Rapid manufacturing- state of the art, analysis and future perspectives

Layer based manufacturing system often referred to as Rapid Prototyping (RP) have been in existence for 22 years, in the past 5 years Rapid Manufacturing (RM) has emerged from these RP systems to produce functional and structural customer focused end use components and products. This keynote paper will review the current range of technologies for metallic systems, it will also evaluate the operating principles, features, potential and limitations of current commercially available systems. Rapid Manufacture is increasingly being used for high value difficult to manufacture components with a new set of design rules required to fully exploit the RM systems inherent characteristics. A case studies approach will be used to show the benefits and pitfalls this new design freedom can provide designers

Validation and clinical implementation of an accurate Monte Carlo code for pencil beam scanning proton therapy.

Monte Carlo (MC)-based dose calculations are generally superior to analytical dose calculations (ADC) in modeling the dose distribution for proton pencil beam scanning (PBS) treatments. The purpose of this paper is to present a methodology for commissioning and validating an accurate MC code for PBS utilizing a parameterized source model, including an implementation of a range shifter, that can independently check the ADC in commercial treatment planning system (TPS) and fast Monte Carlo dose calculation in opensource platform (MCsquare). The source model parameters (including beam size, angular divergence and energy spread) and protons per MU were extracted and tuned at the nozzle exit by comparing Tool for Particle Simulation (TOPAS) simulations with a series of commissioning measurements using scintillation screen/CCD camera detector and ionization chambers. The range shifter was simulated as an independent object with geometric and material information. The MC calculation platform was validated through comprehensive measurements of single spots, field size factors (FSF) and three-dimensional dose distributions of spread-out Bragg peaks (SOBPs), both without and with the range shifter. Differences in field size factors and absolute output at various depths of SOBPs between measurement and simulation were within 2.2%, with and without a range shifter, indicating an accurate source model. TOPAS was also validated against anthropomorphic lung phantom measurements. Comparison of dose distributions and DVHs for representative liver and lung cases between independent MC and analytical dose calculations from a commercial TPS further highlights the limitations of the ADC in situations of highly heterogeneous geometries. The fast MC platform has been implemented within our clinical practice to provide additional independent dose validation/QA of the commercial ADC for patient plans. Using the independent MC, we can more efficiently commission ADC by reducing the amount of measured data required for low dose "halo" modeling, especially when a range shifter is employed

Physician and Nurse Perspectives of an Interprofessional and Integrated Primary Care-Based Program for Seniors

Background: In Canada, primary care practitioners provide the majority of care for elderly patients. Increasing volume and complexity of care compounded by a shortage of specialized geriatric services has lead to problems of fragmented, inefficient,and often ineffective service for this population. Integrated models that bridge primary and secondary care have emerged as a major theme in health reform to address such challenges for care of the elderly. Although primary care practitioners are important stakeholders necessary for successful uptake and sustainability of such integrated models, this perspective has been largely unexplored. Methods and Findings: We used a qualitative thematic approach to bring forward front-line perspectives of nurses and physicians who referred their patients to a newly developed integrated, multidisciplinary program for seniors that was introduced into their primary care clinic. Referrers experienced improved care processes, improved quality of care, as well as an enhanced experience when managing their elderly patients. Unclear assignment of roles and responsibilities created confusion for referring practitioners and their patients.Conclusions: Understanding benefits, limitations, and changes to front-line practitioner experience provides insight into important factors contributing to buy-in and sustainability of integrated programming for the elderly in this setting

Enhanced Locomotion Caused by Loss of the Drosophila DEG/ENaC Protein Pickpocket1

