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The smart factory leads to a strong digitalization of industrial processes and continuous communication between the systems integrated into the production, storage, and supply chains. One of the research areas in Industry 4.0 is the possibility of using autonomous and/or intelligent industrial vehicles. The optimization of the management of the tasks allocated to these vehicles with adaptive behaviours, as well as the increase in vehicle-to-everything communications (V2X) make it possible to develop collective and adaptive intelligence for these vehicles, often grouped in fleets. Task allocation and scheduling are often managed centrally. The requirements for flexibility, robustness, and scalability lead to the consideration of decentralized mechanisms to react to unexpected situations. However, before being definitively adopted, decentralization must first be modelled and then simulated. Thus, we use a multi-agent simulation to test the proposed dynamic task (re)allocation process. A set of problematic situations for the circulation of autonomous industrial vehicles in areas such as smart warehouses (obstacles, breakdowns, etc.) has been identified. These problematic situations could disrupt or harm the successful completion of the process of dynamic (re)allocation of tasks. We have therefore defined scenarios involving them in order to demonstrate through simulation that the process remains reliable. The simulation of new problematic situations also allows us to extend the potential of this process, which we discuss at the end of the article. [ABSTRACT FROM AUTHOR]

Industry 4.0 leads to a strong digitalization of industrial processes, but also a significant increase in communication and cooperation between the machines that make it up. This is the case with autonomous industrial vehicles (AIVs) and other cooperative mobile robots which are multiplying in factories, often in the form of fleets of vehicles, and whose intelligence and autonomy are increasing. While the autonomy of autonomous vehicles has been well characterized in the field of road and road transport, this is not the case for the autonomous vehicles used in industry. The establishment and deployment of AIV fleets raises several challenges, all of which depend on the actual level of autonomy of the AIVs: acceptance by employees, vehicle location, traffic fluidity, collision detection, or vehicle perception of changing environments. Thus, simulation serves to account for the constraints and requirements formulated by the manufacturers and future users of AIVs. In this paper, after having proposed a broad state of the art on the problems to be solved in order to simulate AIVs before proceeding to experiments in real conditions, we present a method to estimate positions of AIVs moving in a closed industrial environment, the extension of a collision detection algorithm to deal with the obstacle avoidance issue, and the development of an agent-based simulation platform for simulating these two methods and algorithms. The resulting/final/subsequent simulation will allow us to experiment in real conditions. [ABSTRACT FROM AUTHOR]

One of the challenges in the field of human activity recognition in smart homes based on IoT sensors is the variability in the recorded data. This variability arises from differences in home configurations, sensor network setups, and the number and habits of inhabitants, resulting in a lack of data that accurately represent the application environment. Although simulators have been proposed in the literature to generate data, they fail to bridge the gap between training and field data or produce diverse datasets. In this article, we propose a solution to address this issue by leveraging the concept of digital twins to reduce the disparity between training and real-world data and generate more varied datasets. We introduce the Virtual Smart Home, a simulator specifically designed for modeling daily life activities in smart homes, which is adapted from the Virtual Home simulator. To assess its realism, we compare a set of activity data recorded in a real-life smart apartment with its replication in the VirtualSmartHome simulator. Additionally, we demonstrate that an activity recognition algorithm trained on the data generated by the VirtualSmartHome simulator can be successfully validated using real-life field data.

Background: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions., Methods: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437., Findings: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts., Interpretation: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer., Funding: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac., (© 2020 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

