A phenomenological model for interfacial water near hydrophilic polymers.

We propose a minimalist phenomenological model for the 'interfacial water' phenomenon that occurs near hydrophilic polymeric surfaces. We achieve this by combining a Ginzburg-Landau approach with Maxwell's equations which leads us to a well-posed model providing a macroscopic interpretation of experimental observations. From the derived governing equations, we estimate the unknown parameters using experimental measurements from the literature. The resulting profiles of the polarization and electric potential show exponential decay near the surface, in qualitative agreement with experiments. Furthermore, the model's quantitative prediction of the electric potential at the hydrophilic surface is in excellent agreement with experiments. The proposed model is a first step towards a more complete parsimonious macroscopic model that will, for example, help to elucidate the effects of interfacial water on cells (e.g. neuronal excitability), the effects of infrared neural stimulation or the effects of drugs mediated by interfacial water.

Slow passage through a Hopf-like bifurcation in piecewise linear systems: Application to elliptic bursting.

The phenomenon of slow passage through a Hopf bifurcation is ubiquitous in multiple-timescale dynamical systems, where a slowly varying quantity replacing a static parameter induces the solutions of the resulting slow-fast system to feel the effect of the Hopf bifurcation with a delay. This phenomenon is well understood in the context of smooth slow-fast dynamical systems; in the present work, we study it for the first time in piecewise linear (PWL) slow-fast systems. This special class of systems is indeed known to reproduce all features of their smooth counterpart while being more amenable to quantitative analysis and offering some level of simplification, in particular, through the existence of canonical (linear) slow manifolds. We provide conditions for a PWL slow-fast system to exhibit a slow passage through a Hopf-like bifurcation, in link with possible connections between canonical attracting and repelling slow manifolds. In doing so, we fully describe the so-called way-in/way-out function. Finally, we investigate this slow passage effect in the Doi-Kumagai model, a neuronal PWL model exhibiting elliptic bursting oscillations.

Canonical models for torus canards in elliptic bursters.

We revisit elliptic bursting dynamics from the viewpoint of torus canard solutions. We show that at the transition to and from elliptic burstings, classical or mixed-type torus canards may appear, the difference between the two being the fast subsystem bifurcation that they approach: saddle-node of cycles for the former and subcritical Hopf for the latter. We first showcase such dynamics in a Wilson-Cowan-type elliptic bursting model, then we consider minimal models for elliptic bursters in view of finding transitions to and from bursting solutions via both kinds of torus canards. We first consider the canonical model proposed by Izhikevich [SIAM J. Appl. Math. 60, 503-535 (2000)] and adapted to elliptic bursting by Ju et al. [Chaos 28, 106317 (2018)] and we show that it does not produce mixed-type torus canards due to a nongeneric transition at one end of the bursting regime. We, therefore, introduce a perturbative term in the slow equation, which extends this canonical form to a new one that we call Leidenator and which supports the right transitions to and from elliptic bursting via classical and mixed-type torus canards, respectively. Throughout the study, we use singular flows ( ε=0) to predict the full system's dynamics ( ε>0 small enough). We consider three singular flows, slow, fast, and average slow, so as to appropriately construct singular orbits corresponding to all relevant dynamics pertaining to elliptic bursting and torus canards. Finally, we comment on possible links with mixed-type torus canards and folded-saddle-node singularities in non-canonical elliptic bursters that possess a natural three-timescale structure.

Stigma in visible skin diseases - a literature review and development of a conceptual model.

