Comparative assessment of clinical rating scales in Wilson’s disease

Background: Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism resulting in multifaceted neurological, hepatic, and psychiatric symptoms. The objective of the study was to comparatively assess two clinical rating scales for WD, the Unified Wilson’s Disease Rating Scale (UWDRS) and the Global Assessment Scale for Wilson’s disease (GAS for WD), and to test the feasibility of the patient reported part of the UWDRS neurological subscale (termed the “minimal UWDRS”). Methods: In this prospective, monocentric, cross-sectional study, 65 patients (median age 35 [range: 15–62] years; 33 female, 32 male) with treated WD were scored according to the two rating scales. Results: The UWDRS neurological subscore correlated with the GAS for WD Tier 2 score (r = 0.80; p < 0.001). Correlations of the UWDRS hepatic subscore and the GAS for WD Tier 1 score with both the Model for End Stage Liver Disease (MELD) score (r = 0.44/r = 0.28; p < 0.001/p = 0.027) and the Child-Pugh score (r = 0.32/r = 0.12; p = 0.015/p = 0.376) were weak. The “minimal UWDRS” score significantly correlated with the UWDRS total score (r = 0.86), the UWDRS neurological subscore (r = 0.89), and the GAS for WD Tier 2 score (r = 0.86). Conclusions: The UWDRS neurological and psychiatric subscales and the GAS for WD Tier 2 score are valuable tools for the clinical assessment of WD patients. The “minimal UWDRS” is a practical prescreening tool outside scientific trials

Different paths to the modern state in Europe: the interaction between domestic political economy and interstate competition

Theoretical work on state formation and capacity has focused mostly on early modern Europe and on the experience of western European states during this period. While a number of European states monopolized domestic tax collection and achieved gains in state capacity during the early modern era, for others revenues stagnated or even declined, and these variations motivated alternative hypotheses for determinants of fiscal and state capacity. In this study we test the basic hypotheses in the existing literature making use of the large date set we have compiled for all of the leading states across the continent. We find strong empirical support for two prevailing threads in the literature, arguing respectively that interstate wars and changes in economic structure towards an urbanized economy had positive fiscal impact. Regarding the main point of contention in the theoretical literature, whether it was representative or authoritarian political regimes that facilitated the gains in fiscal capacity, we do not find conclusive evidence that one performed better than the other. Instead, the empirical evidence we have gathered lends supports to the hypothesis that when under pressure of war, the fiscal performance of representative regimes was better in the more urbanized-commercial economies and the fiscal performance of authoritarian regimes was better in rural-agrarian economie

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Perceived risk, anxiety, and behavioural responses of the general public during the early phase of the Influenza A (H1N1) pandemic in the Netherlands: Results of three consecutive online surveys

Background: Research into risk perception and behavioural responses in case of emerging infectious diseases is still relatively new. The aim of this study was to examine perceptions and behaviours of the general public during the early phase of the Influenza A (H1N1) pandemic in the Netherlands. Methods. Two cross-sectional and one follow-up online survey (survey 1, 30 April-4 May; survey 2, 15-19 June; survey 3, 11-20 August 2009). Adults aged 18 years and above participating in a representative Internet panel were invited (survey 1, n = 456; survey 2, n = 478; follow-up survey 3, n = 934). Main outcome measures were 1) time trends in risk perception, feelings of anxiety, and behavioural responses (survey 1-3) and 2) factors associated with taking preventive measures and strong intention to comply with government-advised preventive measures in the future (survey 3). Results. Between May and August 2009, the level of knowledge regarding Influenza A (H1N1) increased, while perceived severity of the new flu, perceived self-efficacy, and intention to comply with preventive measures decreased. The perceived reliability of information from the government decreased from May to August (62% versus 45%). Feelings of anxiety decreased from May to June, and remained stable afterwards. From June to August 2009, perceived vulnerability increased and more respondents took preventive measures (14% versus 38%). Taking preventive measures was associated with no children in the household, high anxiety, high self-efficacy, more agreement with statements on avoidance, and paying much attention to media information regarding Influenza A (H1N1). Having a strong intention to comply with government-advised preventive measures in the future was associated with higher age, high perceived severity, high anxiety, high perceived efficacy of measures, high self-efficacy, and finding governmental information to be reliable. Conclusions. Decreasing tren

