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Long-term deficits of the vestibulo-ocular reflex (VOR) elicited by head rotation can be partially compensated by catch-up saccades (CuS). These saccades are initially visually guided, but their latency can greatly decrease resulting in short latency CuS (SL-CuS). It is still unclear what triggers these CuS and what are the underlying neural circuits. In this study, we aimed at evaluating the impact of cerebellar pathology on CuS by comparing their characteristics between two groups of patients with bilateral vestibular hypofunction, with or without additional cerebellar dysfunction. We recruited 12 patients with both bilateral vestibular hypofunction and cerebellar dysfunction (BVH-CD group) and 12 patients with isolated bilateral vestibular hypofunction (BVH group). Both groups were matched for age and residual VOR gain. Subjects underwent video head impulse test recording of the horizontal semicircular canals responses as well as recording of visually guided saccades in the step, gap, and overlap paradigms. Latency and gain of the different saccades were calculated. The mean age for BVH-CD and BVH was, respectively, 67.8 and 67.2 years, and the mean residual VOR gain was, respectively, 0.24 and 0.26. The mean latency of the first catch-up saccade was significantly longer for the BVH-CD group than that for the BVH group (204 ms vs 145 ms, p < 0.05). There was no significant difference in the latency of visually guided saccades between the two groups, for none of the three paradigms. The gain of covert saccades tended to be lower in the BVH-CD group than in BVH group (t test; p = 0.06). The mean gain of the 12° or 20° visually guided saccades were not different in both groups. Our results suggest that the cerebellum plays a role in the generation of compensatory SL-CuS observed in BVH patients. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Catch-Up Saccades in Vestibular Hypofunction: A Contribution of the Cerebellum?" published in the journal Cerebellum. The original version of the article contained mistakes in the author names, with their surnames and given names being interchanged. The corrected author list is provided in the correction notice. The original article has been corrected, and the publisher, Springer Nature, remains neutral regarding jurisdictional claims and institutional affiliations. [Extracted from the article]

Antibiotic treatments have detrimental effects on the microbiome and lead to antibiotic resistance. To develop a phage therapy against a diverse range of clinically relevant Escherichia coli, we screened a library of 162 wild-type (WT) phages, identifying eight phages with broad coverage of E. coli, complementary binding to bacterial surface receptors, and the capability to stably carry inserted cargo. Selected phages were engineered with tail fibers and CRISPR–Cas machinery to specifically target E. coli. We show that engineered phages target bacteria in biofilms, reduce the emergence of phage-tolerant E. coli and out-compete their ancestral WT phages in coculture experiments. A combination of the four most complementary bacteriophages, called SNIPR001, is well tolerated in both mouse models and minipigs and reduces E. coli load in the mouse gut better than its constituent components separately. SNIPR001 is in clinical development to selectively kill E. coli, which may cause fatal infections in hematological cancer patients. Phage engineered with tail fibers and CRISPR–Cas reduce Escherichia coli load in animals. [ABSTRACT FROM AUTHOR]

The numerical modelling of the behaviour of materials at the microstructural scale has been greatly developed over the last two decades. Unfortunately, conventional resolution methods cannot simulate polycrystalline aggregates beyond tens of loading cycles, and they do not remain quantitative due to the plasticity behaviour. This work presents the development of a numerical solver for the resolution of the Finite Element modelling of polycrystalline aggregates subjected to cyclic mechanical loading. The method is based on two concepts. The first one consists in maintaining a constant stiffness matrix. The second uses a time/space model reduction method. In order to analyse the applicability and the performance of the use of a space–time separated representation, the simulations are carried out on a three-dimensional polycrystalline aggregate under cyclic loading. Different numbers of elements per grain and two time increments per cycle are investigated. The results show a significant CPU time saving while maintaining good precision. Moreover, increasing the number of elements and the number of time increments per cycle, the model reduction method is faster than the standard solver. [ABSTRACT FROM AUTHOR]