The burden of visible skin diseases (VSDs) includes not only physical symptoms but also psychosocial consequences such as depression, anxiety, impaired quality of life and low self-esteem. Stigmatization was shown to play a major role in people with skin diseases. The aim of the study was to review the evidence for the components, drivers and impacts of (self-)stigma, and to organize the data into a series of conceptual models. A targeted literature search was conducted to identify studies on (self-)stigma in relation to VSD. Conceptual models of stigma in VSDs were developed from existing generic conceptual models for VSD and of generic conceptual models of stigma and were refined after discussion with a board of experts, patient advocacy groups, clinicians and researchers. A total of 580 references were identified, of which 56 references were analysed and summarized. Two conceptual models of stigma were identified: one with external stigma and self-stigma dimensions, the other for self-stigma in mental health. These models were adapted to allow a complete description of stigma in VSDs. For this, a distinction was made between 'discrimination' and 'impact'. Finally, five models were developed: macro-overview; stigma, impact and socio-demographics; stigma, impact and disease characteristics; stigma, impact and quality of life; and stigma, impact and coping. Gaps were identified in available quantitative evidence. To our knowledge, this is the first conceptual model of stigma in VSDs. The model will help to standardize evaluation of stigma and to enhance empirical evaluation of anti-stigma interventions in VSDs. Further research should be conducted to develop a more complete model in stigma due to significant gaps in existing evidence, particularly including the stigma in others (external stigma) and also to cover a broader range of VSDs as their impact on particular dimensions of stigma differs.

Pathogen identification by shotgun metagenomics of patients with necrotizing soft-tissue infections.

BACKGROUND: Necrotizing soft-tissue infections (NSTIs) are life threatening, requiring broad-spectrum antibiotics. Their aetiological diagnosis can be limited by poor performance of cultures and administration of antibiotics before surgery. OBJECTIVES: We aimed (i) to compare 16S-targeted metagenomics (TM) and unbiased semiquantitative panmicroorganism DNA- and RNA-based shotgun metagenomics (SM) with cultures, (ii) to identify patients who would best benefit from metagenomics approaches and (iii) to detect the microbial pathogens in surrounding non-necrotic 'healthy' tissues by SM-based methods. METHODS: A prospective observational study was performed to assess the analytical performance of standard cultures, TM and SM on tissues from 34 patients with NSTIs. Pathogen identification obtained with these three methods was compared. RESULTS: Thirty-four necrotic and 10 healthy tissues were collected from 34 patients. The performance of TM was inferior to that of the other methods (P < 0·05), whereas SM performed better than standard culture, although the result was not statistically significant (P = 0·08). SM was significantly more sensitive than TM for the detection of all bacteria (P = 0·02) and more sensitive than standard culture for the detection of anaerobic bacteria (P < 0·01). There was a strong correlation (r = 0·71, Spearman correlation coefficient) between the semiquantitative abundance of bacteria in the culture and the bacteria-to-human sequence ratio in SM. Low amounts of bacterial DNA were found in healthy tissues, suggesting a bacterial continuum between macroscopically 'healthy' and necrotic tissue. CONCLUSIONS: SM showed a significantly better ability to detect a broader range of pathogens than TM and identify strict anaerobes than standard culture. Patients with diabetes with NSTIs appeared to benefit most from SM. Finally, our results suggest a bacterial continuum between macroscopically 'healthy' non-necrotic areas and necrotic tissues. What's already known about this topic? Necrotizing soft-tissue infections (NSTIs) are characterized by rapidly progressive necrosis of subcutaneous tissues and high mortality, despite surgical debridement combined with broad-spectrum antibiotics. The spectrum of potentially involved pathogens is very large, and identification is often limited by the poor performance of standard cultures, which may be impaired by previous antibiotic intake. Metagenomics-based approaches show promise for better identification of the pathogens that cause these infections, but they have not been evaluated in this medical context. What does this study add? Shotgun metagenomics (SM) showed higher sensitivity than 16S rRNA gene sequencing and a better ability than culture to detect anaerobic bacteria. As a result, a significant proportion of infections with bacteria, such as Pasteurella multocida or Clostridium perfringens, were detected only by SM. SM bacterial quantification enabled better detection of low amounts of bacterial DNA from macroscopically 'healthy' tissue, suggesting a subclinical infectious extension. What is the translational message? The high analytical performance of SM shown in this study should allow its future implementation for the diagnosis of necrotizing fasciitis, complementing or replacing routine methods. The large amount of data, including additional information on antimicrobial resistance, virulence profiles and metabolic adaptation of the pathogens, will improve microbiological documentation. Our results will improve our understanding of infectious pathophysiology in the future, leading to potentially better medical care.

Are bacterial culture quantifications reliable? Comparative performance of the WASP automated inoculation instrument in the era of ISO 15189 accreditation.

