Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach

The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis; however, molecular diagnostics to date have focused largely on first-line drugs and predicting binary susceptibilities. We used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration in 15,211 Mycobacterium tuberculosis patient isolates from 23 countries across five continents. This identified 492 unique MIC-elevating variants across thirteen drugs, as well as 91 mutations resulting in hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms

Seminar on Securities Law

Materials from the UK/CLE Seminar on Securities Law held February 14-15, 1986

Views and Experiences of Sex, Sexuality and Relationships Following Spinal Cord Injury: A Systematic Review and Narrative Synthesis of the Qualitative Literature

Research examining the effects of spinal cord injury on sexuality has largely focused on physiological functioning and quantification of dysfunction following injury. This paper reports a systematic review of qualitative research that focused on the views and experiences of people with spinal cord injury on sex and relationships. The review addressed the following research question: What are the views and experiences of people with spinal cord injury of sex, sexuality and relationships following injury? Five databases were relevant and employed in the review: CINAHL (1989-2016 only), PsychInfo, PubMed, Scopus and Web of Science, for research published between 1 January 1980 and 30 November 2019. After removing duplicates, 257 records remained and were screened using a two-stage approach to inclusion and quality appraisal. Following screening, 27 met the criteria for inclusion and are reported in the paper. The review includes studies from fifteen countries across five continents. Two main approaches to data analysis summary and thematic synthesis were undertaken to analyze the qualitative data reported in the papers. The analysis revealed four main themes: sexual identity; significant and generalized others, sexual embodiment; and; sexual rehabilitation and education

Neoliberalism as Liberation: The Statehood Program and the Remaking of the Palestinian National Movement

The Palestinian statehood-by-2011 program, framed through neoliberal institution building, redefines and diverts the Palestinian liberation struggle. Focusing on its economic aspects, and in particular the underlying neoliberal thought that goes beyond narrow economic policy applications, this essay argues that the program cannot succeed either as the midwife of independence or as a strategy for Palestinian economic development. Its weaknesses, the authors contend, derive not only from neoliberalism’s inability to deliver sustainable and equitable economic growth worldwide, but also because neoliberal “governance” under occupation, however “good,” cannot substitute for the broader struggle for national rights nor ensure the Palestinian right to development

Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin

The Parkinson’s disease factors PINK1 and parkin are strongly implicated in stress-induced mitophagy in vitro, but little is known about their impact on basal mitophagy in vivo. We generated transgenic Drosophila melanogaster expressing fluorescent mitophagy reporters to evaluate the impact of Pink1/parkin mutations on basal mitophagy under physiological conditions. We find that mitophagy is readily detectable and abundant in many tissues, including Parkinson’s disease–relevant dopaminergic neurons. However, we did not detect mitolysosomes in flight muscle. Surprisingly, in Pink1 or parkin null flies, we did not observe any substantial impact on basal mitophagy. Because these flies exhibit locomotor defects and dopaminergic neuron loss, our findings raise questions about current assumptions of the pathogenic mechanism associated with the PINK1/parkin pathway. Our findings provide evidence that Pink1 and parkin are not essential for bulk basal mitophagy in Drosophila. They also emphasize that mechanisms underpinning basal mitophagy remain largely obscure

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation