Rotating Scatter Mask Optimization for Gamma Source Direction Identification

Rotating scattering masks have shown promise as an inexpensive, lightweight method with a large field-of-view for identifying the direction of a gamma emitting source or sources. However, further examination of the current rotating scattering mask design shows that changing the geometry may improve the identification by reducing or eliminating degenerate solutions and lower required count times. These changes should produce more linearly independent characteristics for the mask, resulting in a decrease in the mis-identification probability. Three approaches are introduced to generate alternative mask geometries. The eigenvector method uses a spring–mass system to create a geometry basis. The binary approach uses ones and zeros to represent the geometry with many possible combinations allowing for additional design flexibility. Finally, a Hadamard matrix is modified to examine a decoupled geometric solution. Four criteria are proposed for evaluating these methodologies. An analysis of the resulting detector response matrices demonstrates that these methodologies produced masks with superior identification characteristics than the original design. The eigenvector approach produces the least linearly dependent results, but exhibits a decrease in average efficiency. The binary results are more linearly dependent than the eigenvector approach, but this design achieves a higher average efficiency than original. The Hadamard-based method produced a lower maximum, but a higher average linear dependence than the original design. Further possible design enhancements are discussed

Susceptibility Provision Enhances Effective De-escalation (SPEED): utilizing rapid phenotypic susceptibility testing in Gram-negative bloodstream infections and its potential clinical impact

Abstract Objectives We evaluated the performance and time to result for pathogen identification (ID) and antimicrobial susceptibility testing (AST) of the Accelerate Pheno™ system (AXDX) compared with standard of care (SOC) methods. We also assessed the hypothetical improvement in antibiotic utilization if AXDX had been implemented. Methods Clinical samples from patients with monomicrobial Gram-negative bacteraemia were tested and compared between AXDX and the SOC methods of the VERIGENE® and Bruker MALDI Biotyper® systems for ID and the VITEK® 2 system for AST. Additionally, charts were reviewed to calculate theoretical times to antibiotic de-escalation, escalation and active and optimal therapy Results ID mean time was 21 h for MALDI-TOF MS, 4.4 h for VERIGENE® and 3.7 h for AXDX. AST mean time was 35 h for VITEK® 2 and 9.0 h for AXDX. For ID, positive percentage agreement was 95.9% and negative percentage agreement was 99.9%. For AST, essential agreement was 94.5% and categorical agreement was 93.5%. If AXDX results had been available to inform patient care, 25% of patients could have been put on active therapy sooner, while 78% of patients who had therapy optimized during hospitalization could have had therapy optimized sooner. Additionally, AXDX could have reduced time to de-escalation (16 versus 31 h) and escalation (19 versus 31 h) compared with SOC. Conclusions By providing fast and reliable ID and AST results, AXDX has the potential to improve antimicrobial utilization and enhance antimicrobial stewardship

The Discriminative Lexicon: A Unified Computational Model for the Lexicon and Lexical Processing in Comprehension and Production Grounded Not in (De)Composition but in Linear Discriminative Learning

© 2019 R. Harald Baayen et al. The discriminative lexicon is introduced as a mathematical and computational model of the mental lexicon. This novel theory is inspired by word and paradigm morphology but operationalizes the concept of proportional analogy using the mathematics of linear algebra. It embraces the discriminative perspective on language, rejecting the idea that words' meanings are compositional in the sense of Frege and Russell and arguing instead that the relation between form and meaning is fundamentally discriminative. The discriminative lexicon also incorporates the insight from machine learning that end-to-end modeling is much more effective than working with a cascade of models targeting individual subtasks. The computational engine at the heart of the discriminative lexicon is linear discriminative learning: simple linear networks are used for mapping form onto meaning and meaning onto form, without requiring the hierarchies of post-Bloomfieldian 'hidden' constructs such as phonemes, morphemes, and stems. We show that this novel model meets the criteria of accuracy (it properly recognizes words and produces words correctly), productivity (the model is remarkably successful in understanding and producing novel complex words), and predictivity (it correctly predicts a wide array of experimental phenomena in lexical processing). The discriminative lexicon does not make use of static representations that are stored in memory and that have to be accessed in comprehension and production. It replaces static representations by states of the cognitive system that arise dynamically as a consequence of external or internal stimuli. The discriminative lexicon brings together visual and auditory comprehension as well as speech production into an integrated dynamic system of coupled linear networks

