Copeptin for risk stratification in non-traumatic headache in the emergency setting: a prospective multicenter observational cohort study

In the emergency setting, non-traumatic headache is a benign symptom in 80% of cases, but serious underlying conditions need to be ruled out. Copeptin improves risk stratification in several acute diseases. Herein, we investigated the value of copeptin to discriminate between serious secondary headache and benign headache forms in the emergency setting.; Patients presenting with acute non-traumatic headache were prospectively enrolled into an observational cohort study. Copeptin was measured upon presentation to the emergency department. Primary endpoint was serious secondary headache defined by a neurologic cause requiring immediate treatment of the underlying disease. Secondary endpoint was the combination of mortality and hospitalization within 3 months. Two board-certified neurologist blinded to copeptin levels verified the endpoints after a structured 3-month-telephone interview.; Of the 391 patients included, 75 (19%) had a serious secondary headache. Copeptin was associated with serious secondary headache (OR 2.03, 95%CI 1.52-2.70, p < 0.0001). Area under the curve (AUC) for copeptin to identify the primary endpoint was 0.70 (0.63-0.76). After adjusting for age > 50, focal-neurological abnormalities, and thunderclap onset of symptoms, copeptin remained an independent predictive factor for serious secondary headache (OR 1.74, 95%CI 1.26-2.39, p = 0.001). Moreover, copeptin improved the AUC of the multivariate logistic clinical model (p-LR-test < 0.001). Even though copeptin values were higher in patients reaching the secondary endpoint, this association was not significant in multivariate logistic regression.; Copeptin was independently associated with serious secondary headache as compared to benign headaches forms. Copeptin may be a promising novel blood biomarker that should be further validated to rule out serious secondary headache in the emergency department.; Study Registration on 08/02/2010 as NCT01174901 at clinicaltrials.gov

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Real and Financial Asymmetries in the Euro Area

Within the framework of Optimum Currency Area theory, the proper functioning of a currency union presupposes a sufficient degree of similarity of the participating economies or alternative mechanism to make up for a possible lack of similarity. The most recent economic and financial crisis, the European debt crisis and, lately, the COVID-19 pandemic have revealed the deficiencies of the EA in this respect. To successfully accommodate the various shocks, it is crucial to understand how real and financial markets interact and what the differences between euro area economies are. In this thesis I contribute to this understanding along three dimensions. First, I compute country-specific business and financial cycles and study their similarities between countries. I use the cycles to assess the importance of macrofinancial linkages between real and financial markets. Second, I study the impact of symmetric shocks to GDP, the exchange rate and the interest rate on euro area countries’ trade balances and competitiveness. Third, I investigate if migration and the redistribution of taxes have promoted the unconditional and conditional convergence of incomes in Germany. My analysis of business and financial cycles indicates that asymmetries in euro area real and financial markets continue to exist. In particular, the cycle volatility differs across countries, and it significantly and heterogeneously changes over time. I contribute to the literature by analysing how individual EA countries’ (domestic) financial and business cycles are affected by one another as well as their EA equivalents and find that domestic and EA business and financial cycles can explain roughly 50 percent of the domestic business and financial cycle dynamics. I further contribute to the literature by showing that financial cycles include information about risks to future economic growth. For some countries this implies that booming financial cycles translated into continuously declining means, increasing variances and rising recession probabilities of the conditional real GDP distribution in the period leading to the financial crisis. These developments can be interpreted as early signs of an imminent economic crisis. The analysis of symmetric shocks suggests that differences in economic structures and institutions between countries result in heterogenous responses of their trade balances and competitiveness and might add to macroeconomic imbalances between EA economies. I contribute to the literature by differentiating between countries’ intra-EA and extra-EA trade balances and competitiveness. I find that shocks to real GDP are important drivers of EA trade balances and that these shocks significantly affect the competitiveness of individual EA countries. The impact of exchange rate and interest rate movements on trade balances is only temporary. The example of Germany shows that unconditional convergence of incomes within a currency union will likely be a lengthy process even in the presence of migration and fiscal transfer schemes. The impact of both migration and fiscal transfers depends on initial income conditions. Conversely, conditional convergence of incomes between German states is quasi automatic; migration and fiscal variables do not speed up the process. This finding suggests that income differences in the euro area are likely to exist in the longer run

