Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis

Objective Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose. Design For a case-control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. Results A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93-0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%-97.0%). In the test set, an AUC of 0.94 (95% CI 0.91-0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%-95.5%) and a specificity of 91.3% (95% CI 82.8%-96.4%) were achieved, successfully validating the biomarker signature. Conclusions In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%-99.9%) (training set) and 99.8% (95% CI 99.6%-99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9

Eliciting Dose and Safety Outcomes From a Large Dataset of Standardized Multiple Food Challenges

Background: Food allergy prevalence has continued to rise over the past decade. While studies have reported threshold doses for multiple foods, large-scale multi-food allergen studies are lacking. Our goal was to identify threshold dose distributions and predictors of severe reactions during blinded oral food challenges (OFCs) in multi-food allergic patients.Methods: A retrospective chart review was performed on all Stanford-initiated clinical protocols involving standardized screening OFCs to any of 11 food allergens at 7 sites. Interval-censoring survival analysis was used to calculate eliciting dose (ED) curves for each food. Changes in severity and ED were also analyzed among participants who had repeated challenges to the same food.Results: Of 428 participants, 410 (96%) had at least one positive challenge (1445 standardized OFCs with 1054 total positive challenges). Participants undergoing peanut challenges had the highest ED50 (29.9 mg), while those challenged with egg or pistachio had the lowest (7.07 or 1.7 mg, respectively). The most common adverse event was skin related (54%), followed by gastrointestinal (GI) events (33%). A history of asthma was associated with a significantly higher risk of a severe reaction (hazard ratio [HR]: 2.37, 95% confidence interval [CI]: 1.36, 4.13). Higher values of allergen-specific IgE (sIgE) and sIgE to total IgE ratio (sIgEr) were also associated with higher risk of a severe reaction (1.49 [1.19, 1.85] and 1.84 [1.30, 2.59], respectively). Participants undergoing cashew, peanut, pecan, sesame, and walnut challenges had more severe reactions as ED increased. In participants who underwent repeat challenges, the ED did not change (p = 0.66), but reactions were more severe (p = 0.02).Conclusions: Participants with a history of asthma, high sIgEr, and/or high values of sIgE were found to be at higher risk for severe reactions during food challenges. These findings may help to optimize food challenge dosing schemes in multi-food allergic, atopic patients, specifically at lower doses where the majority of reactions occur.Trials Registration Number: ClinicalTrials. gov number NCT03539692; https://clinicaltrials.gov/ct2/show/NCT03539692

Differential Stress-Induced Neuronal Activation Patterns in Mouse Lines Selectively Bred for High, Normal or Low Anxiety

There is evidence for a disturbed perception and processing of emotional information in pathological anxiety. Using a rat model of trait anxiety generated by selective breeding, we previously revealed differences in challenge-induced neuronal activation in fear/anxiety-related brain areas between high (HAB) and low (LAB) anxiety rats. To confirm whether findings generalize to other species, we used the corresponding HAB/LAB mouse model and investigated c-Fos responses to elevated open arm exposure. Moreover, for the first time we included normal anxiety mice (NAB) for comparison. The results confirm that HAB mice show hyperanxious behavior compared to their LAB counterparts, with NAB mice displaying an intermediate anxiety phenotype. Open arm challenge revealed altered c-Fos response in prefrontal-cortical, limbic and hypothalamic areas in HAB mice as compared to LAB mice, and this was similar to the differences observed previously in the HAB/LAB rat lines. In mice, however, additional differential c-Fos response was observed in subregions of the amygdala, hypothalamus, nucleus accumbens, midbrain and pons. Most of these differences were also seen between HAB and NAB mice, indicating that it is predominately the HAB line showing altered neuronal processing. Hypothalamic hypoactivation detected in LAB versus NAB mice may be associated with their low-anxiety/high-novelty-seeking phenotype. The detection of similarly disturbed activation patterns in a key set of anxiety-related brain areas in two independent models reflecting psychopathological states of trait anxiety confirms the notion that the altered brain activation in HAB animals is indeed characteristic of enhanced (pathological) anxiety, providing information for potential targets of therapeutic intervention

Euroization in Central, Eastern and Southeastern Europe – First Results from the New OeNB Euro Survey

This article presents the main results of a new OeNB survey on foreign currency holdings, which was conducted for the first time in late 2007 in four Central and Eastern European (CEE) as well as seven Southeastern European (SEE) countries. The most important questions asked in the survey pertain to the currency composition and the amounts of foreign currency cash holdings and foreign currency deposits as well as to the motives for holding foreign currency cash and deposits. The authors conclude that the euro plays a dominant role in foreign currency-denominated assets (both cash and deposits) throughout the region.

