results of testing for CAD, cardiac interventions, and chart diagnoses of CAD/acute myocardial infarction (AMI) were recorded. Categorical data were analyzed by Chi-square and continuous data by logistic regression. Results: About 196 patients were enrolled; mean age 57 ± 15 years, 48% female, 67% Hispanic, 50% income <$20,000/year. About 43% (95% confidence interval [CI] 35%-51%) of patients stated that they did not have CAD, yet medical records indicated that they were CAD+. With increasing age, patients were more likely to accurately report the absence of CAD (P < 0.001). There was no association between patients reporting no CAD, but CAD+ in records with respect to the following characteristics: female gender (P = 0.37), Hispanic race (P = 0.73), income (P = 0.41), less than or equal to high school education (P = 0.11), and private insurance (P = 0.71). For patients with prior AMI, 7.2% (95% CI 2.7%-11%) reported no prior history of AMI. Conclusions: Within our study group from a predominantly poor, Hispanic population, patients had a poor recall for the presence of CAD in their medical history.

Comparison of Diplodia Tip Blight Pathogens in Spanish and North American Pine Ecosystems.

Diplodia tip blight is the most ubiquitous and abundant disease in Spanish Pinus radiata plantations. The economic losses in forest stands can be very severe because of its abundance in cones and seeds together with the low genetic diversity of the host. Pinus resinosa is not genetically diverse in North America either, and Diplodia shoot blight is a common disease. Disease control may require management designs to be adapted for each region. The genetic diversity of the pathogen could be an indicator of its virulence and spreading capacity. Our objective was to understand the diversity of Diplodia spp. in Spanish plantations and to compare it with the structure of American populations to collaborate in future management guidelines. Genotypic diversity was investigated using microsatellite markers. Eight loci (SS9-SS16) were polymorphic for the 322 isolates genotyped. The results indicate that Diplodia sapinea is the most frequent Diplodia species present in plantations of the north of Spain and has high genetic diversity. The higher genetic diversity recorded in Spain in comparison to previous studies could be influenced by the intensity of the sampling and the evidence about the remarkable influence of the sample type.

Longitudinal Development of Refractive Error in Children Treated With Intravitreal Bevacizumab or Laser for Retinopathy of Prematurity.

Purpose: To compare the patterns of longitudinal refractive error development during the first 3.5 years in children with severe retinopathy of prematurity (ROP) treated with intravitreal bevacizumab (IVB) or laser photocoagulation. Methods: This prospective cohort study enrolled extremely preterm infants (birth weight < 1000 g, gestational age 23-27 weeks) with type 1 ROP from multiple hospitals in Dallas between 1999 and 2017; IVB group (N = 22); laser group (N = 26). Cycloplegic retinoscopy was conducted from 0.04 years corrected age and every 0.5 to 1.0 years thereafter until 3.5 years old. Right eye spherical equivalent (SEQ) and astigmatism, anisometropia, and better-eye visual acuity were analyzed over time. Results: In all children, both eyes were treated with the same modality. At the final visit, the prevalence of myopia (SEQ ≤ -1D) was 82.7% in the laser group and 47.7% in the IVB group (P < 0.05) with a mean SEQ of -8.0D ± 5.8D in the laser group versus -2.3D ± 4.2D in the IVB group (P < 0.001). Longitudinal SEQ were best fit with a bilinear model. Before one year, the rate of SEQ change was -5.0D/year in the laser group, but only -3.5D/year in the IVB group (T = -5.14, P < 0.001); after one year, there was a significant flattening of these slopes (T = 6.23, P < 0.001). Anisometropia in the IVB group was significantly less than in the laser group (P < 0.05). Final visual acuity in both groups was similar at 0.47 logMAR (∼ 20/60). Conclusions: Children with severe ROP treated with IVB developed less myopic refractive error than those treated with laser largely because of a slower rate of refractive change during the first year of life. Translational Relevance: These findings may inform decisions regarding ROP treatment timing and modality.

Confronting barriers to human-robot cooperation: balancing efficiency and risk in machine behavior.

