Courage-als: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success

Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS). Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial. Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort. Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS)

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

„Was wissen Freizeitreiter über die allgemeine Pferdegesundheit - Brauchen wir einen Pferdeführerschein?“

Der Tierschutzgedanke und die Pferdegesundheit sind aktuelle Themen im Pfer-desport. Auch die Freizeitreiter sollten sich mit diesen Themen beschäftigen, um ihrem Pferd ein psychisch und physisch artgerechtes Leben zu gestalten. Doch wie gut ist das Wissen der Freizeitreiter wirklich? Diese Bachelorarbeit soll das Wissen der Freizeitreiter auf dem Gebiet der Pfer-degesundheit näher beleuchten. Durch eine Umfrage unter den Freizeitreitern soll festgestellt werden, in welchen Bereichen Defizite zu erkennen sind und Hand-lungsbedarf besteht. Es soll erläutert werden, ob die Einführung eines Pferdefüh-rerscheines sinnvoll ist. Der Literaturteil beschäftigt sich mit den wichtigsten Grundlagen der Pferdegesundheit, ihrer Bedeutung und Auswirkungen. Die Befragung der Freizeitreiter hat ergeben, dass deutliche Defizite in den Berei-chen der Vitalparameter, Fütterung und der Pferdehaltung bestehen. Die Perso-nen, die über den Basispass verfügen haben einen höheren Wissensstand, wel-ches in der korrekten Beantwortung der Fragen deutlich wurde. Gründe für das mangelnde Wissen der Personen, die sich mit dem Pferd beschäftigen, wurden nicht erarbeitet. Einen Pferdeführerschein einzuführen wird in der Umsetzung schwierig, jedoch ist deutlich geworden, dass das Vorhandensein des Basispas-ses das Wissen positiv beeinflusst. Zurzeit besteht nur die Möglichkeit an das ei-gene Verantwortungsbewusstsein zu appellieren sich genügend Wissen und Fä-higkeiten anzueignen. Ein Thema, das sicherlich auch in den Verbänden diskutiert werden sollte

Public health and social measures during health emergencies such as the COVID‐19 pandemic: An initial framework to conceptualize and classify measures

Background: Public health and social measures (PHSM) intend to reduce the transmission of infectious diseases and to reduce the burden on health systems, economies and societies. During the COVID-19 pandemic, PHSM have been selected, combined and implemented in a variable manner and inconsistently categorized in policy trackers. This paper presents an initial conceptual framework depicting how PHSM operate in a complex system, enabling a wide-reaching description of these measures and their intended and unintended outcomes. / Methods: In a multi-stage development process, we combined (i) a complexity perspective and systems thinking; (ii) literature on existing COVID-19 PHSM frameworks, taxonomies and policy trackers; (iii) expert input and (iv) application to school and international travel measures. / Results: The initial framework reflects our current understanding of how PHSM are intended to achieve transmission-related outcomes in a complex system, offering visualizations, definitions and worked examples. First, PHSM operate through two basic mechanisms, that is, reducing contacts and/or making contacts safer. Second, PHSM are defined not only by the measures themselves but by their stringency and application to specific populations and settings. Third, PHSM are critically influenced by contextual factors. The framework provides a tool for structured thinking and further development, rather than a ready-to-use tool for practice. / Conclusions: This conceptual framework seeks to facilitate coordinated, interdisciplinary research on PHSM effectiveness, impact and implementation; enable consistent, coherent PHSM monitoring and evaluation; and contribute to evidence-informed decision-making on PHSM implementation, adaptation and de-implementation. We expect this framework to be modified and refined over time

Additional file 1: Figure S1. of α-synuclein interacts with SOD1 and promotes its oligomerization

Concept of the extracellular complementation assay: Cells expressing proteins with n-terminal halve of hGluc or proteins with c-terminal halve of hGluc were lysed, followed by determination the concentrations α-synuclein and SOD1. Lysates were adjusted to the same molarity of α-synuclein or SOD1 and combined. After incubation, luciferase activity was measured. (TIF 2014 kb