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The direct parametrisation method for invariant manifold is a model-order reduction technique that can be applied to nonlinear systems described by PDEs and discretised, for example, with a finite element procedure in order to derive efficient reduced-order models (ROMs). In nonlinear vibrations, it has already been applied to autonomous and non-autonomous problems to propose ROMs that can compute backbone and frequency–response curves of structures with geometric nonlinearity. While previous developments used a first-order expansion to cope with the non-autonomous term, this assumption is here relaxed by proposing a different treatment. The key idea is to enlarge the dimension of the parametrising coordinates with additional entries related to the forcing. A new algorithm is derived with this starting assumption, and as a key consequence, the resonance relationships appearing through the homological equations involve multiple occurrences of the forcing frequency, showing that with this new development, ROMs for systems exhibiting a superharmonic resonance can be derived. The method is implemented and validated on academic test cases involving beams and arches. It is numerically demonstrated that the method generates efficient ROMs for problems involving 3:1 and 2:1 superharmonic resonances, as well as converged results for systems where the first-order truncation on the non-autonomous term showed a clear limitation. [ABSTRACT FROM AUTHOR]

This works presents a methodology, along with its software implementation called "Design 2 Cost", for evaluating the manufacturing cost and complexity of a part built by a subtractive (e.g. milling) or additive (e.g. laser metal deposition, Selective laser melting, wire-arc additive manufacturing) process. The overall manufacturing complexity is calculated as a weighted average of morphological and material criteria, which are defined either locally or globally. The local morphological criteria are calculated over the leaf nodes of an octree representation of the part using a raycasting technique. This allows to efficiently probe the local geometry of the part and compare it with manufacturing constraints emanating from the manufacturing process and its associated effector. This algorithm yields a cartography of the local complexity criteria that helps visualizing the problematic regions for the processes under consideration. The software is accompanied by a database that feeds the required material and process properties needed for the calculation of the manufacturing complexity and cost. The proposed methodology therefore permits a technical and economic comparison of manufacturing processes for a given geometry and material, as well as a comparison of various part geometries and materials for a given manufacturing process. [ABSTRACT FROM AUTHOR]

Coupled Thermal-Hydraulic-Mechanical-Chemical (THMC) approaches may be important for assessing the long-term durability of cementitious materials. We present a multiphysics approach to overcome past limitations of THMC modelling and validate it based on experimental results of accelerated carbonation tests. Our numerical approach rests on a sequential coupling between Hytec and Cast3m. Hytec computes the evolution of hydraulic and mineralogical fields allowing to compute the micromechanical properties (e.g. Young's modulus). The mineral reactions generate tensile stresses and Cast3M computes the associated strain tensors and the damage evolution represented by the opening or sealing of cracks, impacting subsequent reactive transport processes. Our approach manages to qualitatively represent the crack patterns and non-uniform degradation depths observed on microtomographic images of carbonated cement samples, which can only be explained by the coupled dynamics of chemical and mechanical processes. Our approach can be extended to a wide range of cement-concrete pathologies and contexts. [ABSTRACT FROM AUTHOR]

To investigate whether marital status is associated to long-term major fatal and non-fatal cardiovascular events in men and women from the Gubbio Population Study. The incidence of cardiovascular disease (CVD), including stroke and coronary heart disease (CHD) and CVD death together with all-cause mortality were analyzed. The analysis included 2832 persons (44% men, 54 ± 11 years old). Marital status was defined at entry as married (married or living conjugally) versus unmarried subjects (widowed, separated, divorced or single). Married and unmarried subjects did not differ concerning socio-demographic, anthropometric and biological variables at baseline. Over 191 months median follow-up, the incidence of CHD was lower among married versus unmarried women [HR: 0.63 (95% CI 0.41–0.96)] only; the same was true for CHD mortality [HR: 0.43 (95% CI 0.22–0.84)] and all-cause mortality [HR: 0.75 (95% CI 0.59–0.96)] independently of traditional risk factors (age, SBP, total and HDL cholesterol, cigarette smoke and BMI). In men, marital status was not associated to any of the investigated outcomes. In primary care, marital status should be investigated as it can be associated with long-term CHD and all-cause incidence and mortality risks among women. [ABSTRACT FROM AUTHOR]

Background: Primary angiitis of the central nervous system (PACNS) is a rare disease, for which no validated guidelines exist. We report the findings of a survey on the clinical practice of physicians who manage adults with PACNS. Methods: An online survey was distributed through neurology, internal medicine, and rheumatology societies in Canada and Europe. Participants who were directly involved as treating physicians for at least two adult patients with PACNS were eligible for the survey. Results: Ninety-six physicians completed the survey. Most participants were neurologists (n = 38, 40%), internists (n = 34, 35%) or rheumatologists (n = 22, 23%). Participants obtained a CNS biopsy in a median of 25% (IQR: 5–50%) of suspected PACNS cases. When determining the degree to which eight scenarios justified a CNS biopsy, participants achieved fair inter-rater agreement (Gwet's AC2 0.30, 95% CI 0.23–0.41). For induction therapy, 81 (84%) participants reported using glucocorticoids and cyclophosphamide in > 50% of patients. After obtaining remission, 85 (89%) participants systematically introduced or maintained immunosuppressive therapy. Glucocorticoids were prescribed for a median of 12 months. Maintenance therapy with another immunosuppressant was continued for a median of 24 months. In patients who achieved remission, we explored how eight scenarios with different imaging and CSF results supported an increase in treatment. Inter-rater agreement was substantial if the patient was symptomatic (0.66, 95% CI 0.58–0.80) and moderate (0.50, 95% CI 0.45–0.60) if asymptomatic. Conclusion: This survey illustrates current real-world management of PACNS and emphasizes several areas for which physicians still lack study-based evidence and/or clinical practice guidelines. [ABSTRACT FROM AUTHOR]

