A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Determination of fatty acid ethyl esters in dried blood spots by LC-MS/MS as markers for ethanol intake: application in a drinking study.

The forensic utility of fatty acid ethyl esters (FAEEs) in dried blood spots (DBS) as short-term confirmatory markers for ethanol intake was examined. An LC-MS/MS method for the determination of FAEEs in DBS was developed and validated to investigate FAEE formation and elimination in a drinking study, whereby eight subjects ingested 0.66-0.84 g/kg alcohol to reach blood alcohol concentrations (BAC) of 0.8 g/kg. Blood was taken every 1.5-2 h, BAC was determined, and dried blood spots were prepared, with 50 μL of blood, for the determination of FAEEs. Lower limits of quantitation (LLOQ) were between 15 and 37 ng/mL for the four major FAEEs. Validation data are presented in detail. In the drinking study, ethyl palmitate and ethyl oleate proved to be the two most suitable markers for FAEE determination. Maximum FAEE concentrations were reached in samples taken 2 or 4 h after the start of drinking. The following mean peak concentrations (c̅ max) were reached: ethyl myristate 14 ± 4 ng/mL, ethyl palmitate 144 ± 35 ng/mL, ethyl oleate 125 ± 55 ng/mL, ethyl stearate 71 ± 21 ng/mL, total FAEEs 344 ± 91 ng/mL. Detectability of FAEEs was found to be on the same time scale as BAC. In liquid blood samples containing ethanol, FAEE concentrations increase post-sampling. This study shows that the use of DBS fixation prevents additional FAEE formation in blood samples containing ethanol. Positive FAEE results obtained by DBS analysis can be used as evidence for the presence of ethanol in the original blood sample. Graphical Abstract Time courses for fatty acid ethyl ester (FAEE) concentrations in DBS and ethanol concentrations for subject 1 over a period of 7 h. Ethanol ingestion occured during the first hour of the time course.

A novel colourimetric technique to assess chewing function using two-coloured specimens: Validation and application

OBJECTIVES Chewing efficiency may be evaluated using cohesive specimen, especially in elderly or dysphagic patients. The aim of this study was to evaluate three two-coloured chewing gums for a colour-mixing ability test and to validate a new purpose built software (ViewGum©). METHODS Dentate participants (dentate-group) and edentulous patients with mandibular two-implant overdentures (IOD-group) were recruited. First, the dentate-group chewed three different types of two-coloured gum (gum1-gum3) for 5, 10, 20, 30 and 50 chewing cycles. Subsequently the number of chewing cycles with the highest intra- and inter-rater agreement was determined visually by applying a scale (SA) and opto-electronically (ViewGum©, Bland-Altman analysis). The ViewGum© software determines semi-automatically the variance of hue (VOH); inadequate mixing presents with larger VOH than complete mixing. Secondly, the dentate-group and the IOD-group were compared. RESULTS The dentate-group comprised 20 participants (10 female, 30.3±6.7 years); the IOD-group 15 participants (10 female, 74.6±8.3 years). Intra-rater and inter-rater agreement (SA) was very high at 20 chewing cycles (95.00-98.75%). Gums 1-3 showed different colour-mixing characteristics as a function of chewing cycles, gum1 showed a logarithmic association; gum2 and gum3 demonstrated more linear behaviours. However, the number of chewing cycles could be predicted in all specimens from VOH (all p<0.0001, mixed linear regression models). Both analyses proved discriminative to the dental state. CONCLUSION ViewGum© proved to be a reliable and discriminative tool to opto-electronically assess chewing efficiency, given an elastic specimen is chewed for 20 cycles and could be recommended for the evaluation of chewing efficiency in a clinical and research setting. CLINICAL SIGNIFICANCE Chewing is a complex function of the oro-facial structures and the central nervous system. The application of the proposed assessments of the chewing function in geriatrics or special care dentistry could help visualising oro-functional or dental comorbidities in dysphagic patients or those suffering from protein-energy malnutrition.

