Freeform Extrusion of High Solids Loading Ceramic Slurries, Part I: Extrusion Process Modeling

A novel solid freeform fabrication method has been developed for the manufacture of ceramic-based components in an environmentally friendly fashion. The method is based on the extrusion of ceramic slurries using water as the binding media. Aluminum oxide (Al2O3) is currently being used as the part material and solids loading as high as 60 vol. % has been achieved. This paper describes a manufacturing machine that has been developed for the extrusion of high solids loading ceramic slurries. A critical component of the machine is the deposition system, which consists of a syringe, a plunger, a ram actuated by a motor that forces the plunger down to extrude material, and a load cell to measure the extrusion force. An empirical, dynamic model of the ceramic extrusion process, where the input is the commanded ram velocity and the output is the extrusion force, is developed. Several experiments are conducted and empirical modeling techniques are utilized to construct the dynamic model. The results demonstrate that the ceramic extrusion process has a very slow dynamic response, as compared to other non-compressible fluids such as water. A substantial amount of variation exists in the ceramic extrusion process, most notably in the transient dynamics, and a constant ram velocity may either produce a relatively constant steady-state extrusion force or it may cause the extrusion force to steadily increase until the ram motor skips. The ceramic extrusion process is also subjected to significant disturbances such as air bubble release, which causes a dramatic decrease in the extrusion force, and nozzle clogging, which causes the extrusion force to slowly increase until the clog is released or the ram motor skips.Mechanical Engineerin

Freeform Extrusion of High Solids Loading Ceramic Slurries, Part II: Extrusion Process Control

Part I of this paper provided a detailed description of a novel fabrication machine for high solids loading ceramic slurry extrusion and presented an empirical model of the ceramic extrusion process, with ram velocity as the input and extrusion force as the output. A constant force is desirable in freeform extrusion processes as it correlates with a constant material deposition rate and, thus, good part quality. The experimental results in Part I demonstrated that a constant ram velocity will produce a transient extrusion force. In some instances the extrusion force increased until ram motor skipping occurred. Further, process disturbances, such as air bubble release and nozzle clogging that cause sudden changes in extrusion force, were often present. In this paper a feedback controller for the ceramic extrusion process is designed and experimentally implemented. The controller intelligently adjusts the ram motor velocity to maintain a constant extrusion force. Since there is tremendous variability in the extrusion process characteristics, an on-off controller is utilized in this paper. Comparisons are made between parts fabricated with and without the feedback control. It is demonstrated that the use of the feedback control reduces the effect of process disturbances (i.e., air bubble release and nozzle clogging) and dramatically improves part quality.Mechanical Engineerin

Educating Future Nursing Scientists: Recommendations for Integrating Omics Content in PhD Programs

Preparing the next generation of nursing scientists to conduct high-impact, competitive, sustainable, innovative, and interdisciplinary programs of research requires that the curricula for PhD programs keep pace with emerging areas of knowledge and health care/biomedical science. A field of inquiry that holds great potential to influence our understanding of the underlying biology and mechanisms of health and disease is omics. For the purpose of this article, omics refers to genomics, transcriptomics, proteomics, epigenomics, exposomics, microbiomics, and metabolomics. Traditionally, most PhD programs in schools of nursing do not incorporate this content into their core curricula. As part of the Council for the Advancement of Nursing Science\u27s Idea Festival for Nursing Science Education, a work group charged with addressing omics preparation for the next generation of nursing scientists was convened. The purpose of this article is to describe key findings and recommendations from the work group that unanimously and enthusiastically support the incorporation of omics content into the curricula of PhD programs in nursing. The work group also calls to action faculty in schools of nursing to develop strategies to enable students needing immersion in omics science and methods to execute their research goals

Domain-based perceptions of risk:a case study of lay and technical community attitudes towards managed aquifer recharge

Despite growing water scarcity, communities in many parts of the developed world often reject technically and economically sound options for water augmentation. This paper reports findings from a study investigating risk perceptions associated with a proposed Managed Aquifer Recharge scheme in Australia. Q-Methodology was used to compare decision-making frameworks of lay community and „technical expert‟ participants. Technical expert participants were also asked to approximate the decision-making framework of a „typical‟ community member. The emerging contrasts between lay community frameworks and those approximated by technical experts suggest that there are prevailing yet errant assumptions about lay community attitudes towards new technologies. The findings challenge the characterisation of the lay community and technical experts as being in entrenched opposition with one another