The direct parametrisation method for invariant manifolds is used for model order reduction of forced-damped mechanical structures subjected to geometric nonlinearities. Nonlinear mappings are introduced, allowing one to pass from the degrees of freedom of the finite-element model to the normal coordinates. Arbitrary orders of expansions are considered for the unknown mappings and the reduced dynamics, which are then solved sequentially through the homological equations for both autonomous and time-dependent terms. It is emphasised that the two problems share a similar structure, which can be used for an efficient implementation of the non-autonomous added terms. Special emphasis is also put on the new resonance conditions arising due to the presence of the external forcing frequencies, which allow predicting phenomena such as parametric excitation and isolas formation. The method is then applied to structures of academic and industrial interest. First, the large amplitude vibrations of a forced-damped cantilever beam are studied. This example highlights that high-order non-autonomous terms are compulsory to correctly estimate the maximum vibration amplitude experienced by the structure. The birth of isolated solutions is also illustrated on this example. The cantilever is then used to show how quadratic coupling creates conditions for the excitation of the parametric instability, and that this feature is correctly embedded in the reduction process. A shallow arch excited with multi-modal forcing is then studied to detail different forcing effects. Finally, the approach is validated on a structure of industrial relevance, i.e. a comb-driven micro-electro-mechanical resonator. The accuracy and computational performance reported suggest that the proposed methodology can accurately predict the nonlinear dynamic response of a large class of nonlinear vibratory systems. [ABSTRACT FROM AUTHOR]

This paper is devoted to a detailed analysis of the appearance of frequency combs in the dynamics of a micro-electro-mechanical systems (MEMS) resonator featuring 1:2 internal resonance. To that purpose, both experiments and numerical predictions are reported and analysed to predict and follow the appearance of the phononic frequency comb arising as a quasi-periodic regime between two Neimark-Sacker bifurcations. Numerical predictions are based on a reduced-order model built thanks to an implicit condensation method, where both mechanical nonlinearities and electrostatic forces are taken into account. The reduced order model is able to predict a priori, i.e. without the need of experimental calibration of parameters, and in real time, i.e. by solving one or two degrees-of-freedom system of equations, the nonlinear behaviour of the MEMS resonator. Numerical predictions show a good agreement with experiments under different operating conditions, thus proving the great potentiality of the proposed simulation tool. In particular, the bifurcation points and frequency content of the frequency comb are carefully predicted by the model, and the main features of the periodic and quasi-periodic regimes are given with accuracy, underlining that the complex dynamics of such MEMS device is effectively driven by the characteristics of the 1:2 internal resonance. [ABSTRACT FROM AUTHOR]

The incidence of oropharyngeal cancers (OPC) is increasing in the world. Among OPC, those induced by human papillomaviruses have a better prognosis than non-HPV-associated OPC. The objective of this study was to highlight the relevance of HPV16 load, HPV16 DNA integration and HPV16-L1 serology on progression-free survival and overall survival of OPC patients. The PAPILLOPHAR cohort consists of 362 patients with oropharyngeal squamous cell carcinomas prospectively followed up for 5 years after treatment. Tumor biopsies and sera were collected at inclusion to investigate tumor HPV DNA/RNA characteristics and HPV16 L1 serology, respectively. Twenty-seven percent of tumor biopsies were HPV DNA- and RNA-positive and HPV16 represented 93% of HPV-positive cases. Among them, neither HPV16 viral load nor HPV16 DNA integration was associated with overall survival (OS) or progression-free survival (PFS). In contrast, high anti-HPV16 L1 antibody titers were significantly associated with a better OS and PFS. This study reveals that HPV16 load and integration are not relevant prognosis biomarkers in OPC patients. Clinical Relevance: High levels of HPV16 L1 antibodies may be useful to predict OPC patient outcome following treatment. ClinicalTrials.gov Identifier: NCT00918710, May 2017. [ABSTRACT FROM AUTHOR]

An analysis of the water flow generated by a tire rolling over a water film has been carried out on an experimental level. The present investigation is focused on a commercial tire with a winter V-shaped complex sculpture. Flow measurements were performed using an optical technique derived from the standard 2D-PIV, the so-called r(refracted)-PIV. Some specific image processing tools have been developed in order to take into account the jitter of the tire location inside the camera field of view when analyzing a set of independent runs. Considering the analysis of the flow either inside the grooves or in front of the tire, different approaches are proposed. On one hand, a geometrical segmentation of the grooves allows a flow analysis inside these tread elements. A characteristic water velocity deduced from measurements performed over a set of independent runs appears to correlate with the position of the segment under consideration along the contact patch area. It has been considered as the hydrodynamic signature of the present tread design. On the other hand, inside the water-bank in front of the tire, an ensemble averaging process of the local velocity is performed to show the influence of groove presence at small scale and the impact of tread design at large scale. [ABSTRACT FROM AUTHOR]