PURPOSE: Isolating colonies and obtaining accurate colony counts from bacterial cultures are critical steps for the optimal management of infected patients. The uncertainties in the colony count results from the bacterial cultures were evaluated by verifying the performance of the WASP inoculation system according to the International Organization for Standardization (ISO) 15189 standard. METHODOLOGY: We first (i) evaluated the cross-contamination and precision of the WASP instrument (Copan Diagnostics, Italy) and (ii) established enumeration reading grids for urine, swab, bronchopulmonary specimens (BPSs) and catheter tip cultures. Subsequently, 72 clinical samples were tested to compare the results of the WASP, PREVI Isola (bioMérieux, France) and manual inoculation methods. RESULTS: The WASP method did not show cross-contamination. The coefficient of variation for the colony counts in the repeatability experiment was evaluated for 10 µl and 30 µl loop protocols and determined to be 29 and 14 %, respectively. The agreement between the automated and manual methods and between the automated methods for the colony counts was high (94.4 and 100 %, respectively). The WASP method yielded better isolation quality compared to the manual method (P=0.020) and to the PREVI Isola only when polymicrobial specimens were considered (P=0.014). For quantification evaluation, the measurement uncertainty was evaluated to 1.8×103 c.f.u. ml-1 for a suspension of Escherichia coli at 104 c.f.u. ml-1. CONCLUSION: We report the verification of the performance of the WASP instrument and describe a rapid procedure for achieving semi-quantitative cultures from BPSs and catheter tips. Quantitative interpretation of the bacterial cultures should be performed with caution.

The Odyssey of the Ancestral Escherich Strain through Culture Collections: an Example of Allopatric Diversification.

More than a century ago, Theodor Escherich isolated the bacterium that was to become Escherichia coli, one of the most studied organisms. Not long after, the strain began an odyssey and landed in many laboratories across the world. As laboratory culture conditions could be responsible for major changes in bacterial strains, we conducted a genome analysis of isolates of this emblematic strain from different culture collections (England, France, the United States, Germany). Strikingly, many discrepancies between the isolates were observed, as revealed by multilocus sequence typing (MLST), the presence of virulence-associated genes, core genome MLST, and single nucleotide polymorphism/indel analyses. These differences are correlated with the phylogeographic history of the strain and were due to an unprecedented number of mutations in coding DNA repair functions such as mismatch repair (MutL) and oxidized guanine nucleotide pool cleaning (MutT), conferring a specific mutational spectrum and leading to a mutator phenotype. The mutator phenotype was probably acquired during subculturing and corresponded to second-order selection. Furthermore, all of the isolates exhibited hypersusceptibility to antibiotics due to mutations in efflux pump- and porin-encoding genes, as well as a specific mutation in the sigma factor-encoding gene rpoS. These defects reflect a self-preservation and nutritional competence tradeoff allowing survival under the starvation conditions imposed by storage. From a clinical point of view, dealing with such mutator strains can lead microbiologists to draw false conclusions about isolate relatedness and may impact therapeutic effectiveness. IMPORTANCE Mutator phenotypes have been described in laboratory-evolved bacteria, as well as in natural isolates. Several genes can be impacted, each of them being associated with a typical mutational spectrum. By studying one of the oldest strains available, the ancestral Escherich strain, we were able to identify its mutator status leading to tremendous genetic diversity among the isolates from various collections and allowing us to reconstruct the phylogeographic history of the strain. This mutator phenotype was probably acquired during the storage of the strain, promoting adaptation to a specific environment. Other mutations in rpoS and efflux pump- and porin-encoding genes highlight the acclimatization of the strain through self-preservation and nutritional competence regulation. This strain history can be viewed as unintentional experimental evolution in culture collections all over the word since 1885, mimicking the long-term experimental evolution of E. coli of Lenski et al. (O. Tenaillon, J. E. Barrick, N. Ribeck, D. E. Deatherage, J. L. Blanchard, A. Dasgupta, G. C. Wu, S. Wielgoss, S. Cruveiller, C. Médigue, D. Schneider, and R. E. Lenski, Nature 536:165-170, 2016, https://doi.org/10.1038/nature18959) that shares numerous molecular features.

Ducks in space: from nonlinear absolute instability to noise-sustained structures in a pattern-forming system.

