Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression

Deliberation, Unjust Exclusion, and the Rhetorical Turn

Theories of deliberative democracy have faced the charge of leading to the unjust exclusion of voices from public deliberation. The recent rhetorical turn in deliberative theory aims to respond to this charge. I distinguish between two variants of this response: the supplementing approach and the systemic approach. On the supplementing approach, rhetorical modes of political speech may legitimately supplement the deliberative process, for the sake of those excluded from the latter. On the systemic approach, rhetorical modes of political speech are legitimate within public deliberation, just so long as they result in net benefits to the deliberative system. I argue that neither of these two approaches adequately meets the unjust exclusion charge. Whereas the supplementing approach does not go far enough to incorporate rhetorical speech into public deliberation, the systemic approach goes too far by legitimizing forms of rhetoric that risk only exacerbating the problem of unjust exclusion. More constructively, I draw on Aristotle’s conception of rhetoric, as an art (technē) that is a counterpart to dialectic, to argue for a constitutive approach to rhetoric. I show how this approach provides a more expansive notion of deliberation that remains normatively orientated

WHO global research priorities for antimicrobial resistance in human health

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR

WHO global research priorities for antimicrobial resistance in human health

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR

United States Bureau of Mines Bulletin 8190

Report issued by the Bureau of Mines over tests conducted on underground mine slimes from a collection sump. Testing methods and results are discussed. This report includes tables, illustrations, and photographs

Hemophagocytic lymphohistiocytosis after SARS-CoV-2 vaccination

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has led to the approval of novel vaccines with different mechanisms of action. Until now, more than 4.7 billion persons have been vaccinated around the world, and adverse effects not observed in pre-authorization trials are being reported at low frequency. METHODS: We report a case of severe hemophagocytic lymphohistiocytosis (HLH) after SARS-CoV-2 immunization and performed a literature search for all reported cases of COVID-19 vaccine-associated HLH. RESULTS: A 24-year-old female developed HLH after immunization with the mRNA COVID-19 vaccine Comirnaty. Diagnosis was made according to HLH-2004 criteria; the HScore was 259 (> 99% HLH probability) with maximum ferritin of 138.244 µg/L. The patient was initially treated with intravenous immunoglobulins (IVIGs) and dexamethasone without response. The addition of the human interleukin 1 receptor antagonist Anakinra resulted in full recovery within 6 weeks after vaccination. A literature search revealed 15 additional cases of HLH after SARS-CoV-2 vaccination, the majority after immunization with Comirnaty (n = 7) or the viral vector vaccine Vaxzevria (n = 6). Treatment modalities included corticosteroids (n = 13), Anakinra (n = 5), IVIGs (n = 5), and etoposide (n = 2). Eight patients underwent combination treatment. Three of 16 patients died. CONCLUSION: COVID-19 vaccines may occasionally trigger HLH, and Anakinra may be an efficacious treatment option for this condition

Limited field tests in electrokinetic densification of mill tailings /

Bibliography: p. 44.Mode of access: Internet

Genotype–phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

PubMed: 331553582-s2.0-85096794765Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression. © 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.Universität zu Köln, UoCWe gratefully acknowledge our patients and their parents. We thank the Cologne Center for Genomics (CCG) for next-generation sequencing. We thank Prof. Ute Hehr for support in the initial phases of the haplotype analysis. We thank Bakush Bakhouche and Marisol Heise for the technical assistance in Sanger Sequencing. The NGS data were analyzed using the Cologne High Efficiency Operating Platform for Science (CHEOPS) of the Regional Computing Centre (RRZK) at the University of Cologne. We thank Prof. J?rgen Winkler for the clinical discussions on the study in the very early phase of the study. Open access funding enabled and organized by Projekt DEAL