457 KEYNOTE-495/KeyImPaCT: interim analysis of a randomized, biomarker-directed, phase 2 trial of pembrolizumab-based combination therapy for non–small cell lung cancer (NSCLC)

BackgroundT-cell–inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) are clinically validated biomarkers that independently predict pembrolizumab response. This study investigated prospective TcellinfGEP and TMB assessment in evaluating first-line pembrolizumab-based combination therapies; the different treatment combinations evaluated may provide insight into the unique biology of each biomarker subgroup.MethodsKEYNOTE-495/KeyImPaCT is a group-sequential, adaptively randomized, multisite, open-label, phase 2 study investigating first-line pembrolizumab plus the VEGF/FGFR inhibitor lenvatinib, CTLA-4 inhibitor quavonlimab (MK-1308), or LAG-3 inhibitor favezelimab (MK-4280) in patients with advanced NSCLC. DNA and RNA were extracted from tumor tissue to determine TcellinfGEP and TMB; patients were assigned to one of four biomarker-defined subgroups (TcellinfGEPlowTMBlow, TcellinfGEPlowTMBhigh, TcellinfGEPhighTMBlow, TcellinfGEPhighTMBhigh) and randomly assigned 1:1:1 to receive pembrolizumab (200mg IV Q3W)+lenvatinib (20mg oral QD), pembrolizumab+quavonlimab (75mg IV Q6W), or pembrolizumab+favezelimab (200mg [n=30] or 800mg [n=34] Q3W; the initial prespecified dose was 200mg but changed to 800mg based on emerging data). The primary end point was investigator-assessed ORR per RECIST v1.1. Multiple interim analyses will be performed until the prespecified clinical signal is observed. The first interim analysis for each combination therapy occurred after ≥10 patients had ≥12 weeks of follow-up.ResultsAt the data cutoff (January 11, 2021), 208 patients were treated (pembrolizumab+lenvatinib, n=72; pembrolizumab+quavonlimab, n=72; pembrolizumab+favezelimab 200mg, n=30; pembrolizumab+favezelimab 800mg, n=34). The overall assay success rate for testing and determining TcellinfGEP and TMB was 94%. In patients treated with pembrolizumab+lenvatinib, pembrolizumab+quavonlimab, or pembrolizumab+favezelimab, ORRs were generally highest in the TcellinfGEPhighTMBhigh subgroup (table 1); response rates were similar across combinations within this subgroup. ORR was low across combinations within the TcellinfGEPlowTMBlow subgroup. Treatment-related adverse events (TRAEs) occurred in 88%, 65%, 57%, and 59% of patients in the pembrolizumab+lenvatinib, pembrolizumab+quavonlimab, pembrolizumab+favezelimab 200mg and pembrolizumab+favezelimab 800mg arms, respectively. Consistent with the known TRAEs of these agents, most TRAEs were grade 1 or 2 in severity except in the pembrolizumab+lenvatinib arm (grade 3–5, 63%). Three deaths from TRAEs occurred (pembrolizumab+lenvatinib [n=2], brain hemorrhage and myocardial infarction; pembrolizumab+favezelimab 800 mg [n=1], pneumonitis).Abstract 457 Table 1Confirmed ORR by Therapy and Biomarker StatusConclusionsThese data demonstrate the feasibility and clinical usefulness of prospective TcellinfGEP and TMB assessment to study the clinical activity of three first-line pembrolizumab-based combination therapies in patients with advanced NSCLC. Although sample sizes were small, the TcellinfGEPhighTMBhigh subgroup demonstrated the best response among the biomarker subgroups for all three combination therapies; further validation is needed to determine additional signals and may be addressed as more mature data become available.AcknowledgementsJeanne Fahey, PhD, of Merck & Co., Inc., Kenilworth, New Jersey, USA, provided critical review of the abstract. Elisha Dettman PhD, Mark Ayers MS, and Andrey Loboda PhD of Merck & Co., Inc., Kenilworth, New Jersey, USA, provided critical review of study translational data. Medical writing and/or editorial assistance was provided by Shane Walton, PhD, and Lei Bai, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicalTrials.gov, NCT03516981Ethics ApprovalThe study protocol and all amendments were approved by the relevant institutional review board or ethics committee at each study site. All patients provided written informed consent to participate in the clinical trial

The Relationship between Anthropometry and Split Performance in Recreational Male Ironman Triathletes

