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T-cell-engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T-cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using immune mobilizing monoclonal TCRs against cancer (ImmTAC) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the redirected T-cell response. This class of bispecifics binds specific target peptides presented by human leukocyte antigen on the cell surface via an affinity-enhanced T-cell receptor and can redirect T-cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T-cell activation, while strong affinity of both targeting and effector domains significantly reduces maximum cytokine release. Moreover, by optimizing the affinity of both parts of the molecule, it is possible to improve the selectivity. These results could be effectively modelled based on kinetic proofreading with limited signalling. This model explained the experimental observation that strong binding at both ends of the molecules leads to reduced activity, through very stable target-bispecific-effector complexes leading to CD3 entering a non-signalling dark state. These findings have important implications for the design of anti-CD3-based bispecifics with optimal biophysical parameters for both activity and specificity. These studies demonstrate how to optimize the fundamental process of T-cell activation, both in terms of affinity and binding kinetics to target cell and T-cell epitopes. Current theories of T-cell biology are used to build a mathematical model that explains most features of the data. How the kinetics of target and cluster of differentiation 3 binding regulate T-cell activation in the context of the clinically validated immune mobilizing monoclonal TCRs against cancer platform, which directly targets peptide-human leukocyte antigen complexes. [ABSTRACT FROM AUTHOR]

Grain yield and mineral nutrient concentration in cereal crops are usually inversely correlated, undermining biofortification efforts. Here, sink size, expressed as kernel number per cob, was manipulated by controlling the time when the silks of sweetcorn (Zea mays) cv. Hybrix 5 and var. HiZeax 103146 were exposed to pollen. Twelve other varieties were manually pollinated to achieve the maximum potential kernel number per cob, and kernel Zn concentration was correlated with kernel number and kernel mass. As kernel number increased, kernel Zn concentration decreased, with the decrease occurring to similar extents in the embryo tissue and the rest of the kernel. However, total kernel Zn accumulated per cob increased with increasing kernel number, as the small decreases in individual kernel Zn concentration were more than offset by increases in kernel number. When both kernel number and mass were considered, 90% of the variation in kernel Zn concentration was accounted for. Differential distribution of assimilates and Zn to sweetcorn cobs led to significant decreases in kernel Zn concentration with increasing kernel number. This suggests there will be challenges to achieving high kernel Zn concentrations in modern high-yielding sweetcorn varieties unless genotypes with higher Zn translocation rates into kernels can be identified. [ABSTRACT FROM AUTHOR]

Background and Aims Understanding the spatial distribution of inorganic nutrients within edible parts of plant products helps biofortification efforts to identify and focus on specific uptake pathways and storage mechanisms. Methods Kernels of sweetcorn (Zea mays) variety 'High zeaxanthin 103146' and maize inbred line 'Thai Floury 2' were harvested at two different maturity stages, and the distributions of K, P, S, Ca, Zn, Fe and Mn were examined in situ using synchrotron-based X-ray fluorescence microscopy. Key Results The distribution of inorganic nutrients was largely similar between maize and sweetcorn, but differed markedly depending upon the maturity stage after further embryonic development. The micronutrients Zn, Fe and Mn accumulated primarily in the scutellum of the embryo during early kernel development, while trace amounts of these were found in the aleurone layer at the mature stage. Although P accumulated in the scutellum, there was no direct relationship between the concentrations of P and those of the micronutrients, compared with the linear trend between Zn and Fe concentrations. Conclusions This study highlights the important role of the embryo as a micronutrient reserve for sweetcorn and maize kernels, and the need to understand how biofortification efforts can further increase the inorganic nutrient concentration of the embryo for human consumption. [ABSTRACT FROM AUTHOR]

Background: Navy Hospital Corpsmen (HMs) are the Navy equivalent to Emergency Medical Technicians (EMTs) both in-garrison and on the battlefield. In 2000, the Emergency Medical Services (EMS) Education Agenda for the Future highlighted the need for a single certification agency to provide consistent evaluation of entry level competence for each nationally recognized EMS provider level. Administered by the National Registry of EMTs (NREMT), National EMT Certification is currently utilized by 46 states, the District of Columbia, four territories, and six federal organizations as part of their processes for granting licensure. Unlike the Air Force (USAF) and Army (USA), the Navy (USN) does not require National EMT Certification to perform the duties equivalent to a civilian EMT. Our objective is to describe the number of USN HMs, USAF medics, and USA combat medics who have obtained National EMT Certification from 2007 through 2014.Methods: Results from all USN HMs, USAF medics, and USA combat medics who tested between January 1, 2007 and December 31, 2014 were queried from the NREMT database. Descriptive statistics were calculated based on a retrospective review of prospectively collected testing data.Results: During the study period, 89,136 Military Service Members received their EMT certification from the NREMT. The breakdown of the total and percent of total is; USA Combat Medics (n = 69,761; 78.3%), USAF Medics (n = 16,195; 18.1%), and USN HMs (n = 3,180; 3.6%). Approximately 4,000 HMs graduate yearly from the Department of Defense Medical Education and Training Campus at Fort Sam Houston, Texas and 253 HMs obtained certification in 2014.Conclusions: About 6.3% (253/4,000) HMs obtained National EMT Certification in 2014, which is a nationally recognized standard for entry-level competence utilized by civilian EMTs and other branches of the military. More information about those HMs that obtain certification may help Commanders maximize the number of HMs obtaining certification. Mandating National EMT Certification for HMs graduating from initial entry training would increase the numbers obtaining certification and bring them in line with USA, USAF, and national movement toward requiring certification for medical providers at all levels. [ABSTRACT FROM AUTHOR]

