Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of Sulfasalazine for the treatment of progressing malignant gliomas in adults

BACKGROUND: Sulfasalazine, a NF-kappaB and x(c)-cystine/glutamate antiport inhibitor, has demonstrated a strong antitumoral potential in preclinical models of malignant gliomas. As it presents an excellent safety profile, we initiated a phase 1/2 clinical study of this anti-inflammatory drug for the treatment of recurrent WHO grade 3 and 4 astrocytic gliomas in adults. METHODS: 10 patients with advanced recurrent anaplastic astrocytoma (n = 2) or glioblastoma (n = 8) aged 32-62 years were recruited prior to the planned interim analysis of the study. Subjects were randomly assigned to daily doses of 1.5, 3, 4.5, or 6 grams of oral sulfasalazine, and treated until clinical or radiological evidence of disease progression or the development of serious or unbearable side effects. Primary endpoints were the evaluation of toxicities according to the CTCAE v.3.0, and the observation of radiological tumor responses based on MacDonald criteria. RESULTS: No clinical response was observed. One tumor remained stable for 2 months with sulfasalazine treatment, at the lowest daily dose of the drug. The median progression-free survival was 32 days. Side effects were common, as all patients developed grade 1-3 adverse events (mean: 7.2/patient), four patients developed grade 4 toxicity. Two patients died while on treatment or shortly after its discontinuation. CONCLUSION: Although the proper influence of sulfasalazine treatment on patient outcome was difficult to ascertain in these debilitated patients with a large tumor burden (median KPS = 50), ISRCTN45828668 was terminated after its interim analysis. This study urges to exert cautiousness in future trials of Sulfasalazine for the treatment of malignant gliomas. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45828668

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

Low-latency and secure computation offloading assisted by hybrid relay-reflecting intelligent surface

Abstract Recently, the hybrid relay-reflecting intelligent surface (HRRIS) has been introduced as a spectral- and energy-efficient architecture to assist wireless communication systems. In the HRRIS, a single or few active relay elements are deployed along with a large number of passive reflecting elements, allowing it to not only reflect but also amplify the incident signals. In this work, we investigate the potential of the HRRIS in aiding the computation offloading in a single-user mobile edge computing system. The objective is to minimize the offloading latency while ensuring the secrecy of user data against a malicious eavesdropper. We develop efficient solutions to this latency minimization problem based on alternating optimization. Through numerical results, we show that the deployment of the HRRIS can result in a considerable reduction in latency. Furthermore, the latency reduction gain offered by the HRRIS is much more significant than that of the conventional reconfigurable intelligent surface (RIS)

SHREC\u2719 Track: Extended 2D Scene Image-Based 3D Scene Retrieval

In the months following our SHREC 2018-2D Scene Image-Based 3D Scene Retrieval (Scene IBR2018) track, we have extended the number of the scene categories fro the initial 10 classes in the Scene IBR2018 benchmark to 30 classes, resulting in a new benchmark Scene IBR2019 which has 30,000 scene images and 3,000 3D scene models. For that reason, we seek to further evaluate the performance of existing and 2D scene image-based 3D scene retrieval algorithms using this extended and more comprehensive new benchmark. Three groups from the Netherlands, the United States and Vietnam participated and collectively submitted eight runs. This report documents the evaluation of each method based on seven performances metrics, offers an in-depth discussion as well as analysis on the methods employed and discusses future directions that have the potential to address this task. Again, deep learning techniques have demonstrated notable performance in terms of both accuracy and scalability when applied to this exigent retrieval task. To further enrich the current state of 3D scene understanding and retrieval, our evaluation toolkit, all participating methods\u27 results and the comprehensive 2D/3D benchmark have all been make publicly available

Encountering the vietnamese habitus

© 2019, Springer Nature Singapore Pte Ltd. This chapter provides insights into what the Vietnamese habitus may look like – aspects of cultural and social norms, political culture and educational values – through a series of historical experiences that shape contemporary Vietnamese society. Five characteristics of the Vietnamese habitus are considered and discussed in terms of the relationships between people, people and society, society and the State: personal relations that act as the moral foundation of the Vietnamese person, individualistic dispositions in Vietnamese society, nationalism and democratic centralism of Vietnam’s political system, economic pragmatism in everyday life and international influences on the development of Vietnam’s education system and tradition of studying abroad. The chapter foregrounds the Vietnamese habitus in the three ‘fields’ (economic, intellectual and civic) as formative conditions of the returnees’ motivations and expectations of their acquired overseas education and provides the sociocultural logic for returnees’ choice and actions in these fields, which will be discussed in depth in the next four chapters