Aggregation of full length immunoglobulin light chains from AL amyloidosis patients is remodeled by epigallocatechin-3-gallate

Intervention into amyloid deposition with anti-amyloid agents like the polyphenol Epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and Multiple Myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL they form amyloid deposits in vivo. We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms. We isolated nine LC from urine of AL and MM patients. We quantified their thermodynamic stabilities, and monitored their aggregation under physiological conditions by ThT fluorescence, light scattering, SDS-stability and atomic force microscopy. LC from all patients formed amyloid-like aggregates, albeit with individually different kinetics. LC existed as dimers, ~50% of which were linked by disulfide bridges. Our results suggest that cleavage into LC monomers is required for efficient amyloid formation. The kinetics of AL LC displayed a transition point in concentration dependence, which MM LC lacked. The lack of concentration dependence of MM LC aggregation kinetics suggests that conformational change of the light chain is rate-limiting for these proteins. Aggregation kinetics displayed two distinct phases, which corresponded to the formation of oligomers and amyloid fibrils, respectively. EGCG specifically inhibited the second aggregation phase and induced the formation of SDS-stable, non-amyloid LC aggregates. Our data suggest that EGCG intervention does not depend on the individual LC sequence and is similar to the mechanism observed for amyloid-{beta} and {alpha}-synuclein

Critical Values for Yen’s Q3: Identification of Local Dependence in the Rasch model using Residual Correlations

The assumption of local independence is central to all IRT models. Violations can lead to inflated estimates of reliability and problems with construct validity. For the most widely used fit statistic Q3 there are currently no well-documented suggestions of the critical values which should be used to indicate local dependence, and for this reason a variety of arbitrary rules of thumb are used. In this study, we used an empirical data example and Monte Carlo simulation to investigate the different factors that can influence the null distribution of residual correlations, with the objective of proposing guidelines that researchers and practitioners can follow when making decisions about local dependence during scale development and validation. We propose that a parametric bootstrapping procedure should be implemented in each separate situation in order to obtain the critical value of local dependence applicable to the data set, and provide example critical values for a number of data structure situations. The results show that for the Q3 fit statistic no single critical value is appropriate for all situations, as the percentiles in the empirical null distribution are influenced by the number of items, the sample size, and the number of response categories. Furthermore, our results show that local dependence should be considered relative to the average observed residual correlation, rather than to a uniform value, as this results in more stable percentiles for the null distribution of an adjusted fit statistic

Author finding post print - The Multiple Sclerosis-Fatigue Self- Efficacy (MS-FSE) scale: initial validation.

To examine the validity and sensitivity to change of the Multiple Sclerosis-Fatigue Self-Efficacy scale

Rasch Analysis of the Upper-Limb Sub-scale of the STREAM Tool in an Acute Stroke Population

Background – Stroke is a leading cause of disability worldwide. The most common impairment resulting from stroke is upper limb weakness. Objectives - To determine the usefulness and psychometric validity of the upper limb sub-scale of the STREAM in an acute stroke population. Methods: Rasch Analysis, including unidimensionality assumption testing, determining model fit, and analysis of: reliability, residual correlations, & differential item functioning. Results - 125 individuals were assessed using the upper limb sub-scale of the Stroke Rehabilitation Assessment of Movement (STREAM) tool. Rasch analysis suggests the STREAM is a unidimensional measure. However, when scored using the originally proposed method (0-2), or using the response pattern (0-5) neither variant fit the Rasch model (p < 0.05). Although, the reliability was good (Person-Separation Index – 0.847 & 0.903 respectively). Correcting for the disordered thresholds, and thereby producing the new scoring pattern, led to substantial improvement in the overall fit (chi-square probability of fit - 22%), however, the reliability was slightly reduced (PSI – 0.806). Conclusions - The study proposes a new scoring method for the upper limb sub-scale of the STREAM outcome measure in the acute stroke population.Stroke Associatio

BAERLIN2014 -The influence of land surface types on and the horizontal heterogeneity of air pollutant levels in Berlin

Urban air quality and human health are among the key aspects of future urban planning. In order to address pollutants such as ozone and particulate matter, efforts need to be made to quantify and reduce their concentrations. One important aspect in understanding urban air quality is the influence of urban vegetation which may act as both emitter and sink for trace gases and aerosol particles. In this context, the "Berlin Air quality and Ecosystem Research: Local and long-range Impact of anthropogenic and Natural hydrocarbons 2014" (BAERLIN2014) campaign was conducted between 2 June and 29 August in the metropolitan area of Berlin and Brandenburg, Germany. The predominant goals of the campaign were (1) the characterization of urban gaseous and particulate pollution and its attribution to anthropogenic and natural sources in the region of interest, especially considering the connection between biogenic volatile organic compounds and particulates and ozone; (2) the quantification of the impact of urban vegetation on organic trace gas levels and the presence of oxidants such as ozone; and (3) to explain the local heterogeneity of pollutants by defining the distribution of sources and sinks relevant for the interpretation of model simulations. In order to do so, the campaign included stationary measurements at urban background station and mobile observations carried out from bicycle, van and airborne platforms. This paper provides an overview of the mobile measurements (Mobile BAERLIN2014) and general conclusions drawn from the analysis. Bicycle measurements showed micro-scale variations of temperature and particulate matter, displaying a substantial reduction of mean temperatures and particulate levels in the proximity of vegetated areas compared to typical urban residential area (background) measurements. Van measurements extended the area covered by bicycle observations and included continuous measurements of O3, NOx, CO, CO2 and point-wise measurement of volatile organic compounds (VOCs) at representative sites for traffic- and vegetation-affected sites. The quantification displayed notable horizontal heterogeneity of the short-lived gases and particle number concentrations. For example, baseline concentrations of the traffic-related chemical species CO and NO varied on average by up to ±22.2 and ±63.5 %, respectively, on the scale of 100 m around any measurement location. Airborne observations revealed the dominant source of elevated urban particulate number and mass concentrations being local, i.e., not being caused by long-range transport. Surface-based observations related these two parameters predominantly to traffic sources. Vegetated areas lowered the pollutant concentrations substantially with ozone being reduced most by coniferous forests, which is most likely caused by their reactive biogenic VOC emissions. With respect to the overall potential to reduce air pollutant levels, forests were found to result in the largest decrease, followed by parks and facilities for sports and leisure. Surface temperature was generally 0.6–2.1 °C lower in vegetated regions, which in turn will have an impact on tropospheric chemical processes. Based on our findings, effective future mitigation activities to provide a more sustainable and healthier urban environment should focus predominantly on reducing fossil-fuel emissions from traffic as well as on increasing vegetated areas

Aggregation of Full-length Immunoglobulin Light Chains from Systemic Light Chain Amyloidosis (AL) Patients Is Remodeled by Epigallocatechin-3-gallate

Intervention into amyloid deposition with anti-amyloid agents like the polyphenol epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and multiple myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL do they form amyloid deposits in vivo We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms. We isolated nine LC from the urine of AL and MM patients. We quantified their thermodynamic stabilities and monitored their aggregation under physiological conditions by thioflavin T fluorescence, light scattering, SDS stability, and atomic force microscopy. LC from all patients formed amyloid-like aggregates, albeit with individually different kinetics. LC existed as dimers, ∼50% of which were linked by disulfide bridges. Our results suggest that cleavage into LC monomers is required for efficient amyloid formation. The kinetics of AL LC displayed a transition point in concentration dependence, which MM LC lacked. The lack of concentration dependence of MM LC aggregation kinetics suggests that conformational change of the light chain is rate-limiting for these proteins. Aggregation kinetics displayed two distinct phases, which corresponded to the formation of oligomers and amyloid fibrils, respectively. EGCG specifically inhibited the second aggregation phase and induced the formation of SDS-stable, non-amyloid LC aggregates. Our data suggest that EGCG intervention does not depend on the individual LC sequence and is similar to the mechanism observed for amyloid-β and α-synuclein

Efficacy of five ‘sporicidal’ surface disinfectants against Clostridioides difficile spores in suspension tests and 4-field tests

Background: A sporicidal surface disinfection is recommended both for the outbreak and the endemic setting but a comparative evaluation on the efficacy of ‘sporicidal’ surface disinfectants using suspension tests and 4-field tests has not been performed. Aim: To determine the efficacy of five ‘sporicidal’ surface disinfectants (three ready-to-use wipes (A, B, E), two concentrates (C, D) based on peroxides or aldehydes against C. difficile spores. Methods: The efficacy was determined under clean conditions using a suspension test and the 4-field test. Each test was performed in duplicate in two separate laboratories. Wipes were wrung to collect the solution for the suspension tests. Results: Product A (peracetic acid; 5 min), product C (peracetic acid; 2% solution in 15 min or 1% solution in 30 min) and product D (peracetic acid; only 2% solution in 15 min) were effective with at least a 4 log10-reduction of C. difficile spores in suspension and on surfaces. Product B (hydrogen peroxide) was not effective in suspension (0.9 log10 after 15 min; 3.2 log10 after 1 h) and on surfaces (2.8 log10 after 15 and 60 min). Product E based on glutaraldehyde, (ethylendioxy)dimethanol and DDAC demonstrated 0.9 log10 after 4 h in suspension and 4.5 log10 after 4 h on surfaces. Conclusions: Not all surface disinfectants with a sporicidal claim were effective against C. difficile spores in standardized suspension tests and in the 4-field test. In clinical practice preference should be given to products that reliably pass the efficacy criteria of both types of tests.Peer Reviewe