Perceived Threat, Risk Perception, and Efficacy Beliefs Related to SARS and Other (Emerging) Infectious Diseases: Results of an International Survey

PURPOSE: To study the levels of perceived threat, perceived severity, perceived vulnerability, response efficacy, and self-efficacy for severe acute respiratory syndrome (SARS) and eight other diseases in five European and three Asian countries. METHOD: A computer-assisted phone survey was conducted among 3,436 respondents. The questionnaire focused on perceived threat, vulnerability, severity, response efficacy, and self-efficacy related to SARS and eight other diseases. RESULTS: Perceived threat of SARS in case of an outbreak in the country was higher than that of other diseases. Perceived vulnerability of SARS was at an intermediate level and perceived severity was high compared to other diseases. Perceived threat for SARS varied between countries in Europe and Asia with a higher perceived severity of SARS in Europe and a higher perceived vulnerability in Asia. Response efficacy and self-efficacy for SARS were higher in Asia compared to Europe. In multiple linear regression analyses, country was strongly associated with perceived threat. CONCLUSIONS: The relatively high perceived threat for SARS indicates that it is seen as a public health risk and offers a basis for communication in case of an outbreak. The strong association between perceived threat and country and different regional patterns require further researc

Testing theories of post-error slowing

People tend to slow down after they make an error. This phenomenon, generally referred to as post-error slowing, has been hypothesized to reflect perceptual distraction, time wasted on irrelevant processes, an a priori bias against the response made in error, increased variability in a priori bias, or an increase in response caution. Although the response caution interpretation has dominated the empirical literature, little research has attempted to test this interpretation in the context of a formal process model. Here, we used the drift diffusion model to isolate and identify the psychological processes responsible for post-error slowing. In a very large lexical decision data set, we found that post-error slowing was associated with an increase in response caution and—to a lesser extent—a change in response bias. In the present data set, we found no evidence that post-error slowing is caused by perceptual distraction or time wasted on irrelevant processes. These results support a response-monitoring account of post-error slowing

An OBSL1-Cul7Fbxw8 Ubiquitin Ligase Signaling Mechanism Regulates Golgi Morphology and Dendrite Patterning

The elaboration of dendrites in neurons requires secretory trafficking through the Golgi apparatus, but the mechanisms that govern Golgi function in neuronal morphogenesis in the brain have remained largely unexplored. Here, we report that the E3 ubiquitin ligase Cul7Fbxw8 localizes to the Golgi complex in mammalian brain neurons. Inhibition of Cul7Fbxw8 by independent approaches including Fbxw8 knockdown reveals that Cul7Fbxw8 is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo. Inhibition of Cul7Fbxw8 also dramatically impairs the morphology of the Golgi complex, leading to deficient secretory trafficking in neurons. Using an immunoprecipitation/mass spectrometry screening approach, we also uncover the cytoskeletal adaptor protein OBSL1 as a critical regulator of Cul7Fbxw8 in Golgi morphogenesis and dendrite elaboration. OBSL1 forms a physical complex with the scaffold protein Cul7 and thereby localizes Cul7 at the Golgi apparatus. Accordingly, OBSL1 is required for the morphogenesis of the Golgi apparatus and the elaboration of dendrites. Finally, we identify the Golgi protein Grasp65 as a novel and physiologically relevant substrate of Cul7Fbxw8 in the control of Golgi and dendrite morphogenesis in neurons. Collectively, these findings define a novel OBSL1-regulated Cul7Fbxw8 ubiquitin signaling mechanism that orchestrates the morphogenesis of the Golgi apparatus and patterning of dendrites, with fundamental implications for our understanding of brain development