Stability of Ocular Alignment After Teprotumumab Therapy in a Cohort of Patients With Thyroid Eye Disease and Baseline Diplopia.

BACKGROUND: Teprotumumab is a monoclonal antibody that is effective in treating patients with thyroid eye disease (TED) and has been shown to produce subjective improvements in diplopia in this group. The aims of this study were to evaluate the rate and timing of recurrence/worsening of diplopia after teprotumumab treatment in a cohort of patients with TED presenting with diplopia at baseline. METHODS: A retrospective chart review of 15 patients with diplopia secondary to TED, treated with teprotumumab, was conducted in a single-center academic institution. The primary outcome was the rate of recurrence/worsening of diplopia after completing teprotumumab. Secondary outcomes include the time to recurrence/worsening of diplopia and clinical activity scores (CAS) to correlate with changes in ocular alignment. RESULTS: Fifteen patients met the inclusion criteria for this study, and 7 of these had recurrence of diplopia (46.7%). Two patients had worsening of CAS to ≥4, 6 had worsening of CAS to 3, and the other 7 had CAS ≤2 during the follow-up period. The mean follow-up period was 20.4 months (SD 7.2) after completing teprotumumab. The mean time to diplopia recurrence/worsening was 8.8 months (range 6.7-12.2, SD 1.8). CONCLUSIONS: Patients with TED and baseline diplopia have a substantial rate of recurrence/worsening of diplopia after teprotumumab therapy, suggesting that they may not have stable ocular alignment immediately after treatment. Strabismus surgeons may need to weigh the significant risk of disease relapse when planning optimum timing for surgical correction.

Big Data Analysis of Inflammatory Conditions Associated With Optic Neuritis.

BACKGROUND: Previous studies in the United States established multiple sclerosis (MS) as the most common cause of optic neuritis (ON). ON can be associated with other systemic inflammatory conditions including sarcoidosis, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and lupus; however, prospective studies to establish risk of ON associated with these diseases are lacking. Furthermore, appropriate workup for ON is still debated. METHODS: A deidentified electronic medical record of a tertiary care academic center was searched for ON and rheumatologic/neuro-inflammatory diseases in the medical history, diagnoses, and laboratory results; followed by the intersection of ON with each condition. We calculated frequency of systemic conditions among patients with ON and prevalence of ON in those conditions. We also calculated relative risk (RR) of underlying systemic conditions among patients with ON compared with the study patient population. RESULTS: In 6.7 million charts, 5,344 cases of ON were identified. Among those, MS occurred most commonly (20.6%), followed by NMOSD (10.5%). Conversely, ON occurred in 98.4% of NMOSD cases, 53.3% of MOGAD, and 10.0% of MS. NMOSD (RR = 1,233), MOGAD (RR = 688), and MS (RR = 126) had the highest RR among the conditions we evaluated. The subset analysis showed similar findings. CONCLUSIONS: The high RR for ON among patients with NMOSD and MOGAD suggests that clinical suspicion for ON should be high among patients with these conditions presenting with vision changes. Conversely, MS and NMOSD should initially be high on the differential diagnosis for any patient presenting with optic neuritis.

Image-Based Phenotyping of Flowering Intensity in Cool-Season Crops.