Many technical and psychological challenges make it difficult to design machines that effectively cooperate with people. To better understand these challenges, we conducted a series of studies investigating human-human, robot-robot, and human-robot cooperation in a strategically rich resource-sharing scenario, which required players to balance efficiency, fairness, and risk. In these studies, both human-human and robot-robot dyads typically learned efficient and risky cooperative solutions when they could communicate. In the absence of communication, robot dyads still often learned the same efficient solution, but human dyads achieved a less efficient (less risky) form of cooperation. This difference in how people and machines treat risk appeared to discourage human-robot cooperation, as human-robot dyads frequently failed to cooperate without communication. These results indicate that machine behavior should better align with human behavior, promoting efficiency while simultaneously considering human tendencies toward risk and fairness.

First and last authorship by gender in emergency medicine publications- a comparison of 2008 vs. 2018.

BACKGROUND AND OBJECTIVES: Recently, investigators reported that there remain substantial disparities in the proportion of women within emergency medicine (EM) who have achieved promotion to higher academic rankings, received grant funding, and attained departmental leadership positions. In 2007, women were first authors on 24% of EM-based peer-reviewed articles. Currently, 28% of the academic EM physician workforce is comprised of women. The goal of this study was to identify whether the proportion of female first authors of original research published in three U.S.-based EM journals increased in 2018 as compared to 2008. METHODS: This was a retrospective review of published original research articles during 2008 and 2018 in the journals Academic Emergency Medicine (AEM), American Journal of Emergency Medicine (AJEM), and Annals of Emergency Medicine (Annals). Review articles, opinion pieces, consensus statements, practice recommendations based on current guidelines, and case reports were excluded from analysis. Investigators conducted a review of each article to identify the gender of the study's first and last authors. A study author blinded to the previous author's data abstraction reviewed a sample of 25 articles to assess for inter-rater reliability (kappa). Categorical data are presented as frequency of occurrence and analyzed by chi-square. RESULTS: Overall for the study journals, there were 368 original research articles published in 2008 vs. 580 in 2018. There were no significant differences noted for the proportion of female first author publications during 2008 vs 2018 overall (28% vs 30%; p = 0.38), within AJEM (29% vs 28%; p = 0.85), and observed at Annals (25% vs 24%; p = 0.82) respectively. However, there was a significant increase in the number of first author publications by females between the two periods within AEM (28% vs 45%; p < 0.01). There were no significant differences noted for the proportion of female last author publications during 2008 vs. 2018 overall (21% vs 22%; p = 0.70) and within each respective journal: AEM 22%% vs 26% (p = 0.51), AJEM 22% vs 19% (p = 0.55), and Annals 19% vs 22% (p = 0.20). Inter-rater reliability for author gender within the sample articles was excellent (0.83). CONCLUSION: While female physicians make up a disproportionate 28% of the academic workforce, we found that they were proportionally represented as first authors within several of the most prominent U.S.-based EM journals. Female resident physicians remain underrepresented as first authors and women remain underrepresented as last authors in the same journals.

Traumatic Radial Artery Pseudoaneurysm: Vein Graft Repair through a Single Incision.

Radial artery pseudoaneurysms are rare clinical entities usually occurring after penetrating trauma or iatrogenic injury. The radial artery is the least common location for peripheral artery pseudoaneurysms, and no clear standard of treatment exists. We present a case of an adolescent male who developed a radial artery pseudoaneurysm after slitting his wrists. Using a single incision, the radial artery pseudoaneurysm was excised and repaired using a reversed venae comitantes interposition graft. This single incision technique for radial artery pseudoaneurysm repair preserves the dual arterial supply to the hand, which is of particular importance in young patients.

Sensor-triggered sampling to determine instantaneous airborne vapor exposure concentrations.

It is difficult to measure transient airborne exposure peaks by means of integrated sampling for organic chemical vapors, even with very short-duration sampling. Selection of an appropriate time to measure an exposure peak through integrated sampling is problematic, and short-duration time-weighted average (TWA) values obtained with integrated sampling are not likely to accurately determine actual peak concentrations attained when concentrations fluctuate rapidly. Laboratory analysis for integrated exposure samples is preferred from a certainty standpoint over results derived in the field from a sensor, as a sensor user typically must overcome specificity issues and a number of potential interfering factors to obtain similarly reliable data. However, sensors are currently needed to measure intra-exposure period concentration variations (i.e., exposure peaks). In this article, the digitized signal from a photoionization detector (PID) sensor triggered collection of whole-air samples when toluene or trichloroethylene vapors attained pre-determined levels in a laboratory atmosphere generation system. Analysis by gas chromatography-mass spectrometry of whole-air samples (with both 37 and 80% relative humidity) collected using the triggering mechanism with rapidly increasing vapor concentrations showed good agreement with the triggering set point values. Whole-air samples (80% relative humidity) in canisters demonstrated acceptable 17-day storage recoveries, and acceptable precision and bias were obtained. The ability to determine exceedance of a ceiling or peak exposure standard by laboratory analysis of an instantaneously collected sample, and to simultaneously provide a calibration point to verify the correct operation of a sensor was demonstrated. This latter detail may increase the confidence in reliability of sensor data obtained across an entire exposure period.

