A novel tumor-based epithelial-to-mesenchymal transition score that associates with prognosis and metastasis in patients with stage II/III colorectal cancer

It is increasingly appreciated that host factors within the tumor center and microenvironment play a key role in dictating colorectal cancer (CRC) outcomes. As a result, the metastatic process has now been defined as a result of epithelial–mesenchymal transition (EMT). Establishment of the role of EMT within the tumor center and its effect on the tumor microenvironment would be beneficial for prognosis and therapeutic intervention in CRC. The present study assessed five immunohistochemical EMT markers within the tumor center on a 185 Stage II/III CRC patient tissue microarray. In 185 patients with CRC, cytoplasmic snail (HR 1.94 95% confidence interval [CI] 1.15–3.29, p = 0.012) and a novel combined EMT score (HR 3.86 95% CI 2.17–6.86, p < 0.001) were associated with decreased cancer‐specific survival. The combined EMT score was also associated with increased tumor budding (p = 0.046), and systemic inflammation (p = 0.007), as well as decreased memory T‐cells within the stroma (p = 0.030) and at the invasive margin (p = 0.035). Furthermore, the combined EMT score was associated with cancer‐specific survival independent of TNM‐stage (HR 4.12 95% CI 2.30–7.39, p < 0.001). In conclusion, a novel combined EMT score stratifies patient's survival in Stage II/III CRC and associates with key factors of tumor metastasis. Therefore, the combined EMT score could be used to identify patients at risk of micrometastases and who may benefit from standard adjuvant therapy, potentially in combination with EMT blockade

Assessing outcomes of alcohol-related brain damage (ARBD): What should we be measuring?

The recent move towards outcomes-focused assessment in health and social care has made it important to identify which outcomes are relevant to alcohol-related brain damage (ARBD). Clinical outcomes guidance for ARBD is currently absent from policy documentation. Thus, the aim of this review is to evaluate the current evidence base to determine recommendations for the measurement of ARBD outcomes. A total of 71 separate references were identified through a systematic online database and hand search. The screening and exclusion strategy left 7 articles to be included in this review. The findings indicate that research into ARBD has focussed on a number of outcome domains, including type of accommodation and provision of support; drinking status; employment status; number of deaths; mental health and psychiatric symptoms; activities of daily living; social functioning; and cognitive functioning. The identified outcomes suggest that practitioners should focus on a comprehensive range of clinical outcomes for ARBD service users. Nevertheless, the paucity of the existing evidence base makes it difficult to make clinical recommendations for the measurement of ARBD outcomes. Further research is necessary to shed light on long term outcomes for people with ARBD and to increase the strength of the evidence in this area

DER OKONOMISCHE EFFEKT EINER ERHOHUNG DER ARBEITSLOSENLEISTUNGEN : NEUBETRACHT UNTER VERWENDUNG DES ATKINSON MODELLS

In der zweiten Halfte der 1970er begannen sich wirtschaftliche Kennziffern industrialisierter Staaten rapide zu verschlechtern. Gleichzeitig ruckte der Wohlfahrtsstaat als Ursache in das Zentrum der Kritik. Einige Wirtschaftswissenschaftler, insbesondere die deutschen Neo- Liberalisten, hatten bereits seit den 1950ern eine kritische Haltung zum wohlfahrtsstaatlichen Konzept eingenommen. Seit den 1970ern gesellten sich zu diesen Liberalisten auch viele Wirtschaftswissenschaftler, die zuvor den Wohlfahrtsstaat unterstutzt hatten. A.B. Atkinson wies jedoch daraufhin, daB viele der verwandten okonomischen Analysen auf un- fundierten theoretischen Modellen basierten, die die eigentlichen Merkmale des sozialen Wohlfahrtsprogramms auBer Acht lieBen. In der vorliegenden Arbeit gehen wir daher, den wirtschaftlichen Auswirkungen der Arbeitslosenversicherung in Einklang mit Atkinsons Kritik nach. Es gelang ihm gegenteilige Ergebnisse zu dem popularen Shapiro und Stiglitz Shirking Modell, durch Einfuhrung zweier Annahmen, d.h. Arbeitslosenleistungen werden identifizierten Shirkern vorenthalten und Arbeitslosenleistungen werden generell nur fur einen bestimmten Zeitraum angeboten, nachzuweisen. In der vorliegenden Arbeit zeigen wir, daB Gehalt basierende Arbeitslosenleistungen sich positiv auf Produktivitat und Beschaftigung auswirken. Zeitliche Begrenzung und eine ansteigende Sockelleistung alleine haben nicht die gleichen Ergebnisse im Shapiro und Stiglitz Modell

Prediction of Global Functional Outcome and Post-Concussive Symptoms after Mild Traumatic Brain Injury: External Validation of Prognostic Models in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study

The majority of traumatic brain injuries (TBIs) are categorized as mild, according to a baseline Glasgow Coma Scale (GCS) score of 13-15. Prognostic models that were developed to predict functional outcome and persistent post-concussive symptoms (PPCS) after mild TBI have rarely been externally validated. We aimed to externally validate models predicting 3-12-month Glasgow Outcome Scale Extended (GOSE) or PPCS in adu

Performance of novel VUV-sensitive Silicon Photo-Multipliers for nEXO

Liquid xenon time projection chambers are promising detectors to search for neutrinoless double beta decay (0$\nu \beta \beta$), due to their response uniformity, monolithic sensitive volume, scalability to large target masses, and suitability for extremely low background operations. The nEXO collaboration has designed a tonne-scale time projection chamber that aims to search for 0$\nu \beta \beta$ of \ce{^{136}Xe} with projected half-life sensitivity of $1.35\times 10^{28}$~yr. To reach this sensitivity, the design goal for nEXO is $\leq$1\% energy resolution at the decay $Q$-value ($2458.07\pm 0.31$~keV). Reaching this resolution requires the efficient collection of both the ionization and scintillation produced in the detector. The nEXO design employs Silicon Photo-Multipliers (SiPMs) to detect the vacuum ultra-violet, 175 nm scintillation light of liquid xenon. This paper reports on the characterization of the newest vacuum ultra-violet sensitive Fondazione Bruno Kessler VUVHD3 SiPMs specifically designed for nEXO, as well as new measurements on new test samples of previously characterised Hamamatsu VUV4 Multi Pixel Photon Counters (MPPCs). Various SiPM and MPPC parameters, such as dark noise, gain, direct crosstalk, correlated avalanches and photon detection efficiency were measured as a function of the applied over voltage and wavelength at liquid xenon temperature (163~K). The results from this study are used to provide updated estimates of the achievable energy resolution at the decay $Q$-value for the nEXO design

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations

Quality indicators for patients with traumatic brain injury in European intensive care units

Background: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measur

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

JIRAM, the Jovian Infrared Auroral Mapper

JIRAM is an imager/spectrometer on board the Juno spacecraft bound for a polar orbit around Jupiter. JIRAM is composed of IR imager and spectrometer channels. Its scientific goals are to explore the Jovian aurorae and the planet's atmospheric structure, dynamics and composition. This paper explains the characteristics and functionalities of the instrument and reports on the results of ground calibrations. It discusses the main subsystems to the extent needed to understand how the instrument is sequenced and used, the purpose of the calibrations necessary to determine instrument performance, the process for generating the commanding sequences, the main elements of the observational strategy, and the format of the scientific data that JIRAM will produce