Ir \u3csup\u3e4+\u3c/sup\u3e Ions in β-Ga\u3csub\u3e2\u3c/sub\u3eO\u3csub\u3e3\u3c/sub\u3e Crystals: An Unintentional Deep Donor

Electron paramagnetic resonance (EPR) and infrared absorption are used to detect Ir4+ ions in β-Ga2O3 crystals. Mg and Fe doped crystals are investigated, and concentrations of Ir4+ ions greater than 1 × 1018 cm−3 are observed. The source of the unintentional deep iridium donors is the crucible used to grow the crystal. In the Mg-doped crystals, the Ir4+ ions provide compensation for the singly ionized Mg acceptors and thus contribute to the difficulties in producing p-type behavior. The Ir4+ ions replace Ga3+ ions at the Ga(2) sites, with the six oxygen neighbors forming a distorted octahedron. A large spin-orbit coupling causes these Ir4+ ions to have a low-spin (5d5, S = 1/2) ground state. The EPR spectrum consists of one broad line with a significant angular dependence. Principal values of the g matrix are 2.662, 1.815, and 0.541 (with principal axes near the crystal a, b, and c directions, respectively). Ionizing radiation at 77 K decreases the Ir4+ EPR signal in Mg-doped crystals and increases the signal in Fe-doped crystals. In addition to the EPR spectrum, the Ir4+ ions have an infrared absorption band representing a d-d transition within the t2g orbitals. At room temperature, this band peaks near 5153 cm−1 (1.94 μm) and has a width of 17 cm−1. The band is highly polarized: its intensity is maximum when the electric field E is parallel to the b direction in the crystal and is nearly zero when E is along the c direction

Alcohol dehydrogenase gene ADH3 activates glucose alcoholic fermentation in genetically engineered Dekkera bruxellensis yeast

Dekkera bruxellensis is a non-conventional Crabtree-positive yeast with a good ethanol production capability. Compared to Saccharomyces cerevisiae, its tolerance to acidic pH and its utilization of alternative carbon sources make it a promising organism for producing biofuel. In this study, we developed an auxotrophic transformation system and an expression vector, which enabled the manipulation of D. bruxellensis, thereby improving its fermentative performance. Its gene ADH3, coding for alcohol dehydrogenase, was cloned and overexpressed under the control of the strong and constitutive promoter TEF1. Our recombinant D. bruxellensis strain displayed 1.4 and 1.7 times faster specific glucose consumption rate during aerobic and anaerobic glucose fermentations, respectively; it yielded 1.2 times and 1.5 times more ethanol than did the parental strain under aerobic and anaerobic conditions, respectively. The overexpression of ADH3 in D. bruxellensis also reduced the inhibition of fermentation by anaerobiosis, the "Custer effect". Thus, the fermentative capacity of D. bruxellensis could be further improved by metabolic engineering

Factors Contributing to the Biofilm-Deficient Phenotype of Staphylococcus aureus sarA Mutants

Mutation of sarA in Staphylococcus aureus results in a reduced capacity to form a biofilm, but the mechanistic basis for this remains unknown. Previous transcriptional profiling experiments identified a number of genes that are differentially expressed both in a biofilm and in a sarA mutant. This included genes involved in acid tolerance and the production of nucleolytic and proteolytic exoenzymes. Based on this we generated mutations in alsSD, nuc and sspA in the S. aureus clinical isolate UAMS-1 and its isogenic sarA mutant and assessed the impact on biofilm formation. Because expression of alsSD was increased in a biofilm but decreased in a sarA mutant, we also generated a plasmid construct that allowed expression of alsSD in a sarA mutant. Mutation of alsSD limited biofilm formation, but not to the degree observed with the corresponding sarA mutant, and restoration of alsSD expression did not restore the ability to form a biofilm. In contrast, concomitant mutation of sarA and nuc significantly enhanced biofilm formation by comparison to the sarA mutant. Although mutation of sspA had no significant impact on the ability of a sarA mutant to form a biofilm, a combination of protease inhibitors (E-64, 1-10-phenanthroline, and dichloroisocoumarin) that was shown to inhibit the production of multiple extracellular proteases without inhibiting growth was also shown to enhance the ability of a sarA mutant to form a biofilm. This effect was evident only when all three inhibitors were used concurrently. This suggests that the reduced capacity of a sarA mutant to form a biofilm involves extracellular proteases of all three classes (serine, cysteine and metalloproteases). Inclusion of protease inhibitors also enhanced biofilm formation in a sarA/nuc mutant, with the combined effect of mutating nuc and adding protease inhibitors resulting in a level of biofilm formation with the sarA mutant that approached that of the UAMS-1 parent strain. These results demonstrate that the inability of a sarA mutant to repress production of extracellular nuclease and multiple proteases have independent but cumulative effects that make a significant contribution to the biofilm-deficient phenotype of an S. aureus sarA mutant