This article considers the nonlinear dynamics of coupled oscillators featuring strong coupling in 1:2 internal resonance. In forced oscillations, this particular interaction is the source of energy exchange, leading to a particular shape of the response curves, as well as quasi-periodic responses and a saturation phenomenon. These main features are embedded in the simplest system which considers only the two resonant quadratic monomials conveying the 1:2 internal resonance, since they are the proeminent source allowing one to explain these phenomena. However, it has been shown recently that those features can be substantially modified by the presence of non-resonant quadratic terms. The aim of the present study is thus to explain the effect of the non-resonant quadratic terms on the dynamics. To that purpose, the normal form up to the third order is used, since the effect of the non-resonant quadratic terms will be transferred into the resonant cubic terms. Analytical solutions are detailed using a second-order mutliple scale expansion. A thorough investigation of the backbone curves, their stability and bifurcation, and the link to the forced–damped solutions, is detailed, showing in particular interesting features that had not been addressed in earlier studies. Finally, the saturation effect is investigated, and it is shown how to correct the detuning effect of the cubic terms thanks to a specific tuning of non-resonant quadratic terms and resonant cubic terms. This choice, derived analytically, is shown to extend the validity of the saturation effect to larger amplitudes, which can thus be used in all applications where this effect is needed e.g. for control. [ABSTRACT FROM AUTHOR]

This paper investigates model-order reduction methods for geometrically nonlinear structures. The parametrisation method of invariant manifolds is used and adapted to the case of mechanical systems in oscillatory form expressed in the physical basis, so that the technique is directly applicable to mechanical problems discretised by the finite element method. Two nonlinear mappings, respectively related to displacement and velocity, are introduced, and the link between the two is made explicit at arbitrary order of expansion, under the assumption that the damping matrix is diagonalised by the conservative linear eigenvectors. The same development is performed on the reduced-order dynamics which is computed at generic order following different styles of parametrisation. More specifically, three different styles are introduced and commented: the graph style, the complex normal form style and the real normal form style. These developments allow making better connections with earlier works using these parametrisation methods. The technique is then applied to three different examples. A clamped-clamped arch with increasing curvature is first used to show an example of a system with a softening behaviour turning to hardening at larger amplitudes, which can be replicated with a single mode reduction. Secondly, the case of a cantilever beam is investigated. It is shown that invariant manifold of the first mode shows a folding point at large amplitudes. This exemplifies the failure of the graph style due to the folding point on a real structure, whereas the normal form style is able to pass over the folding. Finally, a MEMS (Micro Electro Mechanical System) micromirror undergoing large rotations is used to show the importance of using high-order expansions on an industrial example. [ABSTRACT FROM AUTHOR]

Autophagy is an essential cellular pathway that ensures degradation of a wide range of substrates including damaged organelles or large protein aggregates. Understanding how this proteolytic pathway is regulated would increase our comprehension on its role in cellular physiology and contribute to identify biomarkers or potential drug targets to develop more specific treatments for disease in which autophagy is dysregulated. Here, we report the development of molecular traps based in the tandem disposition of LC3-interacting regions (LIR). The estimated affinity of LC3-traps for distinct recombinant LC3/GABARAP proteins is in the low nanomolar range and allows the capture of these proteins from distinct mammalian cell lines, S. cerevisiae and C. elegans. LC3-traps show preferences for GABARAP/LGG1 or LC3/LGG2 and pull-down substrates targeted to proteaphagy and mitophagy. Therefore, LC3-traps are versatile tools that can be adapted to multiple applications to monitor selective autophagy events in distinct physiologic and pathologic circumstances. [ABSTRACT FROM AUTHOR]

Micro-Electro-Mechanical Systems revolutionized the consumer market for their small dimensions, high performances and low costs. In recent years, the evolution of the Internet of Things is posing new challenges to MEMS designers that have to deal with complex multiphysics systems experiencing highly nonlinear dynamic responses. To be able to simulate a priori and in real-time the behavior of such systems it is thus becoming mandatory to understand the sources of nonlinearities and avoid them when harmful or exploit them for the design of innovative devices. In this work, we present the first numerical tool able to estimate a priori and in real-time the complex nonlinear responses of MEMS devices without resorting to simplified theories. Moreover, the proposed tool predicts different working conditions without the need of ad-hoc calibration procedures. It consists in a nonlinear Model Order Reduction Technique based on the Implicit Static Condensation that allows to condense the high fidelity FEM models into few degrees of freedom, thus greatly speeding-up the solution phase and improving the design process of MEMS devices. In particular, the 1:2 internal resonance experienced in a MEMS gyroscope test-structure fabricated with a commercial process is numerically investigated and an excellent agreement with experiments is found. [ABSTRACT FROM AUTHOR]

Acid mine drainage (AMD) still represents a huge environmental problem. Technical and scientific breakthroughs are still needed to decrease environmental damages, treatment cost, and waste production associated with AMD. The feasibility of combining continuously fed anaerobic sulfate-reducing bioreactor with downstream iron oxidation step was tested, at a laboratory scale, with two types of real arsenic-rich AMD waters from the site of Carnoulès (France), that differed in acidity (pH 3.3 and 4.0), arsenic (As, 18 and 174 mg.L−1), and metal concentrations. Iron remained in solution, while up to 99% of As was precipitated as amorphous orpiment in the anaerobic sulfate-reducing bioreactor. Zinc (Zn) precipitation was also observed, up to 99%; however, the efficiency of Zn precipitation was less stable than that of As. The anaerobic bioreactor presented a stable bacterial community including a Desulfosporosinus-related sulfate reducer. When the effluents from the anaerobic process step were treated in a laboratory aerobic bioreactor, iron was oxidized efficiently. The feasibility of efficient orpiment bio-precipitation coupled with downstream iron oxidation was shown, thus opening the perspective of a low-cost combination of treatment steps for the removal of arsenic, zinc, and iron in As-rich AMDs. [ABSTRACT FROM AUTHOR]