Validation of an enzyme-linked immunosorbent assay (ELISA) for the measurement of canine S100A12.

BACKGROUND Canine S100 calcium-binding protein A12 (cS100A12) shows promise as biomarker of inflammation in dogs. A previously developed cS100A12-radioimmunoassay (RIA) requires radioactive tracers and is not sensitive enough for fecal cS100A12 concentrations in 79% of tested healthy dogs. An ELISA assay may be more sensitive than RIA and does not require radioactive tracers. OBJECTIVE The purpose of the study was to establish a sandwich ELISA for serum and fecal cS100A12, and to establish reference intervals (RI) for normal healthy canine serum and feces. METHODS Polyclonal rabbit anti-cS100A12 antibodies were generated and tested by Western blotting and immunohistochemistry. A sandwich ELISA was developed and validated, including accuracy and precision, and agreement with cS100A12-RIA. The RI, stability, and biologic variation in fecal cS100A12, and the effect of corticosteroids on serum cS100A12 were evaluated. RESULTS Lower detection limits were 5 μg/L (serum) and 1 ng/g (fecal), respectively. Intra- and inter-assay coefficients of variation were ≤ 4.4% and ≤ 10.9%, respectively. Observed-to-expected ratios for linearity and spiking recovery were 98.2 ± 9.8% (mean ± SD) and 93.0 ± 6.1%, respectively. There was a significant bias between the ELISA and the RIA. The RI was 49-320 μg/L for serum and 2-484 ng/g for fecal cS100A12. Fecal cS100A12 was stable for 7 days at 23, 4, -20, and -80°C; biologic variation was negligible but variation within one fecal sample was significant. Corticosteroid treatment had no clinically significant effect on serum cS100A12 concentrations. CONCLUSIONS The cS100A12-ELISA is a precise and accurate assay for serum and fecal cS100A12 in dogs.

More Is Not Always Better: An Experimental Individual-Level Validation of the Randomized Response Technique and the Crosswise Model

Social desirability and the fear of sanctions can deter survey respondents from responding truthfully to sensitive questions. Self-reports on norm breaking behavior such as shoplifting, non-voting, or tax evasion may therefore be subject to considerable misreporting. To mitigate such misreporting, various indirect techniques for asking sensitive questions, such as the randomized response technique (RRT), have been proposed in the literature. In our study, we evaluate the viability of several variants of the RRT, including the recently proposed crosswise-model RRT, by comparing respondents’ self-reports on cheating in dice games to actual cheating behavior, thereby distinguishing between false negatives (underreporting) and false positives (overreporting). The study has been implemented as an online survey on Amazon Mechanical Turk (N = 6,505). Our results indicate that the forced-response RRT and the unrelated-question RRT, as implemented in our survey, fail to reduce the level of misreporting compared to conventional direct questioning. For the crosswise-model RRT, we do observe a reduction of false negatives (that is, an increase in the proportion of cheaters who admit having cheated). At the same time, however, there is an increase in false positives (that is, an increase in non-cheaters who falsely admit having cheated). Overall, our findings suggest that none of the implemented sensitive questions techniques substantially outperforms direct questioning. Furthermore, our study demonstrates the importance of distinguishing false negatives and false positives when evaluating the validity of sensitive question techniques.

Validation of the Swiss methane emission inventory by atmospheric observations and inverse modelling