Epistatic Relationships between sarA and agr in Staphylococcus aureus Biofilm Formation

Background: The accessory gene regulator (agr) and staphylococcal accessory regulator (sarA) play opposing roles in Staphylococcus aureus biofilm formation. There is mounting evidence to suggest that these opposing roles are therapeutically relevant in that mutation of agr results in increased biofilm formation and decreased antibiotic susceptibility while mutation of sarA has the opposite effect. To the extent that induction of agr or inhibition of sarA could potentially be used to limit biofilm formation, this makes it important to understand the epistatic relationships between these two loci. Methodology/Principal Findings: We generated isogenic sarA and agr mutants in clinical isolates of S. aureus and assessed the relative impact on biofilm formation. Mutation of agr resulted in an increased capacity to forma biofilmin the 8325-4 laboratory strain RN6390 but had little impact in clinical isolates S. aureus. In contrast, mutation of sarA resulted in a reduced capacity to form a biofilm in all clinical isolates irrespective of the functional status of agr. This suggests that the regulatory role of sarA in biofilm formation is independent of the interaction between sarA and agr and that sarA is epistatic to agr in this context. This was confirmed by demonstrating that restoration of sarA function restored the ability to form a biofilm even in the corresponding agr mutants. Mutation of sarA in clinical isolates also resulted in increased production of extracellular proteases and extracellular nucleases, both of which contributed to the biofilm-deficient phenotype of sarA mutants. However, studies comparing different strains with and without proteases inhibitors and/or mutation of the nuclease genes demonstrated that the agr-independent, sarA-mediated repression of extracellular proteases plays a primary role in this regard. Conclusions and Significance: The results we report suggest that inhibitors of sarA-mediated regulation could be used to limit biofilm formation in S. aureus and that the efficacy of such inhibitors would not be limited by spontaneous mutation of agr in the human host

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments

Can medical therapy mimic the clinical efficacy or physiological effects of bariatric surgery?

The number of bariatric surgical procedures performed has increased dramatically. This review discusses the clinical and physiological changes, and in particular, the mechanisms behind weight loss and glycaemic improvements, observed following the gastric bypass, sleeve gastrectomy and gastric banding bariatric procedures. The review then examines how close we are to mimicking the clinical or physiological effects of surgery through less invasive and safer modern interventions that are currently available for clinical use. These include dietary interventions, orlistat, lorcaserin, phentermine/topiramate, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, pramlintide, dapagliflozin, the duodenal–jejunal bypass liner, gastric pacemakers and gastric balloons. We conclude that, based on the most recent trials, we cannot fully mimic the clinical or physiological effects of surgery; however, we are getting closer. A ‘medical bypass' may not be as far in the future as we previously thought, as the physician's armamentarium against obesity and type 2 diabetes has recently got stronger through the use of specific dietary modifications, novel medical devices and pharmacotherapy. Novel therapeutic targets include not only appetite but also taste/food preferences, energy expenditure, gut microbiota, bile acid signalling, inflammation, preservation of β-cell function and hepatic glucose output, among others. Although there are no magic bullets, an integrated multimodal approach may yield success. Non-surgical interventions that mimic the metabolic benefits of bariatric surgery, with a reduced morbidity and mortality burden, remain tenable alternatives for patients and health-care professionals

Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment