Residual stress development and evolution in two-phase crystalline material: a discrete dislocation study

Crystalline materials undergo heterogeneous deformation upon the application of external load, which results in the development of incompatible elastic strains in the material as soon as the load is removed. The presence of heterogeneous distribution of elastic strains in the absence of any form of external load results in the building up of stresses referred to as residual stresses. The heterogeneity of strain is attributed either to the presence of multiple phases or to the orientation gradients across the sample volume. This paper is an endeavour to model the presence of second phase in a two-dimensional discrete dislocation dynamics framework, which already contains constitutive rules to include three-dimensional mechanisms, such as line tension and dynamic junction formation. The model is used to investigate residual stress development in single crystals subjected to plane strain loading and then subsequently unloaded to study residual stresses. The dislocation accumulation around the second phase and its effect on the mechanical properties is studied. The orientation dependence of residual stresses as a function of the underlying defect substructure has also been explored. A variety of results are obtained. In particular, the development of stresses as a function of underlying defect substructure is also presented and found to depend upon the orientation of the crystal

Metabolic Imaging in Non-Alcoholic Fatty Liver Disease: Applications of Magnetic Resonance Spectroscopy

Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an integrated approach to uncover molecular mediators, key pathogenic milestones and response to intervention at the metabolic level. The advent of precision imaging has yielded unprecedented insights into these processes. Quantitative imaging biomarkers such as magnetic resonance imaging (MRI), spectroscopy (MRS) and elastography (MRE) present robust, powerful tools with which to probe NAFLD metabolism and fibrogenesis non-invasively,in real time. Specific advantages of MRS include the ability to quantify static metabolite concentrations as well as dynamic substrate fluxin vivo. Thus, a vast range of key metabolic events inthe natural history of NAFLD can be explored using MRS. Here, we provide an overview of MRS for the clinician, as well as key pathways exploitable by MRS in vivo. Development, optimisation and validation of multinuclear MRS, in combination with other quantitative imaging techniques, may ultimately provide a robust, non-invasive alternative to liver biopsy for observational and longitudinal studies. Through enabling deeper insight into inflammatory and fibrogenic cascades, MRS may facilitate identification of novel therapeutic targets and clinically meaningful endpoints in NAFLD. Its widespread use in future could conceivably accelerate study design, data acquisition and availability of disease-modifying therapies at a population leve

Economic evaluation of a community-based diagnostic pathway to stratify adults for non-alcoholic fatty liver disease: a Markov model informed by a feasibility study

Objectives: To assess the long-term cost-effectiveness of a risk stratification pathway, compared with standard care, for detecting non-alcoholic fatty liver disease (NAFLD) in primary care. Setting: Primary care general practices in England. Participants: Adults who have been identified in primary care to have a risk factor for developing NAFLD, that is, type 2 diabetes without a history of excessive alcohol use. Intervention: A community-based pathway, which utilises transient elastography and hepatologists to stratify patients at risk of NAFLD, has been implemented and demonstrated to be feasible (NCT02037867). Earlier identification could mean earlier treatments, referral to specialist, and enrolment into surveillance programmes. Design: The impact of earlier detection and treatment with the risk stratification pathway on progression to later stages of liver disease was examined using decision modelling with Markov chains to estimate lifetime health and economic effects of the two comparators. Data sources: Data from a prospective cross-sectional feasibility study indicating risk stratification pathway and standard care diagnostic accuracies, were combined with a Markov model that comprised the following states: no/mild liver disease, significant liver disease, compensated cirrhosis; decompensated cirrhosis, hepatocellular carcinoma, liver transplant and death. The model data were chosen from up-to-date UK sources, published literature and an expert panel. Outcome measure: An incremental cost-effectiveness ratio (ICER) indicating cost per quality adjusted life year (QALY) of the risk stratification pathway compared with standard care was estimated. Results: The risk stratification pathway was more effective than standard care, and cost ￡2,138 per QALY gained. The ICER was most sensitive to estimates of the rate of fibrosis progression and the effect of treatment on reducing this, and ranged from -￡1,895 to ￡7,032/QALY. The risk stratification pathway demonstrated an 85% probability of cost-effectiveness at the UK willingness-to-pay threshold of ￡20,000/QALY. Conclusions: Implementation of a community-based risk stratification pathway is likely to be cost effective

Mobile ad hoc network testbed using mobile robot technology

MANET (Mobile Ad Hoc Network) researchers have shown increased interest in using mobile robot technology for their testbed platforms. Thus, the main motivation of this paper is to review various robot-based MANET testbeds that have been developed in previously reported research. Additionally, suggestions to heighten mobility mechanisms by using mobile robots to be more practical, easy and inexpensive are also included in this paper, as we unveils ToMRobot, a low-cost MANET robot created from an ordinary remote control car that is capable of performing a real system MANET testbed with the addition of only a few low-cost electronic components. Despite greatly reduced costs, the ToMRobot does not sacrifice any of the necessary MANET basic structures and will still be easily customizable and upgradeable through the use of open hardware technology like Cubieboard2 and Arduino, as its robot controller. This paper will also include guidelines to enable technically limited MANET researchers to design and develop the ToMRobot. It is hoped that this paper achieves its two pronged objectives namely (i) to facilitate other MANET researchers by providing them with a source of reference that eases their decision making for selecting the best and most suitable MANET mobile robots for real mobility in their MANET testbeds (ii) to provide MANET researchers with a prospect of building their own MANET robots that can be applied in their own MANET testbed in the future

Validation of a Model for Identification of Patients With Compensated Cirrhosis at High Risk of Decompensation

Background & Aims: It is important to rapidly identify patients with advanced liver disease. Routine tests to assess liver function and fibrosis provide data that can be used to determine patients’ prognoses. We tested the validated the ability of combined data from the ALBI and FIB-4 scoring systems to identify patients with compensated cirrhosis at highest risk for decompensation.Methods: We collected data from 145 patients with compensated cirrhosis (91% Child A cirrhosis and median MELD scores below 8) from a cohort in Nottingham, United Kingdom, followed for a median 4.59 years (development cohort). We collected baseline clinical features and recorded decompensation events. We used these data to develop a model based on liver function (assessed by the ALBI score) and extent of fibrosis (assessed by the FIB-4 index) to determine risk of decompensation. We validated the model in 2 independent external cohorts (1 in Dublin, Ireland and 1 in Menoufia, Egypt) comprising 234 patients.Results: In the development cohort, 19.3% of the patients developed decompensated cirrhosis. Using a combination of ALBI and FIB-4 scores, we developed a model that identified patients at low vs high risk of decompensation (hazard ratio [HR] for decompensation in patients with high risk score was 7.10). When we tested the scoring system in the validation cohorts, the HR for decompensation in patients with a high-risk score was 12.54 in the Ireland cohort and 5.10 in the Egypt cohort.Conclusion: We developed scoring system, based on a combination of ALBI and FIB-4 scores, that identifies patients at risk for liver decompensation. We validated the scoring system in 2 independent international cohorts (Europe and the Middle East), so it appears to apply to diverse populations

The Pioneer anomaly in the context of the braneworld scenario

We examine the Pioneer anomaly - a reported anomalous acceleration affecting the Pioneer 10/11, Galileo and Ulysses spacecrafts - in the context of a braneworld scenario. We show that effects due to the radion field cannot account for the anomaly, but that a scalar field with an appropriate potential is able to explain the phenomena. Implications and features of our solution are analyzed.Comment: Final version to appear at Classical & Quantum Gravity. Plainlatex 19 page

Effect of damage evolution on the auxetic behavior of 2D and 3D re-entrant type geometries

In this work, a mathematical formulation based on variational asymptotic method (VAM) has been proposed to determine the effect of damage on the auxetic properties of two-dimensional (2D) and three-dimensional (3D) re-entrant geometries. The influence of damage progression on the auxetic behavior was captured using a geometrically exact one-dimensional beam theory and an isotropic damage law, implemented in a nonlinear finite element framework. The effect of material degradation on the macroscale effective elastic properties such as the elastic modulus and Poisson’s ratio for the two-dimensional and three-dimensional re-entrant auxetic geometries was quantified. The mechanical behavior as predicted by the in-house Python-based implementation of the proposed VAM-based formulation is verified with the results from the commercial finite element solver Abaqus, wherein the user material subroutine was used to capture damage evolution. The numerical examples presented in this paper reveal that the macroscale auxetic behavior of the geometries was affected significantly by damage progression. The results of this research will provide insights into the design and analysis of auxetic materials for applications that warrant consideration of damage evolution

Guidelines on the management of ascites in cirrhosis.