A subcritical pattern-forming system with nonlinear advection in a bounded domain is recast as a slow-fast system in space and studied using a combination of geometric singular perturbation theory and numerical continuation. Two types of solutions describing the possible location of stationary fronts are identified, whose origin is traced to the onset of convective and absolute instability when the system is unbounded. The former are present only for non-zero upstream boundary conditions and provide a quantitative understanding of noise-sustained structures in systems of this type. The latter correspond to the onset of a global mode and are present even with zero upstream boundary conditions. The role of canard trajectories in the nonlinear transition between these states is clarified and the stability properties of the resulting spatial structures are determined. Front location in the convective regime is highly sensitive to the upstream boundary condition, and its dependence on this boundary condition is studied using a combination of numerical continuation and Monte Carlo simulations of the partial differential equation. Statistical properties of the system subjected to random or stochastic boundary conditions at the inlet are interpreted using the deterministic slow-fast spatial dynamical system.

Spatiotemporal canards in neural field equations.

Canards are special solutions to ordinary differential equations that follow invariant repelling slow manifolds for long time intervals. In realistic biophysical single-cell models, canards are responsible for several complex neural rhythms observed experimentally, but their existence and role in spatially extended systems is largely unexplored. We identify and describe a type of coherent structure in which a spatial pattern displays temporal canard behavior. Using interfacial dynamics and geometric singular perturbation theory, we classify spatiotemporal canards and give conditions for the existence of folded-saddle and folded-node canards. We find that spatiotemporal canards are robust to changes in the synaptic connectivity and firing rate. The theory correctly predicts the existence of spatiotemporal canards with octahedral symmetry in a neural field model posed on the unit sphere.

Stenotrophomonas maltophilia healthcare-associated infections: identification of two main pathogenic genetic backgrounds.

BACKGROUND: Stenotrophomonas maltophilia is an opportunistic multi-drug-resistant bacterium responsible for healthcare-associated infections. Strategies for in-hospital infection control and management of carriers and environmental reservoirs remain controversial. AIM: To determine the population structure of S. maltophilia strains in hospitalized infected patients and to identify putative highly pathogenic subpopulations that require upgraded infection control measures. METHODS: Eighty-three diverse human strains of various clinical origins from 18 geographically distant hospitals were characterized phenotypically and genotypically using a multi-locus sequence typing (MLST) approach. FINDINGS: Neither a predominant nor emerging sequence type (ST) was identified. Among the 80 typeable strains, only 29% corresponded to described STs, especially ST5 (N=6) and ST4/26/31 (N=2). The ST distribution and the phylogenic tree based on the concatenated MLST genes did not account for geographical, clinical origin or antimicrobial susceptibility clustering. A phylogenic tree that included 173 ST profiles from the MLST database and the 80 typeable strains confirmed the high genetic diversity of S. maltophilia, the previously reported genogroup organization and the predominance of genogroup 6, as it represented 41% (33/80) of the strains. Unexpectedly, genogroup 2 was the second most prevalent genogroup and included 16% (13/80) of the strains. These genogroups represented 57% (20/35) of the strains in respiratory patients and 75% (9/12) of the strains in patients with cystic fibrosis. CONCLUSION: Beyond MLST, the over-representation of some genogroups among strains responsible for healthcare-associated infections was confirmed. Genogrouping affiliation is recommended to implement infection control measures selectively for the most pathogenic strains isolated from patient or environmental reservoirs.

Canards in a minimal piecewise-linear square-wave burster.

We construct a piecewise-linear (PWL) approximation of the Hindmarsh-Rose (HR) neuron model that is minimal, in the sense that the vector field has the least number of linearity zones, in order to reproduce all the dynamics present in the original HR model with classical parameter values. This includes square-wave bursting and also special trajectories called canards, which possess long repelling segments and organise the transitions between stable bursting patterns with n and n + 1 spikes, also referred to as spike-adding canard explosions. We propose a first approximation of the smooth HR model, using a continuous PWL system, and show that its fast subsystem cannot possess a homoclinic bifurcation, which is necessary to obtain proper square-wave bursting. We then relax the assumption of continuity of the vector field across all zones, and we show that we can obtain a homoclinic bifurcation in the fast subsystem. We use the recently developed canard theory for PWL systems in order to reproduce the spike-adding canard explosion feature of the HR model as studied, e.g., in Desroches et al., Chaos 23(4), 046106 (2013).

