Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

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

Recent TWSTFT experiments at INRiM Time and Frequency Laboratory

Two-Way Satellite Time and Frequency Transfer (TWSTFT) is a technique selected by many timing laboratories around the world for the comparison of atomic clocks and time scales over distance. INRiM Time and Frequency laboratory operates two TWSTFT ground stations, whose data contributes to the calculation of the Coordinated Universal Time (UTC) and to the generation and performance monitoring of the Galileo System Time. This paper presents INRiM TWSTFT recent and future development and experiments

Clinicopathological Risk Factors of Unfavorable Outcomes in Vietnamese Women with Primary Invasive Breast Cancer: A Retrospective Cohort Study

Chau Giang Huynh,1 Nghiem Xuan Huynh,1 Bich-Ha Thi Truong,2 Truc Thanh Thai,3 Phuong-Thao Thi Doan4 1Department of Pathology, Hung Vuong Hospital, Ho Chi Minh City, Vietnam; 2Department of Obstetrics and Gynecology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam; 3Department of Medical Statistics and Informatics, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam; 4Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, VietnamCorrespondence: Truc Thanh Thai, University of Medicine and Pharmacy at Ho Chi Minh City, 217 Hong Bang, Ward 11, District 5, Ho Chi Minh City, Vietnam, Tel +84 908 381 266, Email [email protected]: The rate of unfavorable outcomes, such as recurrence and death, in women with invasive breast cancer varies widely across countries and populations. Identifying those with high-risk profiles is critical so that early detection, prediction, and intervention can be made to improve their survival rate. Therefore, our study evaluated the rate of unfavorable outcomes and its association with clinicopathological characteristics in Vietnamese women with primary invasive breast cancer.Methods: A retrospective open cohort study was conducted on Vietnamese women with invasive breast cancer who underwent a mastectomy and were regularly followed up by the hospitals. Kaplan–Meier method was used to estimate the rate of unfavorable outcomes to take into account the follow-up time of each patient. Univariate and multiple Cox regression analyses were conducted to examine the associations between unfavorable outcomes and clinicopathological characteristics.Results: Among 204 women included in the data analysis, the mean age was 54.4 ± 10.9 years. The majority of patients were diagnosed with early-stage (76.5%) or locally advanced (22.5%) breast cancer. The 5-year rate of unfavorable outcomes was 12.8%, and the 8-year rate was 31.7%. Patients with advanced stages had a higher risk of unfavorable outcomes compared to those with early stages (IA, IIA, T2N1). Patients with lymph node metastases and those with triple-negative molecular classification had significantly higher rates of unfavorable outcomes.Conclusion: Although Vietnamese women with breast cancer have a relatively low rate of unfavorable outcomes compared to other countries, findings from this study emphasize the importance of early detection and underscore the need for targeted interventions for patients with advanced stages, lymph node metastases, and triple-negative breast cancer to optimize their treatment, outcomes, and overall prognosis.Keywords: unfavorable outcomes, invasive breast cancer, high-risk profiles, clinicopathological characteristics, Vietnamese wome

Soft Microtubule Muscle-Driven 3-Axis Skin-Stretch Haptic Devices

In the real world, people heavily rely on haptic or touch to manipulate objects. In emergingsystems such as assistive devices, remote surgery, self-driving cars and the guidance of human movements,visual or auditory feedback can be slow, unintuitive and increase the cognitive load. Skin stretch devices(SSDs) that apply tangential force to the skin via a tactor can encode a far richer haptic space, not beinglimited to force, motion, direction, stiffness, indentation and surface geometry. This paper introduces novelhand-worn hydraulic SSDs that can induce 3-axis tangential forces to the skin via a tactor. The developedSSDs are controlled by new soft microtubule muscles (SMMs) which are driven by hydraulic pressurevia custom miniature syringes and DC micromotors. An analytical model is developed to characterizethe responses of SMM output in terms of force and elongation. A kinematic model for the motion of the3-axis SSD is also developed. We evaluate the capability of the tactor head to track circular referencetrajectories within different working spaces using an optical tracking system. Experimental results showthat the developed SSDs have good durability, high-speed, and can generate omnidirectional shear forcesand desired displacement up to 1.8 N and 4.5 mm, respectively. The developed SMMs and SSDs created inthis paper will enable new forms of haptic communication to augment human performance during dailyactivities such as tactile textual language, motion guidance and navigational assistance, remote surgicalsystems, rehabilitation, education, training, entertainment, or virtual and augmented reality