The ongoing transmission of Mycobacterium (M.) leprae reflected in a very slow decline in leprosy incidence, forces us to be innovative and conduct cutting-edge research. Single dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for contacts of leprosy patients, reduces their risk to develop leprosy by 60%. This is a promising new preventive measure that can be integrated into routine leprosy control programmes, as is being demonstrated in the Leprosy Post-Exposure Programme that is currently ongoing in eight countries.The limited (60%) effectiveness of SDR is likely due to the fact that some contacts have a preclinical infection beyond the early stages for which SDR is not sufficient to prevent the development of clinical signs and symptoms of leprosy. An enhanced regimen, more potent against a higher load of leprosy bacteria, would increase the effectiveness of this preventive measure significantly.The Netherlands Leprosy Relief (NLR) is developing a multi-country study aiming to show that breaking the chain of transmission of M. leprae is possible, evidenced by a dramatic reduction in incidence. In this study the assessment of the effectiveness of an enhanced prophylactic regimen for leprosy is an important component. To define the so called PEP++ regimen for this intervention study, NLR convened an Expert Meeting that was attended by clinical leprologists, public health experts, pharmacologists, dermatologists and microbiologists.The Expert Meeting advised on combinations of available drugs, with known efficacy against leprosy, as well as on the duration of the intake, aiming at a risk reduction of 80-90%. To come to a conclusion the Expert Meeting considered the bactericidal, sterilising and bacteriostatic activity of the potential drugs. The criteria used to determine an optimal enhanced regimen were: effectiveness, safety, acceptability, availability, affordability, feasibility and not inducing drug resistance.The Expert Meeting concluded that the enhanced regimen for the PEP++ study should comprise three standard doses of rifampicin 600 mg (weight adjusted when given to children) plus moxifloxacin 400 mg given at four-weekly intervals. For children and for adults with contraindications for moxifloxacin, moxifloxacin should be replaced by clarithromycin 300 mg (weight adjusted).

Background: There is an urgent need for more accurate screening tests for tuberculosis(TB). We assessed the diagnostic accuracy of C-reactive protein (CRP) as a screening test for active TB in HIV-infected ambulatory adults., Methods: CRP levels were measured in blood collected at the time of HIV testing.Diagnostic accuracy of CRP for pulmonary TB was calculated (reference standard: TB culture), compared to the WHO 4-symptom screen, consisting of cough, fever, night sweats, and weight loss. Diagnostic accuracy was also calculated for CRP in a larger cohort of HIV-infected adults with a positive symptom screen (reference standard: clinical or microbiological TB)., Results: Among 425 HIV-infected outpatients systematically tested for pulmonary TB, TB culture was positive in 42 (10%), 279 (66%) had at least one TB-related symptom and 197 (46%) had a CRP more than 5 mg/l. The sensitivity of CRP and the TB symptom screen to detect TB was the same [90.5%; 95% confidence interval 77.4-97.3] but specificity of CRP was higher than for the TB symptom screen (58.5% vs. 37.1%, P < 0.001). Of persons with no symptoms and normal CRP, 99 (98%) had no TB. In another cohort of 749 patients presenting with at least one TB-related symptom and clinically evaluated, CRP had a sensitivity of 98.7% and specificity of 48.3%., Conclusion: In HIV-infected outpatients, CRP was as sensitive but substantially more specific than TB symptom screening. Use of CRP as a screening tool to exclude active TB could identify the same number of HIV-associated TB cases, but reduce the use of diagnostic sputum testing in TB-endemic regions.

Muscle mass in humans is inversely associated with circulating levels of inflammatory cytokines, but the interaction between ageing and training on muscle composition and the intra-muscular signalling behind inflammation and contractile protein synthesis and degradation is unknown. We studied 15 healthy life-long endurance runners, 12 age-matched untrained controls, 10 young trained and 12 young untrained individuals. Thigh muscle composition was investigated by magnetic resonance imaging (MRI), where non-contractile intramuscular tissue (NCIT) area (fat and connective tissue) was found to be greater in older but lower in trained individuals. Subcutaneous adipose tissue was also lower in trained individuals but was not affected by age. In vastus lateralis biopsies, no influence of age or training was found on levels of endomysial collagen, determined by Sirius Red and Collagen III staining, whereas perimysial organisation tended to be more complex in older individuals. No clear difference with training was seen on intramuscular inflammatory signalling, whereas lower protein levels of NFkB subunits p105, p50 and p65 were observed with ageing. Gene expression of IL6 and TNFα was not different between groups, while IL1-receptor and TNFα-receptor1 levels were lower with age. Myostatin mRNA was lower in older and trained groups, while expression of MuRF1 was lower in trained individuals and FoxO3 expression was greater in aged groups. The association of increased muscle NCIT with age-associated muscle loss in humans is not accompanied by any major alterations in intramuscular signalling for inflammation, but rather by direct regulatory factors for protein synthesis and proteolysis in skeletal muscle., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, ≥4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations in Rv0678 that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and clofazimine cross-resistance in Mycobacterium tuberculosis: loss-of-function mutations in pepQ (Rv2535c), which corresponds to a putative Xaa-Pro aminopeptidase. pepQ mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without clofazimine, and were shown to have bedaquiline and clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of Rv0678, mmpS5, or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer bedaquiline and clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs such as D-cycloserine. Here we used the whole-genome sequences from 498 strains of M. tuberculosis to identify new resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss of function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss of function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted use of this toxic drug among patients with susceptible infections.