Quasi-periodic solutions can arise in assemblies of nonlinear oscillators as a consequence of Neimark-Sacker bifurcations. In this work, the appearance of Neimark-Sacker bifurcations is investigated analytically and numerically in the specific case of a system of two coupled oscillators featuring a 1:2 internal resonance. More specifically, the locus of Neimark-Sacker points is analytically derived and its evolution with respect to the system parameters is highlighted. The backbone curves, solution of the conservative system, are first investigated, showing in particular the existence of two families of periodic orbits, denoted as parabolic modes. The behaviour of these modes, when the detuning between the eigenfrequencies of the system is varied, is underlined. The non-vanishing limit value, at the origin of one solution family, allows explaining the appearance of isolated solutions for the damped-forced system. The results are then applied to a Micro-Electro-Mechanical System-like shallow arch structure, to show how the analytical expression of the Neimark-Sacker boundary curve can be used for rapid prediction of the appearance of quasiperiodic regime, and thus frequency combs, in Micro-Electro-Mechanical System dynamics. [ABSTRACT FROM AUTHOR]

Background and Purpose: The aim of this study was to assess the safety and effectiveness of lateral sinus stenosis (LSS) stenting in patients with idiopathic intracranial hypertension (IIH) who are refractory to medical treatment, particularly focusing on visual outcomes including papilledema. Material and Methods: Retrospective study of consecutive patients with IIH refractory to medical treatment who underwent LSS stenting. Clinical features, visual fields and optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thicknesses were assessed before stenting, at 1 month poststenting and at last follow-up. Complications were also recorded. Results: A total of 16 women were included, with a mean age of 39 ± 11 years. All patients had papilledema while 15/16 (94%) had headaches. Mean visual acuity was 0.036 logMAR, range (+0.4 to +0.0 logMAR). The mean RNFL thickness prior to stenting was 121.7 µm (±34.7 µm) and mean GCL thickness was 80.2 µm (±8.9 µm). Mean follow-up was 19.7 months (±11.8 months). After stenting, acetazolamide was discontinued in 15/16 (94%) patients. Papilledema improved in 14/16 (88%) of patients. The mean RNFL thickness was significantly decreased 1 month after stenting (96.3 ± 15.6 µm; p < 0.001) and at last visit (93.4 ± 15.3 µm; p < 0.001). The GCL thickness after LSS stenting was moderately decreased at the last visit examination: 80.2 ± 8.9 µm vs. 78.0 ± 10.7 µm; (p < 0.01). No stent-related complication occurred, while there was one case of restenosis. Conclusion: Improvement of papilledema appears to occur relatively rapidly after the LSS stenting. The results further support the role of LSS stenting in the treatment of IIH, especially with respect to visual symptoms. [ABSTRACT FROM AUTHOR]

The objective of this contribution is to compare two methods proposed recently in order to build efficient reduced-order models for geometrically nonlinear structures. The first method relies on the normal form theory that allows one to obtain a nonlinear change of coordinates for expressing the reduced-order dynamics in an invariant-based span of the phase space. The second method is the modal derivative approach, and more specifically, the quadratic manifold defined in order to derive a second-order nonlinear change of coordinates. Both methods share a common point of view, willing to introduce a nonlinear mapping to better define a reduced-order model that could take more properly into account the nonlinear restoring forces. However, the calculation methods are different and the quadratic manifold approach has not the invariance property embedded in its definition. Modal derivatives and static modal derivatives are investigated, and their distinctive features in the treatment of the quadratic nonlinearity are underlined. Assuming a slow/fast decomposition allows understanding how the three methods tend to share equivalent properties. While they give proper estimations for flat symmetric structures having a specific shape of nonlinearities and a clear slow/fast decomposition between flexural and in-plane modes, the treatment of the quadratic nonlinearity makes the predictions different in the case of curved structures such as arches and shells. In the more general case, normal form approach appears preferable since it allows correct predictions of a number of important nonlinear features, including the hardening/softening behaviour, whatever the relationships between slave and master coordinates are. [ABSTRACT FROM AUTHOR]

Pharmacovigilance reports of cerebral and cardiovascular events in those who use decongestants have triggered alerts related to their use. We aimed to assess the risk of stroke and myocardial infarction (MI) associated with the use of decongestants. We conducted a nested case-crossover study of patients with incident stroke and MI identified in France between 2013 and 2016 in two systematic disease registries. Decongestant use in the three weeks preceding the event was assessed using a structured telephone interview. Conditional logistic multivariable models were used to estimate the odds of incident MI and stroke, also accounting for transient risk factors and comparing week 1 (index at-risk time window, immediately preceding the event) to week 3 (reference). Time-invariant risk factors were controlled by design. In total, 1394 patients with MI and 1403 patients with stroke, mainly 70 years old or younger, were interviewed, including 3.2% who used decongestants during the three weeks prior to the event (1.0% definite exposure in the index at-risk time window, 1.1% in the referent time window; adjusted odds ratio (aOR), 0.78; 95%CI, 0.43–1.42). Secondary analysis yielded similar results for individual events (MI/stroke). We observed no increased risk of MI or stroke for patients 70 years of age and younger without previous MI or stroke who used decongestants. [ABSTRACT FROM AUTHOR]

Wall Shear Stress (WSS) has been demonstrated to be a biomarker of the development of atherosclerosis. In vivo assessment of WSS is still challenging, but 4D Flow MRI represents a promising tool to provide 3D velocity data from which WSS can be calculated. In this study, a system based on Laser Doppler Velocimetry (LDV) was developed to validate new improvements of 4D Flow MRI acquisitions and derived WSS computing. A hydraulic circuit was manufactured to allow both 4D Flow MRI and LDV velocity measurements. WSS profiles were calculated with one 2D and one 3D method. Results indicated an excellent agreement between MRI and LDV velocity data, and thus the set-up enabled the evaluation of the improved performances of 3D with respect to the 2D-WSS computation method. To provide a concrete example of the efficacy of this method, the influence of the spatial resolution of MRI data on derived 3D-WSS profiles was investigated. This investigation showed that, with acquisition times compatible with standard clinical conditions, a refined MRI resolution does not improve WSS assessment, if the impact of noise is unreduced. This study represents a reliable basis to validate with LDV WSS calculation methods based on 4D Flow MRI. [ABSTRACT FROM AUTHOR]

Non-intrusive methods have been used since two decades to derive reduced-order models for geometrically nonlinear structures, with a particular emphasis on the so-called STiffness Evaluation Procedure (STEP), relying on the static application of prescribed displacements in a finite-element context. We show that a particularly slow convergence of the modal expansion is observed when applying the method with 3D elements, because of nonlinear couplings occurring with very high frequency modes involving 3D thickness deformations. Focusing on the case of flat structures, we first show by computing all the modes of the structure that a converged solution can be exhibited by using either static condensation or normal form theory. We then show that static modal derivatives provide the same solution with fewer calculations. Finally, we propose a modified STEP, where the prescribed displacements are imposed solely on specific degrees of freedom of the structure, and show that this adjustment also provides efficiently a converged solution. [ABSTRACT FROM AUTHOR]

Ubiquitous PAP2 lipid phosphatases are involved in a wide array of central physiological functions. PgpB from Escherichia coli constitutes the archetype of this subfamily of membrane proteins. It displays a dual function by catalyzing the biosynthesis of two essential lipids, the phosphatidylglycerol (PG) and the undecaprenyl phosphate (C55-P). C55-P constitutes a lipid carrier allowing the translocation of peptidoglycan subunits across the plasma membrane. PG and C55-P are synthesized in a redundant manner by PgpB and other PAP2 and/or unrelated membrane phosphatases. Here, we show that PgpB is the sole, among these multiple phosphatases, displaying this dual activity. The inactivation of PgpB does not confer any apparent growth defect, but its inactivation together with another PAP2 alters the cell envelope integrity increasing the susceptibility to small hydrophobic compounds. Evidence is also provided of an interplay between PAP2s and the peptidoglycan polymerase PBP1A. In contrast to PGP hydrolysis, which relies on a His/Asp/His catalytic triad of PgpB, the mechanism of C55-PP hydrolysis appeared as only requiring the His/Asp diad, which led us to hypothesize distinct processes. Moreover, thermal stability analyses highlighted a substantial structural change upon phosphate binding by PgpB, supporting an induced-fit model of action. [ABSTRACT FROM AUTHOR]

The present work has been performed in the context of the European H2020 project increased SAfety and Robust certification for ditching of Aircrafts and Helicopters (SARAH) dedicated to improving the safety during aircraft ditching, together with a better understanding of the physics involved during those crucial events. Both numerical and experimental aspects are explored during this project. The present study focuses on the application of the smoothed particle hydrodynamics (SPH) method to the simulation of helicopter ditching, as this method has proved to be particularly adapted to free surface impact cases. Simulations are performed for three different impact configurations, for which the numerical solutions are compared with the experimental results (forces and kinematics) obtained at the wave basin of Ecole Centrale Nantes on a mock-up shape provided by Airbus Helicopters. Elements of sensitivity analysis are also provided when needed, to assess the role of some parameters involved in the helicopter behavior and the fluid pressure forces exerted during the impact. [ABSTRACT FROM AUTHOR]

Purpose: Minimally invasive parathyroid surgery and hypnosis are both increasing in prevalence. The objective of this study was to evaluate the efficacy of hypnoanalgesia compared with sedation during primary hyperparathyroid surgery under local anaesthesia. Methods: All patients who underwent primary hyperparathyroid surgery under local anaesthesia in our department between January 2013 and April 2018 were included retrospectively in two groups: patients operated under hypnoanalgesia (HYP group), and patients operated under sedation (LA group). The evaluation criteria were postoperative pain and analgesic consumption, amount of perioperative anti-emetics required, and length of hospital stay. Results: Thirty-six patients were included, 19 in the HYP group and 17 in the LA group. Postoperative pain levels and analgesic consumption rates were lower in the HYP group (numeric scale = 0.5/10 vs. 2.7/10, p = 0.0001; 11% vs. 47%, p = 4.9 × 10−8). Intraoperative anti-emetics delivery was lower in the HYP group (5% vs. 35%, p = 2.9 × 10−7). The ambulatory care rate was higher in the HYP group (74% vs. 59%, p = 0.03). Conclusion: Local anaesthesia with hypnoanalgesia, compared with sedation during minimally invasive parathyroid surgery, improved early postoperative outcomes, making outpatient management more efficient. [ABSTRACT FROM AUTHOR]

A system composed of two cubic nonlinear oscillators with close natural frequencies, and thus displaying a 1:1 internal resonance, is studied both theoretically and experimentally, with a special emphasis on the free oscillations and the backbone curves. The instability regions of uncoupled solutions are derived and the bifurcation scenario as a function of the parameters of the problem is established, showing in an exhaustive manner all possible solutions. The backbone curves are then experimentally measured on a circular plate, where the asymmetric modes are known to display companion configurations with close eigenfrequencies. A control system based on a Phase-Locked Loop (PLL) is used to measure the backbone curves and also the frequency response function in the forced and damped case, including unstable branches. The model is used for a complete identification of the unknown parameters and an excellent comparison is drawn out between theoretical prediction and measurements. [ABSTRACT FROM AUTHOR]