The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years' time

A revised electronic version of RUCAM for the diagnosis of DILI

Background and Aims: Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI Registry, published literature, and it- erative computer modeling. Approach and Results: RUCAM criteria were updated, clarified, and com- puterized. We removed criteria 3 (risk factors) for lack of added value and cri- teria 4 because we felt it more useful to assess each drug separately. Criteria 6 (drug-specific risk) was anchored to LiverTox likelihood scores. Iterative testing in subsets of 50–100 single-agent, nonherbal cases from both regis- tries was done to optimize performance. We used classification tree analysis to establish diagnostic cutoffs for this revised electronic causality assessment method (RECAM) and compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 DILIN, 96 Spanish DILI). Area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for RECAM and RUCAM. However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, p = 0.14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, p = 0.02; 65 vs. 48 for unlikely/excluded, p = 0.08) than RUCAM diagnostic categories. Conclusions: RECAM is an evidence-based update that is at least as capa- ble as RUCAM in diagnosing DILI compared with expert opinion but is better than RUCAM at the diagnostic extremes. RECAM’s increased objectivity and clarity will improve precision, reliability, and standardization of DILI diagnosis, but further refinement and validation in other cohorts are needed.Funding information The Drug-Induced Liver Injury (DILN) Network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (U24-DK065176, U01-DK065201, U01-DK065184, U01-DK065211, U01DK065193, U01-DK065238, U01-DK083023, U01-DK083027, U01-DK082992, U01-DK083020, and U01-DK100928). Additional support is provided by CTSA grants (UL1 RR025761, UL1TR000083, UL1 RR024134, UL1 RR024986, UL1 RR024982, UL1 RR024150), the Intramural Research Program of the National Institutes of Health, the National Cancer Institute (ClinicalTrials.gov number: NCT00345930), and the 2016 American Association for the Study of Liver Disease (AASLD) Innovations Fund. The Spanish DILI Registry is funded by grants from Instituto de Salud Carlos III, cofounded by Fondo Europeo de Desarrollo Regional - FEDER (PI 18/01804 and PT 20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by ISCIII

Biomarkers of Type IV Collagen Turnover Reflect Disease Activity in Patients with Early-Stage Non-Alcoholic Fatty Liver (NAFL)

Background: Identification of progressive liver disease necessitates the finding of novel non-invasive methods to identify and monitor patients in need of early intervention. Investigating patients with early-liver injury may help identify unique biomarkers. Early-liver injury is characterized by remodeling of the hepatocyte basement membrane (BM) of the extracellular matrix. Thus, we quantified biomarkers targeting two distinct neo-epitopes of the major BM collagen, type IV collagen (PRO-C4 and C4M), in patients spanning the non-alcoholic fatty liver disease (NAFLD) spectrum. Methods: We evaluated PRO-C4 and C4M in a cross-sectional study with 97 patients with NAFLD confirmed on histology. Serological levels of PRO-C4 and C4M were quantified using validated competitive enzyme-linked immunosorbent assays (ELISA). Using the fatty liver inhibition of progression (FLIP) algorithm, we stratified patients into two groups: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Biomarker levels were investigated in the two groups in patients stratified by the NAFLD activity score (NAS). In both groups, biomarker measurements were analyzed in relation to histological scorings of steatosis, inflammation, ballooning, and fibrosis. Results: Patients had a body mass index (BMI) of 30.9 ± 5.6 kg/m2, age of 53 ± 13 years and a NAS range of 1–8. Upon stratification by FLIP, the NASH patients had higher platelets, ALT, and AST levels than the NAFL group. Both PRO-C4 (p = 0.0125) and C4M (p = 0.003) increased with increasing NAS solely within the NAFL group; however, a large variability was present in the NASH group. Furthermore, both markers were significantly associated with lobular inflammation (p = 0.020 and p = 0.048) and steatosis (p = 0.004 and p = 0.015) in patients with NAFL. Conclusions: This study found that type IV collagen turnover increased with the increase in NAS in patients with NAFL; however, this was not the case in patients with NASH. These findings support the assessments of the BM turnover using biomarkers in patients with early-disease development. These biomarkers may be used to track specific processes involved in the early pathobiology of NAFL