The timing and duration of flowering are key agronomic traits that are often associated with the ability of a variety to escape abiotic stress such as heat and drought. Flowering information is valuable in both plant breeding and agricultural production management. Visual assessment, the standard protocol used for phenotyping flowering, is a low-throughput and subjective method. In this study, we evaluated multiple imaging sensors (RGB and multiple multispectral cameras), image resolution (proximal/remote sensing at 1.6 to 30 m above ground level/AGL), and image processing (standard and unsupervised learning) techniques in monitoring flowering intensity of four cool-season crops (canola, camelina, chickpea, and pea) to enhance the accuracy and efficiency in quantifying flowering traits. The features (flower area, percentage of flower area with respect to canopy area) extracted from proximal (1.6-2.2 m AGL) RGB and multispectral (with near infrared, green and blue band) image data were strongly correlated (r up to 0.89) with visual rating scores, especially in pea and canola. The features extracted from unmanned aerial vehicle integrated RGB image data (15-30 m AGL) could also accurately detect and quantify large flowers of winter canola (r up to 0.84), spring canola (r up to 0.72), and pea (r up to 0.72), but not camelina or chickpea flowers. When standard image processing using thresholds and unsupervised machine learning such as k-means clustering were utilized for flower detection and feature extraction, the results were comparable. In general, for applicability of imaging for flower detection, it is recommended that the image data resolution (i.e., ground sampling distance) is at least 2-3 times smaller than that of the flower size. Overall, this study demonstrates the feasibility of utilizing imaging for monitoring flowering intensity in multiple varieties of evaluated crops.

Population Genomic Analysis Reveals Differential Evolutionary Histories and Patterns of Diversity across Subgenomes and Subpopulations of Brassica napus L.

The allotetraploid species Brassica napus L. is a global crop of major economic importance, providing canola oil (seed) and vegetables for human consumption and fodder and meal for livestock feed. Characterizing the genetic diversity present in the extant germplasm pool of B. napus is fundamental to better conserve, manage and utilize the genetic resources of this species. We used sequence-based genotyping to identify and genotype 30,881 SNPs in a diversity panel of 782 B. napus accessions, representing samples of winter and spring growth habits originating from 33 countries across Europe, Asia, and America. We detected strong population structure broadly concordant with growth habit and geography, and identified three major genetic groups: spring (SP), winter Europe (WE), and winter Asia (WA). Subpopulation-specific polymorphism patterns suggest enriched genetic diversity within the WA group and a smaller effective breeding population for the SP group compared to WE. Interestingly, the two subgenomes of B. napus appear to have different geographic origins, with phylogenetic analysis placing WE and WA as basal clades for the other subpopulations in the C and A subgenomes, respectively. Finally, we identified 16 genomic regions where the patterns of diversity differed markedly from the genome-wide average, several of which are suggestive of genomic inversions. The results obtained in this study constitute a valuable resource for worldwide breeding efforts and the genetic dissection and prediction of complex B. napus traits.

Maintenance of Certification Part 4 Credit and recruitment for practice-based research.

BACKGROUND: Competing priorities in pediatric practice have created challenges for practice-based research. To increase recruitment success, researchers must design studies that provide added value to participants. This study evaluates recruitment of pediatricians into a study, before and after the development and addition of a quality improvement (QI) curriculum approved for American Board of Pediatrics Maintenance of Certification (MOC) Part 4 Credit as an enrollment incentive. METHODS: Researchers implemented multiple outreach methods to enroll pediatric practices over 28 months. Field note review revealed that many physicians declined enrollment, stating that they prioritized MOC Part 4 projects over research studies. A QI curriculum meeting standards for MOC Part 4 Credit was developed and added to the study protocol as an enrollment incentive. Enrollment rates and characteristics of practitioners enrolled pre- and post-MOC were compared. RESULTS: Pre-MOC enrollment contributed 48% of practices in 22 months; post-MOC enrollment contributed 49% of practices in 6 months. An average of 3.5 practices enrolled per month pre-MOC, compared with 13.1 per month post-MOC (P < .001). Clinicians in pre- and post-MOC groups were similar in age, gender, race, and time spent on patient care; practices enrolled post-MOC were more likely to be located in federally designated Medically Underserved Areas than those enrolled pre-MOC (28.6% vs 12%, P = .03). CONCLUSIONS: Addition of MOC Part 4 Credit increased recruitment success and increased enrollment of pediatricians working in underserved areas. Including QI initiatives meeting MOC Part 4 criteria in practice-based research protocols may enhance participation and aid in recruiting diverse practice and patient populations.

Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model.

PURPOSE: Targeting epidermal growth factor receptor (EGFR) overexpressed by many epithelial-derived cancer cells with anti-EGFR monoclonal antibodies (mAb) inhibits their growth. A limited number of clinical responses in patients treated with the anti-EGFR mAb, (cetuximab), may reflect variability in EGFR type or signaling in neoplastic cells. This study combines EGFR-targeting with the non-MHC-restricted cytotoxicity of anti-CD3 activated T cells (ATC) to enhance receptor-directed cytotoxicity. EXPERIMENTAL DESIGN: ATC from normal and patient donors were expanded ex vivo. Specific cytolytic activity of ATC armed with anti-CD3 x anti-EGFR (EGFRBi) against EGFR-expressing cancer cells derived from lung, pancreas, colon, prostate, brain, skin, or EGFR-negative breast cancer cells was evaluated in (51)Cr release assays. In vivo studies comparing tumor growth delay induced by EGFRBi-armed ATCs or cetuximab were done in severe combined immunodeficient/Beige mice (SCID-Beige) bearing COLO 356/FG pancreatic and LS174T colorectal tumors. RESULTS: At effector/target ratios from 3.125 to 50, both EGFRBi-armed normal and patient ATC were significantly more cytotoxic, by 23% to 79%, against EGFR-positive cells over ATC, cetuximab, anti-CD3 alone, or ATC armed with irrelevant BiAb directed at CD20. EGFRBi-armed ATC also secreted significantly higher levels of some T(H1)/T(H2) cytokines compared with ATC alone. In mice, i.v. infusions of EGFRBi-armed ATC (0.001 mg equivalent/infusion) were equally effective as cetuximab (1 mg/infusion) alone for significantly delaying growth of established COLO 356/FG but not LS174T tumors compared with mice that received ATC alone or vehicle (P < 0.001). CONCLUSIONS: Combining EGFR antibody targeting with T cell-mediated cytotoxicity may overcome some limitations associated with EGFR-targeting when using cetuximab alone.

Preclinical studies comparing different bispecific antibodies for redirecting T cell cytotoxicity to extracellular antigens on prostate carcinomas.

INTRODUCTION: Bispecific antibodies (BiAbs) are used to enhance targeting of T cells and other cytotoxic agents to tumors while minimizing non-specific tissue toxicities. This study compares the targeting efficacy of 3 BiAbs derived from chemically heteroconjugating a T cell-directed monoclonal antibody (mAb) to 9184, 9187 or 9189, which are mAbs directed at extracellular antigens expressed on human prostate carcinoma cell lines. MATERIALS AND METHODS: 9184 (anti-Her2/neu), 9187 (anti-gp55) and 9189 (anti-gp42) were each heteroconjugated to anti-CD3 to produce BiAbs capable of binding to ("arming") anti-CD3 activated T cells (ATC) and redirecting their cytotoxicity to prostate cancer cells expressing the respective antigen. ATC from cancer patients and/or normal subjects were armed with each BiAb and tested in co-cultures with PC-3, DU 145, and LNCaP cells for binding, cytotoxicity, and cytokine secretion. RESULTS: All 3 tumor-directed mAbs bound to each of the prostate cancer cell lines. ATC armed with 9184Bi statistically augmented cytotoxicity directed at PC-3 and increased IFN-gamma, TNF-alpha, and GM-CSF secretion as well as induced IFN-gamma EliSpots above that seen for 9187Bi, 9189Bi, ATC alone or ATC armed with an irrelevant BiAb. 9184Bi-armed ATC mediated significant cytotoxicity against LNCaP and DU 145 cells as well. When we armed ATC from 6 cancer patients with 9184Bi, 9184Bi markedly enhanced cytotoxicity of ATC from 5 of the 6 patients. CONCLUSION: Arming ATC with BiAbs augments cytotoxicity directed at prostate cancer lines expressing the target antigens. Arming with 9184Bi was the most effective at redirecting cytotoxicity at PC-3 cells and inducing cytokine secretion. As an alternative to mAb therapy with anti-HER2, the HER2 antigen may provide a suitable target for redirecting anti-cancer immune cells, immunobiologicals, or other agents to HRPC.