Gyroscopic effects are also addressed for continuous rotor systems [[27]], and the nonlinear dynamics and stability of fiber reinforced polymer structures [[28]], and plates with nonlinear fractional damping [[29]], are also investigated. The present Special Issue was initially conceived for presenting a survey of recent studies carried out by researchers participating in the Dynamics and Stability Group (GADeS) within the Italian Society of Theoretical and Applied Mechanics (AIMETA). A first grouping of papers deals with problems of stability and bifurcations arising in fluid/structure problems with a special emphasis on aeroelastic systems. We also hope that our initiative is welcome and timely and that this Special Issue will stimulate new ideas and new challenges in the wide and fascinating research field of dynamics and stability of mechanical systems. [Extracted from the article]

The recent success of checkpoint inhibitors in the treatment of Merkel cell carcinoma (MCC) confirms that MCC tumors can be immunogenic. However, no treatment directly targeting the tumor is available for use in combination with these checkpoint inhibitors to enhance their efficacity. This study was carried out to characterize MCC line sensitivity to cellular lysis and to identify cell surface antigens that could be used for direct targeting of this tumor. For five representative MCC lines, the absence or low expression of MICA, MICB, HLA-I, and ICAM-1 was associated with low level of recognition by NK cells and T lymphocytes. However, expression of HLA-I and ICAM-1 and sensitivity to cellular lysis could be restored or increased after exposure to INFγ. We tested 41 antibodies specific for 41 different antigens using a novel antibody-dependent cellular cytotoxicity (ADCC) screening system for target antigens. Anti-CD326 (EpCAM) was the only antibody capable of inducing ADCC on the five MCC lines tested. Because MCC tumors are often directly accessible, local pharmacologic manipulation to restore HLA class-I and ICAM-1 cell surface expression (and thus sensitivity to cell lysis) can potentially benefit immune therapeutic intervention. In line with this, our observation that ADCC against EpCAM can induce lysis of MCC lines and suggests that therapeutic targeting of this antigen deserves to be explored further. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. The main etiological agent is Merkel cell polyomavirus (MCPyV), detected in 80% of cases. About 5% of cases, called combined MCC, feature an admixture of neuroendocrine and non-neuroendocrine tumor cells. Reports of the presence or absence of MCPyV in combined MCC are conflicting, most favoring the absence, which suggests that combined MCC might have independent etiological factors and pathogenesis. These discrepancies might occur with the use of different virus identification assays, with different sensitivities. In this study, we aimed to determine the viral status of combined MCC by a multimodal approach. We histologically reviewed 128 cases of MCC and sub-classified them as "combined" or "conventional." Both groups were compared by clinical data (age, sex, site, American Joint Committee on Cancer [AJCC] stage, immunosuppression, risk of recurrence, and death during follow-up) and immunochemical features (cytokeratin 20 and 7, thyroid transcription factor 1 [TTF1], p53, large T antigen [CM2B4], CD8 infiltrates). After a first calibration step with 12 conventional MCCs and 12 cutaneous squamous cell carcinomas as controls, all eight cases of combined MCC were investigated for MCPyV viral status by combining two independent molecular procedures. Furthermore, on multiplex genotyping assay, the samples were examined for the presence of other polyoma- and papillomaviruses. Combined MCC differed from conventional MCC in earlier AJCC stage, increased risk of recurrence and death, decreased CD8 infiltrates, more frequent TTF1 positivity (5/8), abnormal p53 expression (8/8), and frequent lack of large T antigen expression (7/8). With the molecular procedure, half of the combined MCC cases were positive for MCPyV in the neuroendocrine component. Beta papillomaviruses were detected in 5/8 combined MCC cases and 9/12 conventional MCC cases. In conclusion, the detection of MCPyV DNA in half of the combined MCC cases suggests similar routes of carcinogenesis for combined and conventional MCC. [ABSTRACT FROM AUTHOR]

Background and purpose: We investigated whether university education is more likely in cervical artery dissection (CeAD)-patients than in age- and sex-matched patients with ischemic stroke (IS) due to other causes (non-CeAD-IS-patients).Methods: Patients from the Cervical Artery Dissection and Ischemic Stroke Patients study with documented self-reported profession before onset of IS due to CeAD (n = 715) or non-CeAD causes (n = 631) were analyzed. In the reported profession, the absence or presence of university education was assessed. Professions could be rated as academic or non-academic in 518 CeAD and 456 non-CeAD patients. Clinical outcome at 3 months was defined as excellent if modified Rankin Scale was 0-1.Results: University education was more frequent in CeAD-patients (100 of 518, 19.3%) than in non-CeAD-IS-patients (61 of 456, 13.4%, p = 0.008). CeAD-patients with and without university education differed significantly with regard to smoking (39 vs. 57%, p = 0.001) and excellent outcome (80 vs. 66%, p = 0.004). In logistic regression analysis, university education was associated with excellent outcome in CeAD-patients (OR 2.44, 95% CI 1.37-5.38) independent of other outcome predictors such as age (OR 0.97, 95% CI 0.84-0.99), NIHSS (OR 0.80, 95% CI 0.76-0.84) and local signs (OR 2.77, 95% CI 1.37-5.57).Conclusion: We observed a higher rate of university education in patients with CeAD compared with non-CeAD patients in our study population. University education was associated with favorable outcome in CeAD-patients. The mechanism behind this association remains unclear. [ABSTRACT FROM AUTHOR]

