Understanding symptoms in RYR1-Related Myopathies: A mixed-methods analysis based on participants' experience

Background: In rare diseases such as ryanodine receptor 1-related myopathies (RYR1-RM), health-related quality of life (HRQoL) measures are critically important so clinicians and researchers can better understand what symptoms are most important to participants, with the ultimate goal of finding tangible solutions for them. Objectives: The main objective of this study was to characterize symptoms in individuals with RYR1-RM to inform future research. A secondary objective of this study was to analyze positive and negative sentiments regarding symptoms and treatment effects post N-acetylcysteine (NAC) administration in individuals with RYR1-RM. Methods: The study used a mixed-methods design applying methodological triangulation. Qualitative data were collected via semi-structured interviews at three visits to characterize symptoms in individuals with RYR1-RM and to analyze treatment effects. Qualitative data were then transformed into quantitative results to measure the frequency with which each symptom was mentioned by participants. Results: A total of 12 symptoms were identified as areas of interest to participants with RYR1-RM, highlighting fatigue and weakness as key symptoms. Data transformation categorized more than 1000 citations, reporting a greater number of positive comments for post-intervention interviews than for baseline and pre-intervention visits and that NAC group participants stated more positive comments regarding treatment effect than did the placebo group. Conclusions: We present a comprehensive characterization of symptoms in RYR1-RM and how those symptoms influence HRQoL. Furthermore, the introduction of mixed methods may be a valuable way to better understand patient-centered data in rare diseases to support affected individuals in coping with their symptoms

Mixed methods analysis of Health-Related Quality of Life in ambulant individuals affected with RYR1-related myopathies pre-post-N-acetylcysteine therapy

Purpose: To characterize Health-Related Quality of Life (HRQoL) in ambulant individuals with RYR1-RM and to determine if a qualitative PRO tool (subjective self-assessment) complements PROMIS and Neuro-QoL scales to detect changes in HRQoL in ambulant individuals with RYR1-RM post N-acetylcysteine (NAC) treatment. Methods: The study used a mixed methods research (MMR) design applying methodological triangulation. Qualitative data were collected via semi-structured interviews using open-ended questions. Quantitative data were gathered through PROMIS and Neuro-QoL instruments. Additionally, qualitative data were transformed into quantitative data for subjective self-assessment and frequency analyses. Results: Qualitative results identified five domains and 33 subdomains as areas of interest. The most valuable were the importance of social impacts, the development of several coping strategies, both physical and psychological, and the identification of fatigue and weakness as key symptoms. Data transformation then categorized more than 3100 citations on frequency analyses, globally and by domain, visit, and participant. Regarding quantitative results, there was no clear evidence that any of the three PRO tools captured positive changes as a result of NAC treatment. Conclusion: Qualitative results showed a comprehensive characterization of HRQoL in this population based on a symptom/patient-centered approach. These findings will inform future studies. Furthermore, given the similar findings across our multiple methods and endpoints, the introduction of MMR may be a valuable, complementary approach to clinical trials. MMR may be especially useful to incorporate in order to address and follow the FDA's guidance and prioritization on the inclusion of affected individuals' perspectives in clinical trials

COST COMPARISONS OF REMEDIAL METHODS TO CORRECT TRACK SUBSTRUCTURE INSTABILITY

The effectiveness and costs of various remedies for stabilizing track over a soft clay subgrade were tested and compared. To date, the techniques of repeated tamping, increasing granular layer thickness, and placing a geoweb layer have been tested under 39-kip (170-kN) wheel-load traffic. Using typical industry cost figures, economic analysis shows that the most cost-effective selection depends on traffic volume. For the heavy-axle load conditions studied at the Facility for Accelerated Service Testing (located at the Federal Railroad Administration\u27s Transportation Technology Center, Inc., near Pueblo, Colorado), analysis indicates that continued tamping of the ballast can be the best choice when the annual tonnage is less than about 40 million gross tons (MGT; 360 GN). For annual tonnage levels greater than 50 MGT (450 GN), fixing the problem by use of a remedial technique is less costly. Of the two remedies tested, increasing the granular layer thickness appears to be the lower cost option, mainly because of the lower material cost compared with geoweb. The intent of this analysis is to help railroads decide whether to make temporary repairs with low initial costs or more permanent remediation with higher initial costs

IMPROVED SPIRAL GEOMETRY FOR HIGH-SPEED RAIL AND PREDICTED VEHICLE RESPONSE

Two railroad curve transition spiral shapes are compared with respect to their dynamic performance: the traditional linear shape and an improved shape intended to provide optimal dynamic performance. The improved shape is attractive because it gives much better dynamic performance and flows from an improved way of thinking about spirals. The improved spiral design method and spiral shape to be evaluated are discussed, then results from simulating the operation of a rail vehicle over an improved spiral and over the corresponding traditional spiral are compared. The simulations were done using the NUCARS simulation program and a model of the Amtrak Acela passenger car. The simulated motion of the vehicle over the traditional spiral exhibits undesirable fluctuations of two types with different strengths and distinct causes. The weaker fluctuations are the result of impacts of wheel flanges against the outside rail partway through the spiral. These impacts might be softened or eliminated by use of a truck design that could steer more effectively than the design that was simulated (or by making spirals much longer). They are not much affected by the kind of spiral geometry used. The stronger fluctuations are caused by the shape of the traditional spiral and particularly by the abruptness with which superelevation ramp angle changes at each end. The improved spiral geometry eliminates these fluctuations almost completely and thereby will improve ride comfort and may reduce the cost of maintaining spiral track alignment