Real and Financial Asymmetries in the Euro Area

Within the framework of Optimum Currency Area theory, the proper functioning of a currency union presupposes a sufficient degree of similarity of the participating economies or alternative mechanism to make up for a possible lack of similarity. The most recent economic and financial crisis, the European debt crisis and, lately, the COVID-19 pandemic have revealed the deficiencies of the EA in this respect. To successfully accommodate the various shocks, it is crucial to understand how real and financial markets interact and what the differences between euro area economies are. In this thesis I contribute to this understanding along three dimensions. First, I compute country-specific business and financial cycles and study their similarities between countries. I use the cycles to assess the importance of macrofinancial linkages between real and financial markets. Second, I study the impact of symmetric shocks to GDP, the exchange rate and the interest rate on euro area countries’ trade balances and competitiveness. Third, I investigate if migration and the redistribution of taxes have promoted the unconditional and conditional convergence of incomes in Germany. My analysis of business and financial cycles indicates that asymmetries in euro area real and financial markets continue to exist. In particular, the cycle volatility differs across countries, and it significantly and heterogeneously changes over time. I contribute to the literature by analysing how individual EA countries’ (domestic) financial and business cycles are affected by one another as well as their EA equivalents and find that domestic and EA business and financial cycles can explain roughly 50 percent of the domestic business and financial cycle dynamics. I further contribute to the literature by showing that financial cycles include information about risks to future economic growth. For some countries this implies that booming financial cycles translated into continuously declining means, increasing variances and rising recession probabilities of the conditional real GDP distribution in the period leading to the financial crisis. These developments can be interpreted as early signs of an imminent economic crisis. The analysis of symmetric shocks suggests that differences in economic structures and institutions between countries result in heterogenous responses of their trade balances and competitiveness and might add to macroeconomic imbalances between EA economies. I contribute to the literature by differentiating between countries’ intra-EA and extra-EA trade balances and competitiveness. I find that shocks to real GDP are important drivers of EA trade balances and that these shocks significantly affect the competitiveness of individual EA countries. The impact of exchange rate and interest rate movements on trade balances is only temporary. The example of Germany shows that unconditional convergence of incomes within a currency union will likely be a lengthy process even in the presence of migration and fiscal transfer schemes. The impact of both migration and fiscal transfers depends on initial income conditions. Conversely, conditional convergence of incomes between German states is quasi automatic; migration and fiscal variables do not speed up the process. This finding suggests that income differences in the euro area are likely to exist in the longer run

Determinants of regional growth and convergence in Germany

In this paper, we analyse the sources of real per capita income growth and convergence in the 16 German states over the period 1995-2014 using a panel approach. The empirical analysis applies the popular growth – initial income equation. We augment the basic model specification with a trend term and a crisis dummy. We then augment the model with additional explanatory variables and account for non-linear interaction effects. Overall, we find evidence of slow but significant convergence once the crisis and a trend are appropriately accounted for. Internal migration has a positive impact on growth in the East and thus contributes to the convergence between Eastern and Western states. Horizontal tax equalisation is ineffective in promoting growth and convergence, but we do find some evidence that federal supplementary grants have contributed to convergence between grant receiving and non-receiving states. Structural funding is found to have opposing growth effects on Eastern and Western states and has significantly promoted convergence

Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder?

Immunological abnormalities associated with pathological conditions, such as higher infection rates, inflammatory diseases, cancer or cardiovascular events are common in patients with panic disorder. In the present study, T cell receptor excision circles (TRECs), Fork-head-Box-Protein P3 gene (FOXP3) methylation of regulatory T cells (Tregs) and relative telomere lengths (RTLs) were investigated in a total and subsamples of 131 patients with panic disorder as compared to 131 age-and sex-matched healthy controls in order to test for a potential dysfunction and premature aging of the immune system in anxiety disorders. Significantly lower TRECs (p = 0.004) as well as significant hypermethylation of the FOXP3 promoter region (p = 0.005) were observed in female (but not in male) patients with panic disorder as compared to healthy controls. No difference in relative telomere length was discerned between patients and controls, but significantly shorter telomeres in females, smokers and older persons within the patient group. The presently observed reduced TRECs in panic disorder patients and FOXP3 hypermethylation in female patients with panic disorder potentially reflect impaired thymus and immunosuppressive Treg function, which might partly account for the known increased morbidity and mortality of anxiety disorders conferred by e.g. cancer and cardiovascular disorders