Structural modification of lipid A, the lipid anchor of LPS, is one of the strategies used by Gram-negative bacteria to evade host innate immunity. Francisella tularensis is a human pathogen that infects and replicates within phagocytic cells. It produces an atypical lipid A, whose structure precludes an efficient recognition by both innate immune players, TLR4 and cationic antimicrobial peptides. Interestingly, a recent report indicates that the lipid A of Francisella (LVS vaccinal strain) undergoes polar modifications when bacteria are grown in human macrophages as compared to in broth. To characterize the structural modifications of lipid A that may be induced intracellularly, Francisella novicida , a surrogate strain for the highly virulent F. tularensis , was submitted to different stress conditions mimicking the harsh environment encountered in the macrophages. To analyze lipid A directly from intact bacteria without any chemical treatment or purification steps, we used a rapid and sensitive MALDI-TOF mass spectrometry approach. Among the many conditions tested, only bacteria exposure to acidic pHs (from 6 to 5) induced a change in lipid A structure. These changes were characterized by an increase in the relative abundance of molecular species bearing an additional hexose unit on the diglucosamine backbone, similar to species present when bacteria are grown under reduced environmental temperature. This lipid A glyco-form, which is observed in trace amounts in normal in vitro growth conditions at 37 °C, may contribute to the intracellular parasitism of macrophages by Francisella . [ABSTRACT FROM AUTHOR]

FFT-based homogenization methods aim at calculating the effective behavior of heterogeneous materials with periodic microstructures. These methods operate on a regular grid of voxels, and hence require an appropriate spatial discretization of periodic microstructures. However, when different microstructural length scales are involved, it is not always possible to have sufficient spatial resolutions to explicitly consider the influence of fine microstructural features (e.g. voids, second-phase particles). To circumvent this difficulty, one solution consists of using composite voxel methods to define the effective properties and the effective internal variables of heterogeneous voxels. In this work, different composite voxel methods are proposed to deal with inelastic materials with multiple length scales. These methods use simple homogenization rules to calculate the effective behavior of heterogeneous voxels. The first part of this paper is dedicated to the description of the composite voxel methods, which are based either on the Voigt, laminate structure or Mori–Tanaka approximations. In the second part, these methods are used to model the elasto-plastic behavior of a pearlitic steel polycrystalline aggregate. According to the results, the Voigt approximation, which ignores morphological features, is not appropriate for treating heterogeneous voxels. When morphological information is accounted for, with either the laminate structure or Mori–Tanaka approximations, a better agreement with experimental observations is obtained. Though none of these methods is universal, they offer some possibilities to investigate the mechanical behavior of heterogeneous materials involving multiple length scales. [ABSTRACT FROM AUTHOR]

The macroscopic behavior of polycrystalline materials is largely influenced by the shape, the arrangement and the orientation of crystallites. Different methods have thus been developed to determine the effective behavior of such materials as a function of their microstructural features. In this work, which focuses on polycrystalline materials with an elastic–viscoplastic behavior, the self-consistent, finite element and spectral methods are compared. These common methods are used to determine the effective behavior of different 316L polycrystalline aggregates subjected to various loading conditions. Though no major difference is observed at the macroscopic scale, the hardening rate is found to be slightly overestimated with the finite element method. Indeed, spatial convergence cannot be guaranteed for finite element calculations, even when fine mesh resolutions, for which the computational cost is important, are used. Also, as the self-consistent method does not explicitly account for neighborhood effects, important discrepancies between the self-consistent method and the other methods exist regarding the mechanical response of a specific grain. The self-consistent method nevertheless provides a reasonable description of the average response obtained for a group of grains with identical features (e.g. shape, orientation). [ABSTRACT FROM AUTHOR]

An analysis of high cycle fatigue behaviour is undertaken via the numerical simulation of polycrystalline aggregates. The metallic material chosen for investigation is Copper, which has a FCC crystalline structure. The REV, which is composed of 300 randomly orientated equiaxed grains, is loaded at the fatigue limit determined at 107 cycles. The aim is to calculate the mechanical quantities at the mesoscopic scale (average quantities in the grains) after cyclic stabilisation has been achieved. The results highlight the fact that the mechanical quantities at this scale have a large scatter. A statistical analysis of the response of the aggregate for different loading conditions (tensile, torsion, and in-phase tension-torsion) is done. Thanks to the sufficiently large number of different microstructures investigated, a critical analysis of the Dang Van and Crossland multiaxial fatigue criteria has been undertaken, using the local mechanical quantities. [ABSTRACT FROM AUTHOR]