Distribution and antimicrobial susceptibility of bacteria from adults with community-acquired pneumonia or complicated skin and soft tissue infections in France: the nationwide French PREMIUM study.

The empirical therapy of community-acquired pneumonia (CAP) and complicated skin and soft tissue infections (cSSTIs) must be based on updated bacterial distribution and susceptibility data. A nationwide study consecutively collected 1288 isolates from CAP (n=467) and cSSTIs (n=821) from 18 French hospitals between 2012 and 2013. The MIC values of commonly used antimicrobial agents, including ceftaroline, were determined. Bacterial distribution featured Pneumococcus, Haemophilus influenzae, and Staphylococcus aureus for CAPs and S. aureus, ß-hemolytic streptococci and Enterobacteriaceae for cSSTIs. Antimicrobial susceptibility testing indicated i) the sustained third-generation cephalosporins and levofloxacin activity against pneumococci and H. influenzae, ii) no methicillin-resistant Staphylococcus aureus emergence among respiratory pathogens, iii) the high in vitro activity of ceftaroline against staphylococci from cSSTIs (98.7% susceptibility), and iv) the worrisome decreasing fluoroquinolone and third-generation cephalosporin susceptibilities among Enterobacteriaceae. This laboratory-based survey depicts a contrasting situation and supports the scoring of patients for the resistant pathogen risk before empirical therapy.

Inflection, canards and excitability threshold in neuronal models.

A technique is presented, based on the differential geometry of planar curves, to evaluate the excitability threshold of neuronal models. The aim is to determine regions of the phase plane where solutions to the model equations have zero local curvature, thereby defining a zero-curvature (inflection) set that discerns between sub-threshold and spiking electrical activity. This transition can arise through a Hopf bifurcation, via the so-called canard explosion that happens in an exponentially small parameter variation, and this is typical for a large class of planar neuronal models (FitzHugh-Nagumo, reduced Hodgkin-Huxley), namely, type II neurons (resonators). This transition can also correspond to the crossing of the stable manifold of a saddle equilibrium, in the case of type I neurons (integrators). We compute inflection sets and study how well they approximate the excitability threshold of these neuron models, that is, both in the canard and in the non-canard regime, using tools from invariant manifold theory and singularity theory. With the latter, we investigate the topological changes that inflection sets undergo upon parameter variation. Finally, we show that the concept of inflection set gives a good approximation of the threshold in both the so-called resonator and integrator neuronal cases.

Focal dependent pleural thickening at MDCT: pleural lesion or functional abnormality?

PURPOSE: To describe the characteristics of reversible focal pleural thickenings (PTs) mimicking real plaques, that firstly suggest asbestos exposure or pleural metastasis; to propose an imaging strategy and propose an explanation for their mechanism of formation. PATIENTS AND METHODS: Retrospective review of data from 19 patients with PTs fitting the description of pleural plaques at chest computed tomography (CT) and presenting modifications (clearance or appearance) of at least one PT at an additional chest examination in prone position. RESULTS: A total of 152 PTs were recorded on the first chest CT examinations with a range of two to 19 pleural opacities per patient. All PTs had a posterior distribution in the lower lobes. On the additional acquisitions, 144 PTs disappeared. Seventeen patients presented complete regression of PTs and two patients presented persistence of eight PTs. CONCLUSION: Additional low dose acquisition in prone position should be performed in all patients presenting with focal PT in a dependent and basal location. This may allow to exclude a pleural plaque in case of asbestos exposure but also a pleural metastasis in oncologic patients. These reversible dependent PTs could be related to physiological focal accumulation of lymphatic fluid in subpleural area.

Canards of mixed type in a neural burster.

Canards are solutions of slow-fast systems that spend long times near branches of repelling equilibria, periodic orbits, or higher-dimensional invariant sets. Here, we report on the observation of a new type of canard orbit, labeled a canard of mixed type. This canard orbit is a hybrid of the classical limit cycle canards, which spend long times near attracting and repelling branches of equilibria, and torus canards, which spend long times near attracting and repelling branches of periodic orbits. The canards of mixed type arise in a model of neural bursting activity of fold-fold cycle type, and, as other canard phenomena, separate different dynamic states.