The OeNB Euro Survey in Central, Eastern and Southeastern Europe - The 2008 Spring Wave Update

This paper presents the main results of the second wave of the OeNB Euro Survey conducted in Central, Eastern and Southeastern Europe (CESEE) in May/June 2008. The results on foreign currency-denominated assets, both cash and deposits, broadly confirm the picture obtained from the first wave of the survey, namely that the euro plays a dominant role throughout the CESEE region. New evidence on foreign currency loans (FCLs) reveals that the share of FCLs in total household loans is substantial, both in Central and Eastern Europe (CEE) and Southeastern Europe (SEE). The article for the first time presents survey results on people’s general economic sentiment, comprising their assessment of the present and future economic situation, perceived and expected inflation and expected exchange rate developments. Finally, the paper provides an update on the expected date of euro adoption in the EU Member States surveyed.

The 2008 Fall Wave of the OeNB Euro Survey – A First Glimpse of Households’ Reactions to the Global Financial Crisis

This article presents selected results of the third wave of the OeNB Euro Survey, which was conducted in Central, Eastern and Southeastern Europe (CESEE) in October/November 2008, i.e. at a time when the global financial crisis had arrived in Europe. Therefore, this article focuses on first evidence of households’ reactions to the crisis by comparing the most recent results with those of the preceding survey wave of May/June 2008. Although people’s general assessment of the economic situation and their trust in banks have both deteriorated substantially, according to our results, this has not (yet) changed people’s behavioral patterns in terms of their foreign currency holdings. In particular, the dissemination of euro cash holdings and euro-denominated savings deposits remained stable relative to earlier waves of the OeNB uro Survey.Euroization, global financial crisis, economic sentiment, survey data, CEE, SEE

CESEE Households amid the Financial Crisis: Euro Survey Shows Darkened Economic Sentiment and Changes in Savings Behavior

This paper utilizes information from the OeNB Euro Survey, which was launched in 2007 and is conducted twice a year in ten CESEE countries. The most recent survey wave of May to June 2009 focused on the impact of the financial crisis on CESEE households. Results show, first, that the financial crisis is in fact severely felt throughout the region: Respondents’ assessment of the current economic situation has deteriorated, trust in the future stability of local currencies has diminished, and trust in banks has declined in almost all countries surveyed. Second, the analysis of aggregate monetary statistics reveals that households reacted by adjusting their portfolios immediately, but developments differ substantially across countries. Third, in countries with more persistent withdrawals, euro cash in circulation, surprisingly, has declined because households resorted to dissaving to compensate for decreasing income. The authors conclude that although a massive shock has hit the region, no dramatic changes in the overall degree of euroization have occurred. This subdued impact is likely to signal that past stabilization efforts have paid off and that the economic and monetary policy measures taken in the course of t the crisis were successful.Euroization, global financial crisis, portfolio decision, trust, survey data, Central, Eastern and Southeastern Europe

Combination of multivariate data analysis and mixing modelling to assess tracer potential of contaminants of emerging concern in aquifers

Collected evidence has shown that contaminants of emerging concern (CECs) in conjunction with more conventional tracers (major ions, nutrients, isotopes etc.) can be used to trace pollution origin in aquatic systems. However, in highly mixed aquifer systems signals obtained from conventional tracers overlap diminishing their potential to be used as tracers. In this study, we present an approach that incorporates multivariate statistical analysis (principal component analysis (PCA) and Kohonen's Self-Organizing Map method (SOM)) and mixing modelling to identify the most suitable CECs to be employed as anthropogenic tracers. The study area is located in the Besòs River Delta (Barcelona, NE Spain) and represents the highly mixed aquifer system. A one-year monthly based monitoring campaign was performed to collect the information about the concentrations of 105 CECs as well as major and minor ions in the river and along the groundwater flow. The dimensionality of the obtained dataset was reduced to 25 CECs, based on their estimated health risk effects, for multivariate data analysis. The obtained results showed the overlap of conventional tracers' signals obtained from PCA. In case of CECs, PCA revealed differences in their distributions allowing the differentiation of the roles of natural attenuation processes, local and regional flows on their occurrence in different parts of the aquifer. This was not possible to do using solely CECs' distribution profiles. SOMs provided the lacking information about the modality of the distribution of each CECs, revealing their ability to represent factors controlling the groundwater hydrochemistry, which assist in defining their tracer potential. Based on the obtained results four identified persistent CECs, two with unimodal (lamotrigine and 5-Desamino-5-oxo-lamotrigine) and two with bimodal (carbamazepine and diazepam (higher modality was not revealed)) distributions, were selected to run a mixing model to compare their tracer performance.IDAEA-CSIC is a Centre of Excellence Severo Ochoa (Spanish Ministry of Science and Innovation, Project CEX2018-000794-S). ON and AJ gratefully acknowledge the support from the Spanish National Research Council through the call for Scientific Cooperation with Ukraine IUCRAN2022 (Ref: UCRAN20070). EP gratefully acknowledges the support received through the grant RYC2020-029225-I funded by MCIN/AEI/10.13039/501100011033 and by “ ESF Investing in your future”. AJ also thanks to the Ministry of Science, Innovation and Universities, for funding the project INTEGRATE (Ref: PID2019-107945RJ-I00) under the 2019 call of the “Proyectos de I+D Retos Investigación”.Peer reviewe