Purpose: The aim of this study was to investigate the relation between anthropometric variables and total race time including split times in 184 recreational male Ironman triathletes. Methods: Body mass, body height, body mass index, lengths and circumferences of limbs, thicknesses of skin-folds, sum of skin-fold thicknesses, and percent body fat were related to total race time including split times using correlation analysis and effect size. Results: A large effect size (r>0.37) was found for the association between body mass index and time in the run split and between both the sum of skin-folds and percent body fat with total race time. A medium effect size (r=0.24-0.36) was observed in the association between body mass and both the split time in running and total race time, between body mass index and total race time, between both the circumferences of upper arm and thigh with split time in the run and between both the sum of skin-folds and percent body fat with split times in swimming, cycling and running. Conclusions: The results of this study showed that lower body mass, lower body mass index and lower body fat were associated with both a faster Ironman race and a faster run split; lower circumferences of upper arm and thigh were also related with a faster run split

5′UTR Variants of Ribosomal Protein S19 Transcript Determine Translational Efficiency: Implications for Diamond-Blackfan Anemia and Tissue Variability

Background: Diamond-Blackfan anemia (DBA) is a lineage specific and congenital erythroblastopenia. The disease is associated with mutations in genes encoding ribosomal proteins resulting in perturbed ribosomal subunit biosynthesis. The RPS19 gene is mutated in approximately 25 % of DBA patients and a variety of coding mutations have been described, all presumably leading to haploinsufficiency. A subset of patients carries rare polymorphic sequence variants within the 59untranslated region (59UTR) of RPS19. The functional significance of these variants remains unclear. Methodology/Principal Findings: We analyzed the distribution of transcriptional start sites (TSS) for RPS19 mRNAs in testis and K562 cells. Twenty-nine novel RPS19 transcripts were identified with different 59UTR length. Quantification of expressed w.t. 59UTR variants revealed that a short 59UTR correlates with high levels of RPS19. The total levels of RPS19 transcripts showed a broad variation between tissues. We also expressed three polymorphic RPS19 59UTR variants identified in DBA patients. The sequence variants include two insertions (c.-147_-146insGCCA and c.-147_-146insAGCC) and one deletion (c.-144_-141delTTTC). The three 59UTR polymorphisms are associated with a 20–30 % reduction in RPS19 protein levels when compared to the wild-type (w.t.) 59UTR of corresponding length. Conclusions: The RPS19 gene uses a broad range of TSS and a short 59UTR is associated with increased levels of RPS19. Comparisons between tissues showed a broad variation in the total amount of RPS19 mRNA and in the distribution of TS

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Maternal hormonal milieu influence on fetal brain development

An adverse maternal hormonal environment during pregnancy can be associated with abnormal brain growth. Subtle changes in fetal brain development have been observed even for maternal hormone levels within the currently accepted physiologic ranges. In this review, we provide an update of the research data on maternal hormonal impact on fetal neurodevelopment, giving particular emphasis to thyroid hormones and glucocorticoids. Thyroid hormones are required for normal brain development. Despite serum TSH appearing to be the most accurate indicator of thyroid function in pregnancy, maternal serum free T4 levels in the first trimester of pregnancy are the major determinant of postnatal psychomotor development. Even a transient period of maternal hypothyroxinemia at the beginning of neurogenesis can confer a higher risk of expressive language and nonverbal cognitive delays in offspring. Nevertheless, most recent clinical guidelines advocate for targeted high-risk case finding during first trimester of pregnancy despite universal thyroid function screening. Corticosteroids are determinant in suppressing cell proliferation and stimulating terminal differentiation, a fundamental switch for the maturation of fetal organs. Not surprisingly, intrauterine exposure to stress or high levels of glucocorticoids, endogenous or synthetic, has a molecular and structural impact on brain development and appears to impair cognition and increase anxiety and reactivity to stress. Limbic regions, such as hippocampus and amygdala, are particularly sensitive. Repeated doses of prenatal corticosteroids seem to have short-term benefits of less respiratory distress and fewer serious health problems in offspring. Nevertheless, neurodevelopmental growth in later childhood and adulthood needs further clarification. Future studies should address the relevance of monitoring the level of thyroid hormones and corticosteroids during pregnancy in the risk stratification for impaired postnatal neurodevelopment.This work was supported by the grant "Doutoramento em Medicina Jose de Mello Saude 2014" by Jose de Mello Saude to AM