Atmospheric inverse modelling has the potential to provide observation-based estimates of greenhouse gas emissions at the country scale, thereby allowing for an independent validation of national emission inventories. Here, we present a regional-scale inverse modelling study to quantify the emissions of methane (CH₄) from Switzerland, making use of the newly established CarboCount-CH measurement network and a high-resolution Lagrangian transport model. In our reference inversion, prior emissions were taken from the "bottom-up" Swiss Greenhouse Gas Inventory (SGHGI) as published by the Swiss Federal Office for the Environment in 2014 for the year 2012. Overall we estimate national CH₄ emissions to be 196 ± 18 Gg yr⁻¹ for the year 2013 (1σ uncertainty). This result is in close agreement with the recently revised SGHGI estimate of 206 ± 33 Gg yr⁻¹ as reported in 2015 for the year 2012. Results from sensitivity inversions using alternative prior emissions, uncertainty covariance settings, large-scale background mole fractions, two different inverse algorithms (Bayesian and extended Kalman filter), and two different transport models confirm the robustness and independent character of our estimate. According to the latest SGHGI estimate the main CH₄ source categories in Switzerland are agriculture (78 %), waste handling (15 %) and natural gas distribution and combustion (6 %). The spatial distribution and seasonal variability of our posterior emissions suggest an overestimation of agricultural CH₄ emissions by 10 to 20 % in the most recent SGHGI, which is likely due to an overestimation of emissions from manure handling. Urban areas do not appear as emission hotspots in our posterior results, suggesting that leakages from natural gas distribution are only a minor source of CH₄ in Switzerland. This is consistent with rather low emissions of 8.4 Gg yr⁻¹ reported by the SGHGI but inconsistent with the much higher value of 32 Gg yr⁻¹ implied by the EDGARv4.2 inventory for this sector. Increased CH₄ emissions (up to 30 % compared to the prior) were deduced for the north-eastern parts of Switzerland. This feature was common to most sensitivity inversions, which is a strong indicator that it is a real feature and not an artefact of the transport model and the inversion system. However, it was not possible to assign an unambiguous source process to the region. The observations of the CarboCount-CH network provided invaluable and independent information for the validation of the national bottom-up inventory. Similar systems need to be sustained to provide independent monitoring of future climate agreements.

Measuring the Social Identity of Entrepreneurs: Scale Development and International Validation

Recent research indicates that social identity theory offers an important lens to improve our understanding of founders as enterprising individuals, the venture creation process, and its outcomes. Yet, further advances are hindered by the lack of a valid scale that could be used to measure founders' social identities - a problem that is particularly severe because social identity is a multidimensional construct that needs to be assessed properly so that organizational phenomena can be understood. Drawing on social identity theory and the systematic classification of founders' social identities (Darwinians, Communitarians, Missionaries) provided in Fauchart and Gruber (2011), this study develops and empirically validates a 12-item scale that allows scholars to capture the multidimensional nature of social identities of entrepreneurs. Our validation tests are unusually comprehensive and solid, as we not only validate the developed scale in the Alpine region (where it was originally conceived), but also in 12 additional countries and the Anglo-American region. Scholars can use the scale to identify founders' social identities and to relate these identities to micro-level processes and outcomes in new firm creation. Scholars may also link founders' social identities to other levels of analysis such as industries (e.g., industry evolution) or whole economies (e.g., economic growth).

Screening for Language Disorders in Stroke: German Validation of the Language Screening Test (LAST)

BACKGROUND Screening of aphasia in acute stroke is crucial for directing patients to early language therapy. The Language Screening Test (LAST), originally developed in French, is a validated language screening test that allows detection of a language deficit within a few minutes. The aim of the present study was to develop and validate two parallel German versions of the LAST. METHODS The LAST includes subtests for naming, repetition, automatic speech, and comprehension. For the translation into German, task constructs and psycholinguistic criteria for item selection were identical to the French LAST. A cohort of 101 stroke patients were tested, all of whom were native German speakers. Validation of the LAST was based on (1) analysis of equivalence of the German versions, which was established by administering both versions successively in a subset of patients, (2) internal validity by means of internal consistency analysis, and (3) external validity by comparison with the short version of the Token Test in another subset of patients. RESULTS The two German versions were equivalent as demonstrated by a high intraclass correlation coefficient of 0.91. Furthermore, an acceptable internal structure of the LAST was found (Cronbach's α = 0.74). A highly significant correlation (r = 0.74, p < 0.0001) between the LAST and the short version of the Token Test indicated good external validity of the scale. CONCLUSION The German version of the LAST, available in two parallel versions, is a new and valid language screening test in stroke.