Progressive in vivo development of resistance to cefiderocol in Pseudomonas aeruginosa.

We report in vivo development of cefiderocol (FDC) resistance among four sequential Pseudomonas aeruginosa clinical isolates ST244 recovered from a single patient, without exposure to FDC, which raises concern about the effectiveness of this novel drug. The first recovered P. aeruginosa isolate (P-01) was susceptible to FDC (2 μg/mL), albeit this MIC value was higher than that of a wild-type P. aeruginosa (0.12-0.25 μg/ml). The subsequent isolated strains (P-02, P-03, P-04) displayed increasing levels of FDC MICs (8, 16, and 64 μg/ml, respectively). Those isolates also showed variable and gradual increasing levels of resistance to most β-lactams tested in this study. Surprisingly, no acquired β-lactamase was identified in any of those isolates. Whole-genome sequence analysis suggested that this resistance was driven by multifactorial mechanisms including mutational changes in iron transporter proteins associated with FDC uptake, ampC gene overproduction, and mexAB-oprM overexpression. These findings highlight that a susceptibility testing to FDC must be performed prior to any prescription

Simulation of the deflected cutting tool trajectory in complex surface milling

Since industry is rapidly developing, either locally or globally, manufacturers witness harder challenges due to the growing competitivity. This urges them to better consider the four factors linked to production and output: quality, quantity, cost and price, quality being of course the most important factor which constitutes their main concern. Efforts will be concentrated—in this research—on improving the quality and securing more accuracy for a machined surface in ball-end milling. Quality and precision are two essential criteria in industrial milling. However, milling errors and imperfections, duemainly to the cutting tool deflection, hinder the full achieving of these targets. Our task, all along this paper, consists in studying and realizing the simulation of the deflected cutting tool trajectory, by using the methods which are available. In a future stage, and in the frame of a deeper research, the simulation process will help to carry out the correction and the compensation of the errors resulting from the tool deflection. The corrected trajectory which is obtained by the method mirror will be sent to the machine. To achieve this goal, the next process consists—as a first step—in selecting a model of cutting forces for a ball-end mill. This allows to define—later on—the behavior of this tool, and the emergence of three methods namely the analytical model, the finite elements method, and the experimental method. It is possible to tackle the cutting forces simulation, all along the tool trajectory, while this latter is carrying out the sweeping of the part to be machined in milling and taking into consideration the cutting conditions, as well as the geography of the workpiece. A simulation of the deflected cutting tool trajectory dependent on the cutting forces has been realized

Points to consider in cardiovascular disease risk management among patients with rheumatoid arthritis living in South Africa, an unequal middle income country

ABSTRACT: Background: It is plausible that optimal cardiovascular disease (CVD) risk management differs in patients with rheumatoid arthritis (RA) from low or middle income compared to high income populations. This study aimed at producing evidence-based points to consider for CVD prevention in South African RA patients. Methods: Five rheumatologists, one cardiologist and one epidemiologist with experience in CVD risk management in RA patients, as well as two patient representatives, two health professionals and one radiologist, one rheumatology fellow and 11 rheumatologists that treat RA patients regularly contributed. Systematic literature searches were performed and the level of evidence was determined according to standard guidelines. Results: Eighteen points to consider were formulated. These were grouped into 6 categories that comprised overall CVD risk assessment and management (n=4), and specific interventions aimed at reducing CVD risk including RA control with disease modifying anti-rheumatic drugs, glucocorticoids and non-steroidal anti-inflammatory drugs (n=3), lipid lowering agents (n=8), antihypertensive drugs (n=1), low dose aspirin (n=1) and lifestyle modification (n=1). Each point to consider differs partially or completely from recommendations previously reported for CVD risk management in RA patients from high income populations. Currently recommended CVD risk calculators do not reliably identify South African black RA patients with very high-risk atherosclerosis as represented by carotid artery plaque presence on ultrasound. Conclusions: Our findings indicate that optimal cardiovascular risk management likely differs substantially in RA patients from low or middle income compared to high income populations. There is an urgent need for future multicentre longitudinal studies on CVD risk in black African patients with RA.The first meeting held amongst local Rheumatologists was funded by the South African Arthritis and Rheumatology Association. The studies by Professor González-Gay have been supported by grants from “Fondo de Investigaciones Sanitarias” PI06/0024, PS09/00748, PI12/00060, PI15/00525, PI18/00043, and RD12/0009/0013 and RD16/0012 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain), co-funded by FEDER funds

Expression of osteoprotegerin and its ligands, RANKL and TRAIL, in rheumatoid arthritis

Osteoprotegerin (OPG), receptor activator of nuclear factor-?B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have been involved in rheumatoid arthritis (RA) pathophysiology. In this study, we assessed messenger RNA (mRNA) expression of these molecules by qPCR in peripheral blood from 26 patients with RA (12 of them with ischemic heart disease -IHD) and 10 healthy controls. Correlation coefficients between OPG, RANKL and TRAIL expression levels in RA patients and their clinical and demographic characteristics were also evaluated. Whereas OPG and OPG/TRAIL ratio expression were significantly increased in RA patients compared to controls (fold change?=?1.79, p?=?0.013 and 2.07, p?=?0.030, respectively), RANKL/OPG ratio was significantly decreased (fold change?=?0.50, p?=?0.020). No significant differences were found between patients and controls in RANKL and TRAIL expression. Interestingly, TRAIL expression was significantly higher in RA patients with IHD compared to those without IHD (fold change?=?1.46, p?=?0.033). Moreover, biologic disease-modifying antirheumatic drugs (DMARDs) significantly decreased RANKL expression in RA patients (p?=?0.016). Our study supports an important role of OPG and TRAIL in RA. Furthermore, it highlights an effect of biologic DMARDs in the modulation of RANKL

