The question concerning human rights and human rightlessness: disposability and struggle in the Bhopal gas disaster

In the midst of concerns about diminishing political support for human rights, individuals and groups across the globe continue to invoke them in their diverse struggles against oppression and injustice. Yet both those concerned with the future of human rights and those who champion rights activism as essential to resistance, assume that human rights – as law, discourse and practices of rights claiming – can ameliorate rightlessness. In questioning this assumption, this article seeks also to reconceptualise rightlessness by engaging with contemporary discussions of disposability and social abandonment in an attempt to be attentive to forms of rightlessness co-emergent with the operations of global capital. Developing a heuristic analytics of rightlessness, it evaluates the relatively recent attempts to mobilise human rights as a frame for analysis and action in the campaigns for justice following the 3 December 1984 gas leak from Union Carbide Corporation’s (UCC) pesticide manufacturing plant in Bhopal, India. Informed by the complex effects of human rights in the amelioration of rightlessness, the article calls for reconstituting human rights as an optics of rightlessness

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

A portfolio of compositions and arrangements [music manuscripts].

Thesis (M.Mus.)-University of Natal, Durban, 1998.No abstract available

University of Kwazulu-Natal Jazz Storytellers Ensemble and the VCU Africa Combo

Two file set First hal

Using exome data to identify malignant hyperthermia susceptibility mutations

Background: Malignant hyperthermia susceptibility (MHS) is a life-threatening, inherited disorder of muscle calcium metabolism, triggered by anesthetics and depolarizing muscle relaxants. An unselected cohort was screened for MHS mutations using exome sequencing. The aim of this study was to pilot a strategy for the RYR1 and CACNA1S genes. Methods: Exome sequencing was performed on 870 volunteers not ascertained for MHS. Variants in RYR1 and CACNA1S were annotated using an algorithm that filtered results based on mutation type, frequency, and information in mutation databases. Variants were scored on a six-point pathogenicity scale. Medical histories and pedigrees were reviewed for malignant hyperthermia and related disorders. Results: The authors identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but the authors excluded synonymous variants. In RYR1, the authors identified 65 missense mutations, one nonsense, two that affected splicing, and one non-frameshift indel. In CACNA1S, 48 missense, one frameshift deletion, one splicing, and one non-frameshift indel were identified. RYR1 variants predicted to be pathogenic for MHS were found in three participants without medical or family histories of MHS. Numerous variants, previously described as pathogenic in mutation databases, were reclassified by the authors as being of unknown pathogenicity. Conclusions: Exome sequencing can identify asymptomatic patients at risk for MHS, although the interpretation of exome variants can be challenging. The use of exome sequencing in unselected cohorts is an important tool to understand the prevalence and penetrance of MHS, a critical challenge for the field. hyperkalemia, as well some or all of the following symptoms: tachycardia, tachypnea, arrhythmias, skeletal muscle rigidity, and lethal hyperthermia. It is inherited in a predominately autosomal dominant pattern and associated with RYR1 or CACNA1S mutations, with other mapped loci. Seventy to 86% of patients with MHS have RYR1 mutations1-5 and 1% have CACNA1S mutations.6 The prevalence and penetrance of MHS mutations are difficult to determine because the pharmacologic exposure rate is low and it is an inconsistently manifesting gene-environment interaction; that is, when a susceptible patient is exposed to a triggering agent, the probability of malignant hyperthermia (MH) is less than 100%. Most MHS gene and variant studies have been performed on families with multiple generations affected with typical MHS. Studying these families made possible the discovery of the two implicated genes. However, these studies had ascertainment biases for those with severe reactions to the drugs. This has complicated efforts to establish the true prevalence and penetrance of MHS mutations. In addition, assigning pathogenicity to RYR1 and CACNA1S variants is challenging for several reasons. First is the issue of locus heterogeneity. With several mapped loci without identified genes, some RYR1 and CACNA1S variants may have been erroneously determined to be pathogenic when there was a causative variant in another (untested) gene. In addition, RYR1 and CACNA1S are large genes with 106 and 44 exons, respectively, making mutation screening challenging. Thus, some RYR1 and CACNA1S variants previously determined to be pathogenic may be benign, as has been shown for other genes.7 New sequencing technologies, including exome sequencing (ES), have made sequencing of the human exome (exons of known genes) feasible. This provides the opportunity to detect mutations in MHS genes in a less biased manner. Using this approach, we can improve our understanding of the mutational spectra of the RYR1 and CACNA1S genes, and estimate their penetrance. Our objective was to identify mutations in RYR1 and CACNA1S in a population not ascertained for MHS, as a pilot for the use of exome data for predictive medicine

Individualized iterative phenotyping for genome-wide analysis of loss-of-function mutations

Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-of-function (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p = 0.0001) and prior report of other mutations in the same exon (p = 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine