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

Increasing the Impact Toughness of Cellulose Fiber Reinforced Polypropylene Composites—Influence of Different Impact Modifiers and Production Scales

While cellulose fiber reinforced polypropylene (PP) composites typically offer good stiffness and strength in combination with ecological benefits and a high potential for lightweight construction, they often require measures taken to improve their impact performance. In this work, the influence of different types of impact modifier on the mechanical performance of a PP–cellulose composite was systematically investigated, with a particular focus on the improvement of the notched impact strength and the accompanying loss of stiffness. Among the tested impact modifiers, ethylene-octene copolymers appeared to be the most suitable class to achieve a good overall performance. A high modifier viscosity increased its potential to improve the notched impact strength of the composite. Additionally, composite production on a larger scale improved the impact performance without significantly affecting the tensile properties. Several composites from this study surpassed the overall mechanical performance of a benchmark commercial PP–cellulose composite. While the impact strength of commercial high-impact PP–talc composites could not be reached, the considerably lower density of the PP–cellulose composites is worth mentioning

TOUCH® Prosthesis for Thumb Carpometacarpal Joint Osteoarthritis: A Prospective Case Series

The dual mobility concept currently represents the newest generation of thumb carpometacarpal prostheses. The aim of this study was to evaluate the short-term outcomes of TOUCH® prosthesis. From September 2019 to July 2020, 40 prosthesis were implanted in 37 patients suffering from symptomatic stage III osteoarthritis. All included patients with a median age of 57.7 (IQR: 13.6) finished the systematic follow-up regimen (4, 8, 16 weeks, 6, and 12 months postoperatively). All parameters significantly improved (p < 0.0001) compared to the preoperative status. At 1 year follow-up, median DASH Scores decreased from 54 (IQR 22) to 12 (IQR 28) and pain levels improved from 8 (IQR 2) to 1 (IQR 2). Moreover, key-pinch strength increased from 3.8 (2.0) to 5.8 (2.5), while palmar abduction, radial abduction, and opposition also significantly improved. 35/37 patients were satisfied with the functional outcomes. We observed 10 complications, of which 6 were tendon-related issues, and 2 were due to an inappropriate choice of neck size. We could detect one dislocation but no evidence of cup loosening, tilting or subsidence in any patient. Despite the occurrence of some complications, we recommend implantation of this prosthesis type due to favorable clinical and radiological performance

Liparthroplasty for Thumb Carpometacarpal Joint Osteoarthritis: A Case Series with Median 5 Years of Follow-Up

Liparthroplasty has recently been discussed as a promising bridging therapy after failed conservative treatment options to postpone arthroplasty surgery of the thumb carpometacarpal joint as long as possible. The current study investigates the sustainability of this method in seven stage II and twenty-four stage III osteoarthritis patients (twenty-seven female and four male cases). Data were evaluated preinterventionally, six months postinterventionally, and two years postinterventionally, as well as a final follow-up assessment after median 5.1 years. We found a significant reduction of all postinterventional disabilities of the arm, shoulder, and hand (dash) scores and pain levels compared to the ones prior to liparthroplasty. Moreover, we even detected a reduction in both parameters within the postinterventional course, so that the DASH scores of our final investigation were significantly lower than the values after six months. Furthermore, 12 of our 31 cases demanded a surgical conversion due to recurrence of symptoms. A binary regression analysis found smokers to have 11 times higher odds for therapy failure, leading to surgical conversion. Seventeen out of nineteen patients in our final assessment stated that they were pleased with liparthroplasty. Due to favorable mid-term outcomes of 61% of the 31 initially treated patients, we recommend liparthroplasty as a reliable bridging therapy for preserving joint integrity as long as possible, especially in non-smoking patients

Morphology and Characterisation of Novolac–LDPE-Based Mixtures as Matrix for Injection Moulded Green Bodies for Bio-Based SiC Ceramics

This work focuses on the influence of the composition of novolac–LDPE-based mixtures, which serve as a matrix for the green bodies for bio-based silicon carbide (C/Si/SiC) ceramics, on the morphology and the mechanical properties of the green bodies and the ceramics produced thereof. The green bodies were obtained through compounding and injection moulding, and were characterised by scanning electron microscopy (SEM) and mechanical testing. Selected formulations were reinforced with natural fibres, pyrolysed to yield porous carbon templates, and converted into C/Si/SiC ceramics via liquid silicon infiltration. The carbon and ceramic specimens were characterised by light optical microscopy (LOM) and mechanical testing. Without further additives, very coarse morphologies of the novolac–LDPE-based mixtures were obtained, but the miscibility could be improved by the addition of a coupling agent and a lubricant. The pore structure of the carbon specimens was dependent on the phase distribution in the green bodies, and in turn determined the morphology of the C/Si/SiC ceramics. In all steps of the process chain, the morphology had a very strong influence on the mechanical properties. From green bodies with a homogeneous phase distribution, ceramic specimens with a SiC content of up to 75 vol% could be obtained

Determination of the gel point of formaldehyde-based wood adhesives by using a multiwave technique

Determining the instant of gelation of formaldehyde-based wood adhesives as an assessment parameter for their curing rate is important for optimizing the curing behavior. Due to the stoichiometrically imbalanced networks of formaldehyde-based adhesives, the crossover point of storage G′ and loss modulus G″ cannot unconditionally be assumed as the gel point in oscillatory time sweeps as the material response is frequency-dependent. This study aims to determine the gel point of selected adhesives by the isothermal multiwave oscillatory shear test. A thorough comparison between the gel and the crossover point of G′ and G″ is performed. Rheokinetic analysis showed no significant difference between the activation energies calculated at the gel point determined by a multiwave test and the crossover point obtained by the time sweep test. Hence, for resins with similar curing reactions, a reliable determination of gel point by applying a multiwave test is needed for a comparison of their reactivity

Pr@senZ - P@CE: Mobile Interaction with Virtual Reality

Weber M, Pfeiffer T, Jung B. Pr@senZ - P@CE: Mobile Interaction with Virtual Reality. In: Tscheligi M, Bernhaupt R, Mihalic K, Association for Computing Machinery, eds. MOBILE HCI 05 Proceedings of the 7th International Conference on Human Computer Interaction with Mobile Devices and Services. ACM Digital Library. New York: ACM; 2005: 351-352.Recently videoconferencing has been extended from human face-to-face communication to human machine interaction with Virtual Environments (VE)[6]. Relying on established videoconferencing (VC) protocol standards this thin client solution does not require specialised 3D soft- or hardware and scales well to multimedia enabled mobile devices. This would bring a whole range of new applications to the mobile platform. To facilitate our research in mobile interaction the Open Source project P@CE has been started to bring a fullfeatured VC client to the Pocket PC platform

Characterization of polyhydroxyalkanoates produced by Synechocystis salina from digestate supernatant

The current commercial production of polyhydroxyalkanoates (PHA) is based on heterotrophic bacteria, using organic carbon sources from crops. To avoid the competition with food and feed production, cyanobacteria, metabolising PHA from carbon dioxide can be used. This research focuses on the investigation of the thermal and rheological properties of PHA polymers accumulated by Synechocystis salina, which had been cultivated in digestate supernatant and a mineral medium. The dried bacterial cells had a polymer content of 5.5-6.6%. The relevance of the derived PHA polymers for the common melt polymer processing was correlated with their molecular mass distribution as well as with their thermal and rheological properties. The determined thermal and rheological properties showed that PHA polymers accumulated by S. salina on digestate supernatant or mineral medium are comparable with the commercial available poly(3-hydroxybutyrate). However, the results showed that PHA polymers in general require modification before melt processing to increase their stability in the molten state. © 2017 Elsevier B.V.Austrian Climate and Energy Funds (Austrian Research Promotion Agency) [834422]; EVN AG; ANDRITZ AG; European Regional Development Fund (ERDF) through the program IWB Upper Austria; project Biorest; Ministry of Education, Youth and Sports of the Czech Republic within the NPU I program [LO1504

Gift from nature : cyclomarin s kills Mycobacteria and malaria parasites by distinct modes of action

Malaria continues to be one of the most devastating human diseases despite many efforts to limit its spread by prevention of infection or by pharmaceutical treatment of patients. We have conducted a screen for antiplasmodial compounds by using a natural product library. Here we report on cyclomarin A as a potent growth inhibitor of Plasmodium falciparum and the identification of its molecular target, diadenosine triphosphate hydrolase (PfAp3Aase), by chemical proteomics. Using a biochemical assay, we could show that cyclomarin A is a specific inhibitor of the plasmodial enzyme but not of the closest human homologue hFHIT. Co-crystallisation experiments demonstrate a unique binding mode of the inhibitor. One molecule of cyclomarin A binds a dimeric PfAp3Aase and prevents the formation of the enzyme⋅substrate complex. These results validate PfAp3Aase as a new drug target for the treatment of malaria. We have previously elucidated the structurally unrelated regulatory subunit ClpC1 of the ClpP protease as the molecular target of cyclomarin A in Mycobacterium tuberculosis. Thus, cyclomarin A is a rare example of a natural product with two distinct and specific modes of action