As a protective envelope surrounding the bacterial cell, the peptidoglycan sacculus is a site of vulnerability and an antibiotic target. Peptidoglycan components, assembled in the cytoplasm, are shuttled across the membrane in a cycle that uses undecaprenyl-phosphate. A product of peptidoglycan synthesis, undecaprenyl-pyrophosphate, is converted to undecaprenyl-phosphate for reuse in the cycle by the membrane integral pyrophosphatase, BacA. To understand how BacA functions, we determine its crystal structure at 2.6 Å resolution. The enzyme is open to the periplasm and to the periplasmic leaflet via a pocket that extends into the membrane. Conserved residues map to the pocket where pyrophosphorolysis occurs. BacA incorporates an interdigitated inverted topology repeat, a topology type thus far only reported in transporters and channels. This unique topology raises issues regarding the ancestry of BacA, the possibility that BacA has alternate active sites on either side of the membrane and its possible function as a flippase. [ABSTRACT FROM AUTHOR]

The violent water entry of flat plates is investigated using a Riemann-arbitrary Eulerian-Lagrangian (ALE) smoothed particle hydrodynamics (SPH) model. The test conditions are of interest for problems related to aircraft and helicopter emergency landing in water. Three main parameters are considered: the horizontal velocity, the approach angle (i.e., vertical to horizontal velocity ratio) and the pitch angle, α. Regarding the latter, small angles are considered in this study. As described in the theoretical work by Zhao and Faltinsen (1993), for small α a very thin, high-speed jet of water is formed, and the time-spatial gradients of the pressure field are extremely high. These test conditions are very challenging for numerical solvers. In the present study an enhanced SPH model is firstly tested on a purely vertical impact with deadrise angle α = 4°. An in-depth validation against analytical solutions and experimental results is carried out, highlighting the several critical aspects of the numerical modelling of this kind of flow, especially when pressure peaks are to be captured. A discussion on the main difficulties when comparing to model scale experiments is also provided. Then, the more realistic case of a plate with both horizontal and vertical velocity components is discussed and compared to ditching experiments recently carried out at CNR-INSEAN. In the latter case both 2-D and 3-D simulations are considered and the importance of 3-D effects on the pressure peak is discussed for α = 4° and α = 10°. [ABSTRACT FROM AUTHOR]

Type 2 phosphatidic acid phosphatases (PAP2s) can be either soluble or integral membrane enzymes. In bacteria, integral membrane PAP2s play major roles in the metabolisms of glycerophospholipids, undecaprenyl-phosphate (C-P) lipid carrier and lipopolysaccharides. By in vivo functional experiments and biochemical characterization we show that the membrane PAP2 coded by the Bacillus subtilis yodM gene is the principal phosphatidylglycerol phosphate (PGP) phosphatase of B. subtilis. We also confirm that this enzyme, renamed bsPgpB, has a weaker activity on C-PP. Moreover, we solved the crystal structure of bsPgpB at 2.25 Å resolution, with tungstate (a phosphate analog) in the active site. The structure reveals two lipid chains in the active site vicinity, allowing for PGP substrate modeling and molecular dynamic simulation. Site-directed mutagenesis confirmed the residues important for substrate specificity, providing a basis for predicting the lipids preferentially dephosphorylated by membrane PAP2s. [ABSTRACT FROM AUTHOR]

It has been suggested that spontaneous cervical carotid artery dissection (sCAD) may result from arterial inflammation. Periarterial edema (PAE), occasionally described in the vicinity of the mural hematoma in patients with sCAD, may support this hypothesis. Using cervical high-resolution magnetic resonance imaging, three readers, blinded to the mechanism of carotid artery dissection, searched for PAE, defined as periarterial T2-hyperintensity and T1-hypointensity, in 29 consecutive CAD patients categorized as spontaneous CAD (sCAD, n = 18) or traumatic CAD (tCAD, n = 11; i.e., major head or neck trauma within 2 weeks before the clinical onset). The relationships between PAE, inflammatory biological markers, history of infection and CAD mechanism were explored. Multiple CADs (n = 8) were found only in sCAD patients. Compared with tCAD, patients with sCAD were more likely to have a recent history of infection (OR = 12.5 [(95%)CI = 1.3-119], p = 0.03), PAE (83% vs. 27%; OR = 13.3 [(95%)CI = 2.2-82.0], p = 0.005) and to have elevated CRP (OR = 6.1 [(95%)CI = 1.2-32.1], p = 0.0002) or ESR (OR = 8.8 [(95%)CI = 1.5-50.1], p = 0.002) values. Interobserver agreement was 0.84 or higher for PAE identification. sCAD was associated with PAE and biological inflammation. Our results support the hypothesis of an underlying arterial inflammation in sCAD. [ABSTRACT FROM AUTHOR]

The purpose of this case-control study was to determine whether an asymmetry of size of the intracranial internal carotid artery (ICA) on 3D time-of-flight MR angiography (MRA) is predictive of a high-grade cervical ICA stenosis. Ninety-six stroke/TIA consecutive patients were recruited for the study, of whom 32 had unilateral high-grade ICA stenosis (>or=70% NASCET) and were included into the case group, and the remaining 64 did not have such high-grade stenosis and were included in the control group. On intracranial MRA, two observers, blinded to the characteristics of cervical ICA stenosis, independently searched for qualitative size asymmetry between ICAs and measured the cross-sectional surface of the intracranial ICAs. An intracranial size asymmetry was seen in 28 of the 32 high-grade stenoses by both readers, and in 10 (reader(1)) and 8 (reader(2)) of the 64 controls (sensitivity =88%, specificity =84-88%). In patients without agenesia of the A1 segment of the circle of Willis (n=70), sensitivity was >or=90% and specificity =96%. Surfaces ratios were significantly different (p<0.001) between cases and controls. However, using ROC curves analysis, the quantitative processing did not improve the detection when compared with the qualitative assessment of intracranial ICA asymmetry. A size asymmetry of the intracranial ICAs reveals the presence of an underlying high-grade cervical stenosis, with a high degree of confidence, especially in patients without anatomical variant of the anterior part of the circle of Willis. This sign may allow an early detection of high-grade cervical carotid stenosis in stroke patients before dedicated neck imaging is performed. [ABSTRACT FROM AUTHOR]