Yield reduction in Brassica napus, B. rapa, B. juncea, and Sinapis alba caused by flea beetle (Phyllotreta cruciferae (Goeze) (Coleoptera: Chrysomelidae)) infestation in northern Idaho.

Phyllotreta cruciferae is an important insect pest of spring-planted Brassica crops, especially during the seedling stage. To determine the effect of early season P. cruciferae infestation on seed yield, 10 genotypes from each of two canola species (Brassica napus L. and Brassica rapa L.) and two mustard species (Brassica juncea L. and Sinapis alba L.) were grown in 2 yr under three different P. cruciferae treatments: (1) no insecticide control; (2) foliar applications of endosulfan; and (3) carbofuran with seed at planting plus foliar application of carbaryl. Averaged over 10 genotypes, B. rapa showed most visible P. cruciferae injury and showed greatest yield reduction without insecticide application. Mustard species (S. alba and B. juncea) showed least visible injury and higher yield without insecticide compared with canola species (B. napus and B. rapa). Indeed, average seed yield of S. alba without insecticide was higher than either B. napus or B. rapa with most effective P. cruciferae control. Significant variation occurred within each species. A number of lines from B. napus, B. juncea, anid S. alba showed less feeding injury and yield reduction as a result of P. cruciferae infestation compared with other lines from the same species examined, thus having potential genetic background for developing resistant cultivars.

Treatment of otitis media with observation and a safety-net antibiotic prescription.

OBJECTIVE: Several studies have demonstrated that acute otitis media (AOM) in children can be managed without antibiotics. Because children with AOM have traditionally been treated with antibiotics in the United States, there are concerns that parents may not be comfortable with their children being treated with pain control alone. Recently, Cates in England showed that antibiotic usage for AOM could be decreased by prescribing a safety-net antibiotic prescription (SNAP) to be filled if symptoms do not resolve with observation after 48 hours. It is not clear whether a SNAP will be acceptable to parents in other settings such as the United States. The objective of our study was to determine whether parents in the United States find a SNAP for AOM acceptable and whether antibiotic usage could be decreased by its use. METHODS: A pediatric practice-based research network in a midwestern community of 1.8 million was the setting for this study. The Cincinnati Pediatric Research Group (CPRG) includes practices in Ohio, Kentucky, and Indiana. Children who were between 1 and 12 years of age and presented to the offices of the CPRG with uncomplicated AOM were eligible for the study. Children were excluded when they had temperature >101.5 degrees F, had an ear infection in the past 3 months, showed signs of another bacterial infection, or were toxic appearing. Families were given acetaminophen, ibuprofen, or topical otic anesthetic drops for pain control. They were also given a prescription for an antibiotic and instructed not to fill it unless symptoms either increased or did not resolve after 48 hours. The data were entered directly by investigators via an Internet site. RESULTS: A total of 194 children were enrolled in 11 offices over 12 months; 175 (90%) completed the follow-up interview. The average child's age was 5.0 years. Only 55 (31%) of the 175 who were contacted for follow-up had filled their antibiotic prescription. Compared with their previous experience, parents were overwhelmingly willing to treat AOM with pain medication alone (chi(2) = 111). Seventy-eight percent (95% confidence interval: 71%-84%) of parents reported that the pain medication was effective. Sixty-three percent (95% confidence interval: 55%-70%) of parents reported that they would be willing to treat future AOM episodes without antibiotics and with pain medication alone. CONCLUSIONS: A subset of parents find a safety-net prescription and pain control acceptable in the treatment of AOM, and antibiotic usage can be lowered with this strategy.