Background: The continued advance of antibiotic resistance threatens the treatment and control of many infectious diseases. This is exemplified by the largest global outbreak of extensively drug-resistant (XDR) tuberculosis (TB) identified in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 that continues today. It is unclear whether the emergence of XDR-TB in KwaZulu-Natal was due to recent inadequacies in TB control in conjunction with HIV or other factors. Understanding the origins of drug resistance in this fatal outbreak of XDR will inform the control and prevention of drug-resistant TB in other settings. In this study, we used whole genome sequencing and dating analysis to determine if XDR-TB had emerged recently or had ancient antecedents., Methods and Findings: We performed whole genome sequencing and drug susceptibility testing on 337 clinical isolates of Mycobacterium tuberculosis collected in KwaZulu-Natal from 2008 to 2013, in addition to three historical isolates, collected from patients in the same province and including an isolate from the 2005 Tugela Ferry XDR outbreak, a multidrug-resistant (MDR) isolate from 1994, and a pansusceptible isolate from 1995. We utilized an array of whole genome comparative techniques to assess the relatedness among strains, to establish the order of acquisition of drug resistance mutations, including the timing of acquisitions leading to XDR-TB in the LAM4 spoligotype, and to calculate the number of independent evolutionary emergences of MDR and XDR. Our sequencing and analysis revealed a 50-member clone of XDR M. tuberculosis that was highly related to the Tugela Ferry XDR outbreak strain. We estimated that mutations conferring isoniazid and streptomycin resistance in this clone were acquired 50 y prior to the Tugela Ferry outbreak (katG S315T [isoniazid]; gidB 130 bp deletion [streptomycin]; 1957 [95% highest posterior density (HPD): 1937-1971]), with the subsequent emergence of MDR and XDR occurring 20 y (rpoB L452P [rifampicin]; pncA 1 bp insertion [pyrazinamide]; 1984 [95% HPD: 1974-1992]) and 10 y (rpoB D435G [rifampicin]; rrs 1400 [kanamycin]; gyrA A90V [ofloxacin]; 1995 [95% HPD: 1988-1999]) prior to the outbreak, respectively. We observed frequent de novo evolution of MDR and XDR, with 56 and nine independent evolutionary events, respectively. Isoniazid resistance evolved before rifampicin resistance 46 times, whereas rifampicin resistance evolved prior to isoniazid only twice. We identified additional putative compensatory mutations to rifampicin in this dataset. One major limitation of this study is that the conclusions with respect to ordering and timing of acquisition of mutations may not represent universal patterns of drug resistance emergence in other areas of the globe., Conclusions: In the first whole genome-based analysis of the emergence of drug resistance among clinical isolates of M. tuberculosis, we show that the ancestral precursor of the LAM4 XDR outbreak strain in Tugela Ferry gained mutations to first-line drugs at the beginning of the antibiotic era. Subsequent accumulation of stepwise resistance mutations, occurring over decades and prior to the explosion of HIV in this region, yielded MDR and XDR, permitting the emergence of compensatory mutations. Our results suggest that drug-resistant strains circulating today reflect not only vulnerabilities of current TB control efforts but also those that date back 50 y. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics employed in South Africa that assess only rifampicin resistance.