In clinical trials, assessing efficacy is based on validated scales, and the primary endpoint is usually based on a single scale. The aim of the review is to revisit the concepts and methods to design and analyze studies focused on restoration, recovery and or compensation. These studies are becoming more frequent with the development of restorative medicine. After discussing the definitions of recovery, we address the concept of recovery as the regain of lost capabilities, when the patient reaches a new equilibrium. Recovery is a dynamic process which assessment includes information from initial and final status, their difference, the difference between the final status of the patient and normality, and the speed of restoration. Finally, recovery can be assessed either for a specific function (focal restoration) or for a more global restoration. A single scale is not able to assess all the facets of a skill or a function, therefore complementary information should be collected and analyzed simultaneously to be tested in a single analysis. We are suggesting that recovery should be considered as a latent variable and therefore cannot be measured in pure form. We are also suggesting to customize the data collection and analysis according to the characteristics of the subjects, the mechanisms of action and consequences of the intervention. Moreover, recovery trials should benefit from latent variable analysis methods. Structural equation modeling is likely the best candidate for this approach applicable in pre-clinical and clinical studies. [ABSTRACT FROM AUTHOR]

The design and characterisation of a magnetic vibration absorber (MVA), completely relying on magnetic forces, is addressed. A distinctive feature of the absorber is the ability of tuning the linear stiffness together with the nonlinear cubic and quintic stiffnesses by means of repulsive magnets located in the axis of the main vibrating magnetic mass, together with a set of corrective magnets located off the main axis. The tuning methodology is passive and relies only on three geometrical parameters. Consequently, the MVA can be adjusted to design either a nonlinear tuned vibration absorber, a nonlinear energy sink or a bi-stable absorber with negative linear stiffness. The expressions of the stiffnesses are given from a multipole expansion of the magnetic fields of repulsive and corrective magnets. A complete static and dynamic characterisation is performed, showing the robustness of the modelling together with the ability of the MVA to work properly in different vibratory regimes, thus making it a suitable candidate for passive vibration mitigation in a wide variety of contexts. [ABSTRACT FROM AUTHOR]

The aim of this paper was to estimate the potential leakage of acrylamide monomer, used for flocculation in a settling basin, towards the groundwaters. Surface-groundwater interactions were conceptualized with a groundwater transport model, using a transfer rate to describe the clogged properties of the interface. The change in the transfer rate as a function of the spreading of the clogged layer in the settling basin was characterized with respect to time. It is shown that the water and the Acrylamide transfer rate are not controlled by the spreading of the clogged layer until this layer fully covers the interface. When the clogged layer spreads out, the transfer rate remains in the same order of magnitude until the area covered reaches 80 %. The main flux takes place through bank seepage. In these early stage conditions of a working settling basin, the acrylamide flux towards groundwaters remains constant, at close to 10 g/year (±5). [ABSTRACT FROM AUTHOR]

Aggregate quarries play a major role in land settlement. However, like all industrial operations, they can have impacts on the environment, notably due to the use of polyacrylamide (PAM)-based flocculants, which contain residual acrylamide (AMD), a carcinogenic, mutagenic, and reprotoxic monomer. In this study, the dissemination of AMD throughout the environment has been investigated in a French quarry. The presence of AMD has been determined in the process water and in the sludge, as well as in the surrounding surface water and groundwater. From the results of several sampling campaigns carried out on this case study, we can (a) confirm that the AMD contained in the commercial product is found in the quarry's water circuit (0.41 to 5.66 μg/l); (b) show that AMD is transported to the surrounding environment, as confirmed by the contamination of a pond near the installation (0.07 to 0.08 μg/l) and the presence of AMD in groundwater (0.01 to 0.02 μg/l); and (c) show that the sludge in both the current and former settling basins contains AMD (between 4 and 26 μg/kg of dry sludge). Therefore, we demonstrated in this case study that using PAM-based flocculants leads to the release of AMD to the environment beyond the treatment plant and creates a reserve of AMD in sludge basins. [ABSTRACT FROM AUTHOR]

The presence of acrylamide in natural systems is of concern from both environmental and health points of view. We developed an accurate and robust analytical procedure (offline solid phase extraction combined with UPLC/MS/MS) with a limit of quantification (20 ng L) compatible with toxicity threshold values. The optimized (considering the nature of extraction phases, sampling volumes, and solvent of elution) solid phase extraction (SPE) was validated according to ISO Standard ISO/IEC 17025 on groundwater, surface water, and industrial process water samples. Acrylamide is highly polar, which induces a high variability during the SPE step, therefore requiring the use of C-labeled acrylamide as an internal standard to guarantee the accuracy and robustness of the method (uncertainty about 25 % ( k = 2) at limit of quantification level). The specificity of the method and the stability of acrylamide were studied for these environmental media, and it was shown that the method is suitable for measuring acrylamide in environmental studies. [ABSTRACT FROM AUTHOR]

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10−3; combined P = 1.00 × 10−11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions. [ABSTRACT FROM AUTHOR]