A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14.

PURPOSE: Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. DESIGN: Cohort study. PARTICIPANTS: AREDS and AREDS2 participants. METHODS: AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. MAIN OUTCOME MEASURES: Genotype-phenotype associations. RESULTS: A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 × 10-7). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 × 10-4). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 × 10-7) and were more likely to have a first-degree relative with AMD (P = 5.38 × 10-6). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid (P = 2.29 × 10-11 and P = 3.20 × 10-9, respectively) and the center subfield (P = 1.24 × 10-9 and P = 6.68 × 10-8, respectively). SNP rs570618 was additionally associated with the presence of calcified drusen (P = 5.38 × 10-6). Except for positive family history of AMD with rs3750846, all genotype-phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. CONCLUSIONS: The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD.

Automatic analysis of the retinal avascular area in the rat oxygen-induced retinopathy model.

Purpose: The aim of this study was to create an algorithm to automate, accelerate, and standardize the process of avascular area segmentation in images from a rat oxygen-induced retinopathy (OIR) model. Methods: Within 6 h of birth, full-term pups born to Sprague Dawley rat dams that had undergone partial bilateral uterine artery ligation at embryonic day 19.5 were placed into a controlled oxygen environment (Oxycycler, BioSpherix, Parish, NY) at 50% oxygen for 48 h, followed by cycling between 10% and 50% oxygen every 24 h until day 15. The pups were then moved into room air until day 18.5. Ten lectin-stained retinal flat mounts were imaged in montage fashion at 10x magnification. Three masked human reviewers measured two parameters, total retinal area and peripheral avascular area, for each image using the ImageJ freehand selection tool. The outputs of each read were measured as number of pixels. The gold standard value for each image was the mean of the three human reads. Interrater agreement for the measurement of total retinal area, avascular area, and percent avascular area was calculated using type A intraclass correlation coefficients (ICCs) with a two-way random effects model. Automated avascular area identification (A3ID) is a method written in ImageJ Macro that is intended for use in the Fiji (Fiji is Just ImageJ) image processing platform. The input for A3ID is a rat retinal image, and the output is the avascular area (in pixels). A3ID utilizes a random forest classifier with a connected-components algorithm and post-processing filters for size and shape. A separate algorithm calculates the total retinal area. We compared the output of both algorithms to gold standard measurements by calculating ICCs, performing linear regression, and determining the Dice coefficients for both algorithms. We also constructed a Bland-Altman plot for A3ID output. Results: The ICC for percent peripheral avascular/total area between human readers was 0.995 (CI: 0.974-0.999), with p<0.001. The ICC between A3ID and the gold standard was calculated for three image parameters-avascular area: 0.974 (CI: 0.899-0.993), with p<0.001; total retinal area: 0.465 (CI: 0.0-0.851), with p=0.001; and the percent peripheral avascular/total area: 0.94 (CI: 0.326-0.989), with p<0.001. In the linear regression analysis, the slope for prediction of the gold standard percent peripheral avascular/total area from A3ID was 0.98, with R2=0.975. A3ID and the total retinal area algorithm achieve an average Dice coefficient of 0.891 and 0.952, respectively. The Bland-Altman analysis revealed a trend for computer underestimation of the peripheral avascular area in images with low peripheral avascular area and overestimation of peripheral avascular area in images with large peripheral avascular areas. Conclusions: A3ID reliably predicts peripheral avascular area based on rat OIR retinal images. When the peripheral avascular area is particularly high or low, hand segmentation of images may be superior.

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary 'VoxTox' research programme.

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.