AbstractCoordination of rhythmic locomotion depends upon a precisely balanced interplay between central and peripheral control mechanisms [1]. Although poorly understood, peripheral proprioceptive mechanosensory input is thought to provide information about body position for moment-to-moment modifications of central mechanisms mediating rhythmic motor output [2]. Pickpocket1 (PPK1) is a Drosophila subunit of the epithelial sodium channel (ENaC) family displaying limited expression in multiple dendritic (md) sensory neurons tiling the larval body wall and a small number of bipolar neurons in the upper brain [3]. ppk1 null mutant larvae had normal external touch sensation and md neuron morphology but displayed striking alterations in crawling behavior. Loss of PPK1 function caused an increase in crawling speed and an unusual straight path with decreased stops and turns relative to wild-type. This enhanced locomotion resulted from sustained peristaltic contraction wave cycling at higher frequency with a significant decrease in pause period between contraction cycles. The mutant phenotype was rescued by a wild-type PPK1 transgene and duplicated by expressing a ppk1RNAi transgene or a dominant-negative PPK1 isoform. These results demonstrate that the PPK1 channel plays an essential role in controlling rhythmic locomotion and provide a powerful genetic model system for further analysis of central and peripheral control mechanisms and their role in movement disorders

Evaluating the Plausible Range of N2O Biosignatures on Exo-Earths: An Integrated Biogeochemical, Photochemical, and Spectral Modeling Approach

Nitrous oxide (N2O) -- a product of microbial nitrogen metabolism -- is a compelling exoplanet biosignature gas with distinctive spectral features in the near- and mid-infrared, and only minor abiotic sources on Earth. Previous investigations of N2O as a biosignature have examined scenarios using Earthlike N2O mixing ratios or surface fluxes, or those inferred from Earth's geologic record. However, biological fluxes of N2O could be substantially higher, due to a lack of metal catalysts or if the last step of the denitrification metabolism that yields N2 from N2O had never evolved. Here, we use a global biogeochemical model coupled with photochemical and spectral models to systematically quantify the limits of plausible N2O abundances and spectral detectability for Earth analogs orbiting main-sequence (FGKM) stars. We examine N2O buildup over a range of oxygen conditions (1%-100% present atmospheric level) and N2O fluxes (0.01-100 teramole per year; Tmol = 10^12 mole) that are compatible with Earth's history. We find that N2O fluxes of 10 [100] Tmol yr$^{-1}$ would lead to maximum N2O abundances of ~5 [50] ppm for Earth-Sun analogs, 90 [1600] ppm for Earths around late K dwarfs, and 30 [300] ppm for an Earthlike TRAPPIST-1e. We simulate emission and transmission spectra for intermediate and maximum N2O concentrations that are relevant to current and future space-based telescopes. We calculate the detectability of N2O spectral features for high-flux scenarios for TRAPPIST-1e with JWST. We review potential false positives, including chemodenitrification and abiotic production via stellar activity, and identify key spectral and contextual discriminants to confirm or refute the biogenicity of the observed N2O.Comment: 22 pages, 17 figures; ApJ, 937, 10

A Statistical Model for Assessing Genetic Susceptibility as a Risk Factor in Multifactorial Diseases: Lessons from Occupational Asthma

BACKGROUND: Incorporating the influence of genetic variation in the risk assessment process is often considered, but no generalized approach exists. Many common human diseases such as asthma, cancer, and cardiovascular disease are complex in nature, as they are influenced variably by environmental, physiologic, and genetic factors. The genetic components most responsible for differences in individual disease risk are thought to be DNA variants (polymorphisms) that influence the expression or function of mediators involved in the pathological processes. OBJECTIVE: The purpose of this study was to estimate the combinatorial contribution of multiple genetic variants to disease risk. METHODS: We used a logistic regression model to help estimate the joint contribution that multiple genetic variants would have on disease risk. This model was developed using data collected from molecular epidemiology studies of allergic asthma that examined variants in 16 susceptibility genes. RESULTS: Based on the product of single gene variant odds ratios, the risk of developing asthma was assigned to genotype profiles, and the frequency of each profile was estimated for the general population. Our model predicts that multiple disease variants broaden the risk distribution, facilitating the identification of susceptible populations. This model also allows for incorporation of exposure information as an independent variable, which will be important for risk variants associated with specific exposures. CONCLUSION: The present model provided an opportunity to estimate the relative change in risk associated with multiple genetic variants. This will facilitate identification of susceptible populations and help provide a framework to model the genetic contribution in probabilistic risk assessment

Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility

NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that is partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IκB function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100