A Shift-Invariant Latent Variable Model for Automatic Music Transcription

In this work, a probabilistic model for multiple-instrument automatic music transcription is proposed. The model extends the shift-invariant probabilistic latent component analysis method, which is used for spectrogram factorization. Proposed extensions support the use of multiple spectral templates per pitch and per instrument source, as well as a time-varying pitch contribution for each source. Thus, this method can effectively be used for multiple-instrument automatic transcription. In addition, the shift-invariant aspect of the method can be exploited for detecting tuning changes and frequency modulations, as well as for visualizing pitch content. For note tracking and smoothing, pitch-wise hidden Markov models are used. For training, pitch templates from eight orchestral instruments were extracted, covering their complete note range. The transcription system was tested on multiple-instrument polyphonic recordings from the RWC database, a Disklavier data set, and the MIREX 2007 multi-F0 data set. Results demonstrate that the proposed method outperforms leading approaches from the transcription literature, using several error metrics

Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice.

Gut dysbiosis due to the adverse effects of antibiotics affects outcomes of lung infection. Previous murine models relied on significant depletion of both gut and lung microbiota, rendering the analysis of immune gut-lung cross-talk difficult. Here, we study the effects of antibiotic-induced gut dysbiosis without lung dysbiosis on lung immunity and the consequences on acute P. aeruginosa lung infection. C57BL6 mice received 7 days oral vancomycin-colistin, followed by normal regimen or fecal microbial transplant or Fms-related tyrosine kinase 3 ligand (Flt3-Ligand) over 2 days, and then intra-nasal P. aeruginosa strain PAO1. Gut and lung microbiota were studied by next-generation sequencing, and lung infection outcomes were studied at 24 h. Effects of vancomycin-colistin on underlying immunity and bone marrow progenitors were studied in uninfected mice by flow cytometry in the lung, spleen, and bone marrow. Vancomycin-colistin administration induces widespread cellular immunosuppression in both the lung and spleen, decreases circulating hematopoietic cytokine Flt3-Ligand, and depresses dendritic cell bone marrow progenitors leading to worsening of P. aeruginosa lung infection outcomes (bacterial loads, lung injury, and survival). Reversal of these effects by fecal microbial transplant shows that these alterations are related to gut dysbiosis. Recombinant Flt3-Ligand reverses the effects of antibiotics on subsequent lung infection. These results show that gut dysbiosis strongly impairs monocyte/dendritic progenitors and lung immunity, worsening outcomes of P. aeruginosa lung infection. Treatment with a fecal microbial transplant or immune stimulation by Flt3-Ligand both restore lung cellular responses to and outcomes of P. aeruginosa following antibiotic-induced gut dysbiosis

Kidney function, endothelial activation and atherosclerosis in black and white Africans with rheumatoid arthritis

OBJECTIVE: To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with rheumatoid arthritis (RA). METHODS: We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients. RESULTS: The CKD-EPI eGFR was 0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold. CONCLUSION: Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients

Multiple-instrument polyphonic music transcription using a temporally constrained shift-invariant model

A method for automatic transcription of polyphonic music is proposed in this work that models the temporal evolution of musical tones. The model extends the shift-invariant probabilistic latent component analysis method by supporting the use of spectral templates that correspond to sound states such as attack, sustain, and decay. The order of these templates is controlled using hidden Markov model-based temporal constraints. In addition, the model can exploit multiple templates per pitch and instrument source. The shift-invariant aspect of the model makes it suitable for music signals that exhibit frequency modulations or tuning changes. Pitch-wise hidden Markov models are also utilized in a postprocessing step for note tracking. For training, sound state templates were extracted for various orchestral instruments using isolated note samples. The proposed transcription system was tested on multiple-instrument recordings from various datasets. Experimental results show that the proposed model is superior to a non-temporally constrained model and also outperforms various state-of-the-art transcription systems for the same experiment

Vocal imitations and the identification of sound events

International audienceIt is commonly observed that a speaker vocally imitates a sound that she or he intends to communicate to an interlocutor. We report on an experiment that examined the assumption that vocal imitations can e ffectively communicate a referent sound, and that they do so by conveying the features necessary for the identifi cation of the referent sound event. Subjects were required to sort a set of vocal imitations of everyday sounds. The resulting clusters corresponded in most of the cases to the categories of the referent sound events, indicating that the imitations enabled the listeners to recover what was imitated. Furthermore, a binary decision tree analysis showed that a few characteristic acoustic features predicted the clusters. These features also predicted the classi fication of the referent sounds, but did not generalize to the categorization of other sounds. This showed that, for the speaker, vocally imitating a sound consists of conveying the acoustic features important for recognition, within the constraints of human vocal production. As such vocal imitations prove to be a phenomenon potentially useful to study sound identifi cation