[Inhibitors of aurora kinases]. / Les inhibiteurs des kinases Aurora.

Aurora kinases (A, B and C) are proteins expressed only in cells which divide actively and their increase is a factor of bad prognosis in cancer. They regulate the maturation of centrosomes, the separation and the condensation of chromosomes, mitotic checkpoint and cytokinesis. The inhibition of aurora kinases, by powerful and selective inhibitors, is due to the formation of abnormal cells which are eliminated by apoptosis. The purpose of this article is to present the role, the antitumor activity and the tolerability of these inhibitors. They can be administered orally or intravenously, on weekly or monthly schedules. In our knowledge, twelve molecules are evaluated at the present time and will be discussed only the most advanced namely: VX-680, ZM 447439, MLN 8054, AZD 1152, PHA 739358, SU 6668 and AT 9283. The main indications are breast, colon, lung, pancreas and bladder cancers as well as hematologic tumors such as leukemia (ALL, AML, CML) and lymphoma. These inhibitors can be associated with other chemotherapies. They seem well tolerated; the reported side effects are digestive disorders (diarrhea), fever, asthenia, alopecia, slumber, neutropenia, myelosuppression and disturbance of the biological markers.

[Photosensitizing anticancer tetrapyrroles: or how photophysics becomes a mechanism of action]. / Tétrapyrroles anticancéreux photosensibilisants : ou comment la photophysique devient mécanisme d'action.

The macrocyclic tetrapyrrole derivatives used for the treatment of certain solid tumors include porphyrins and their chlorine and bacteriochlorin derivatives. These are highly conjugated, rigid molecules characterized by a strong absorbance in the spectral domain from near ultra-violet to far red (350-750 nm). The combination of tetrapyrroles plus light is called dynamic phototherapy (DPT). This combination transforms the molecule to its triplet form which by deactivation generates free radicals and a singlet oxygen from molecular oxygen, causing tumor destruction. Tetrapyrroles are thus, with psoralens, used for the treatment of psoriasis. They are the only drugs whose mechanism of action results exclusively from their electronic and photophysical spectroscopic characteristics. This class of anticancer agents is usually free of any specific cytotoxic effect. We describe here the current elements linking structure and spectroscopy and observations leading to the design of compounds with strong tumor selectivity and optimal cytotoxic properties.

Comparison of the in vitro efficacies of moxifloxacin and amoxicillin against Listeria monocytogenes.

Listeria monocytogenes is a facultative intracellular bacterium that causes severe infections associated with a high mortality rate. Moxifloxacin presents extended activity against gram-positive bacteria and has recently been suggested to be a potential alternative in the treatment of listeriosis. We evaluated the in vitro efficacy of moxifloxacin against L. monocytogenes using a combination of epidemiological and experimental approaches. The median MIC of moxifloxacin for a large collection of L. monocytogenes strains of various origins (human, food, and environment) was 0.5 microg/ml (MIC range, 0.064 to 1 microg/ml). No differences were observed, irrespective of the origin of the strains. Moreover, no cross-resistance with fluoroquinolones was detected in strains that have been reported to be resistant to ciprofloxacin. The in vitro activities of moxifloxacin and amoxicillin were compared by time-kill curve and inhibition of intracellular growth experiments by using a model of bone marrow-derived mouse macrophages infected by L. monocytogenes EGDe. Both moxifloxacin and amoxicillin were bactericidal in broth against extracellular forms of L. monocytogenes. However, moxifloxacin acted much more rapidly, beginning to exert its effects in the first 3 h and achieving complete broth sterilization within 24 h of incubation. Moxifloxacin has a rapid bactericidal effect against intracellular reservoirs of bacteria, whereas amoxicillin is only bacteriostatic and appears to prevent cellular lysis and the subsequent bacterial spreading to adjacent cells. No resistant bacteria were selected during the in vitro experiments. Taken together, our results suggest that moxifloxacin is an interesting alternative to the reference treatment, combining rapid and bactericidal activity, even against intracellular bacteria.