Introduction: As part of a Military Emergency Medical Services (EMS) system process improvement initiative, the authors sought to objectively evaluate the U.S. military EMS system for the island of Okinawa. They applied a program evaluation tool currently utilized by the U.S. National Park Service (NPS).Methods: A comprehensive needs assessment was conducted to evaluate the current Military EMS system in Okinawa, Japan. The NPS EMS Program Audit Worksheet was used to get an overall "score" of our assessment. After all the data had been collected, a joint committee of Military EMS physicians reviewed the findings and made formal recommendations.Results: From 2011 to 2014, U.S. military EMS on Okinawa averaged 1,345 ± 137 patient transports annually. An advanced life support (ALS) provider would have been dispatched on 558 EMS runs (38%) based on chief complaint in 2014 had they been available. Over 36,000 man-hours were expended during this period to provide National Registry Emergency Medical Technician (EMT)-accredited instruction to certify 141 Navy Corpsman as EMT Basics. The NPS EMS Program Audit Worksheet was used and the program scored a total of 31, suggesting the program is well planned and operating within standards.Conclusion: This evaluation of the Military EMS system on Okinawa using the NPS program assessment and audit worksheet demonstrates the NPS evaluation instruments may offer a useful assessment tool for the evaluation of Military EMS systems. [ABSTRACT FROM AUTHOR]

Trauma airway management is a critical skill for medical providers supporting combat casualties since it is an integral component of damage control resuscitation and surgery. This clinical practice guideline presents methods for optimizing the airway management of patients with traumatic injury in the operational medical treatment facility environment. The guidelines represent the knowledge and experience of 10 co-authors from 3 allied countries representing Emergency Medicine, Surgery and Anesthesia. [ABSTRACT FROM AUTHOR]

The article critiques the book "Canterbury Tales," by Geoffrey Chaucer, particularly asserting that the role of the lord's squire, Jankyn, in the chapter "Summoner's Tale," is that of a court fool. It provides an introduction of Chaucerian discourse of antifraternal satire in Jankyn, as well as notes the form and content of Jankyn's casuistry.

Introduction Military medics function similarly to civilian emergency medical technicians (EMTs); however, they perform their emergency medical care in combat zones and military treatment facilities. Both civilian and military EMTs must take and pass the National Registry of EMT's cognitive examination to be certified as a Nationally Registered EMT; however, there is a discrepancy in requirements for obtaining and maintaining National EMT Certification between the military branches of the DoD. In our study, we aimed to compare the performance of the U.S. Air Force (USAF), U.S. Army (USA), and U.S. Navy (USN) EMT candidates on the National EMT Certification cognitive examination from 2015 to 2017. Materials and Methods We performed a cross-sectional analysis of the National Registry of EMT's database for the examination results of all military EMT candidates who attempted the National EMT Certification cognitive examination between January 1, 2015, and December 31, 2017. First and cumulative third attempt pass rates and cognitive performance from mean ability estimates (MAEs) on the examination were assessed. Descriptive statistics were calculated and comparisons between branches with regard to passing rates and MAEs were made using chi-square tests and ANOVA, respectively, at the alpha level of 0.05. Results During the 3-year study period, a total of 3,642 USAF, 14,050 USA, and 1,187 USN candidates attempted the cognitive examination one or more times. The USA candidates demonstrated the highest first attempt pass rates (2015: 78%; 2016: 78%; and 2017: 81%) followed by the USAF candidates (2015: 58%; 2016: 62%; and 2017: 64%) and the USN candidates (2015: 41%; 2016: 56%; and 2017: 62%). The cumulative third attempt pass rates followed a similar trend (e.g. USA: 2015: 94%; 2016: 95%; and 2017: 96%). These differences by branch were statistically significant for each year (P  < .001). The overall test MAE scores also differed by branch, but only the USN candidates' MAE scores differed by year. The USA candidates demonstrated the highest MAE from 2015 to 2017 (523) followed by the USAF (489) and the USN (464) candidates. The overall test MAE scores for the USN candidates improved over the study period (2015: 449; 2016: 475; and 2017: 479, P  < .001). Conclusion Military EMT candidates had different performances on the EMT cognitive examination between branches. The USA candidates demonstrated higher pass rates and cognitive performance on the examination compared to their counterparts from the USAF and USN from 2015 to 2017. Further work should be directed at defining the cause of the differences in military EMT candidate performance and determining the characteristics that impact these differences. [ABSTRACT FROM AUTHOR]

Background: Navy medical personnel have been recording en route care (ERC) missions through Search and Rescue (SAR) reports since the 1970's. Our objective was to report clinical ERC cases treated by Navy operational assets from January 2012 to January 2015.Methods: The Search and Rescue Model Manager office collects SAR reports for all patient transports involving Navy personnel and equipment. From these reports, descriptive statistics to include total number of patients transported, percentages of Advanced Life Support versus Basic Life Support transports, time of transport, and type of ERC provider for the transport were collected. Data reported as median (interquartile range) or percentages.Results: During a 3-year period, 428 patients were transported. Transport time was 54 (30-78) minutes. Missions were staffed by more than one provider 22% of the time. Individual providers included 76% Search and Rescue Medical Technicians, 25% Flight Surgeons, and 21% Other. Patients required ALS transport 54% of the time. Less than half (48%) of the patients were trauma related.Conclusion: In our review of 428 SAR reports from Navy ERC (2012-2015), we found that 76% of the missions were performed by Search and Rescue Medical Technicians and 54% met Advanced Life Support transport criteria. [ABSTRACT FROM AUTHOR]