• Microstructure-sensitive framework has been extended and applied to SLM 316L. • As-built surface roughness has been considered explicitly in the finite element model. • Textured microstructure of SLM 316L has been evaluated concerning fatigue strength. • Competitive effects of surface defect and microstructure have been distinguished. This paper aims to study the individual and competitive effects of surface defects and microstructural components in an AM 316L by numerical methods. Based on the microstructure sensitive modeling framework, numerical simulations of models in different surface states with virtual quasi-realistic explicit microstructures are performed. Problems encountered during the establishment of the numerical polycrystalline aggregate model are discussed, including the grain morphology, the strongly textured microstructure with preferential crystallographic directions, roughness and surface defect. A statistical method based on generalized extreme value distribution along with a non-local method is used to describe the stochasticity of microstructural attributes. Simulations of differently configured explicit microstructure models are analyzed and discussed. [ABSTRACT FROM AUTHOR]

This paper deals with the effect of defect size and shape under high cycle fatigue for metallic alloys. A large simulation campaign based on a multiaxial fatigue criterion and a non-local approach is presented. A relative defect size based on a ratio between the defect size and a characteristic length introduced by the non-local approach is defined. A normalized Kitagawa–Takahashi diagram is then obtained. A competition between the highly stressed volume size and the local maxima due to the defect is observed and seem dependent on the relative defect size. The effect of the loading mode (uniaxial and pure shear) and of the plasticity are discussed. Finally, a comparison of the simulation results with experimental data on a 316L L-PBF demonstrates the robustness of the proposed approach and explains the negligible effect of the defect morphology compared to its size. • The effect of defect size and shape under high cycle fatigue is investigated. • A multiaxial fatigue criteria with a non-local approach is applied. • A competition between the highly stressed volume and the local maxima is underlined. • A simulated normalized Kitagawa–Takahashi diagram is proposed. • The effect of the loading mode and the plasticity is discussed. [ABSTRACT FROM AUTHOR]

In this work, stainless steel 316L obtained by Laser Powder Bed Fusion (L‐PBF) has been produced and characterized. The experimental campaign focuses on the samples in the as‐built state under cyclic tension‐compression loadings. Low cycle fatigue (LCF) and high cycle fatigue (HCF) tests are carried out. Microstructure observations are performed before and after the loadings. As‐built L‐PBF 316L has a good LCF performance despite the presence of surface defects but a low fatigue limit in the HCF regime. Removing the surface roughness has a beneficial effect but does not improve the fatigue strength to that of machined wrought 316L. Observations on the microstructure of fatigue samples indicate that LCF is dominated by the local plastic deformation, which is mostly achieved by the slip in the studied material and is not sensitive to the defect. The lack‐of‐fusion defect impairs the fatigue resistance in the HCF regime. Highlights: Monotonic tensile and LCF behavior of L‐PBF 316L are not sensitive to the surface defects.HCF behavior of L‐PBF 316L is dominated by the surface or subsurface defects.Slip planes produced during cyclic deformation are not affected by the melt pool boundaries. [ABSTRACT FROM AUTHOR]

• Explicit virtual microstructure is introduced to the numerical models. • Different configurations of grain size and morphology are investigated. • Stress-based fatigue criteria combined with two non-local methods are applied. • Kitagawa-Takahashi effect is reproduced and explained via the proposed framework. This study aims at investigating the effect of defect on the high cycle fatigue behavior of polycrystalline aggregates. An explicit virtual microstructure finite element model is created to conduct fatigue simulations. Different stress-based criteria frequently applied in fatigue assessment are tested with a combination of the non-local methods. Two realizations of the non-local method are used and compared. Simulation results are compared to experimental results of 316L. From the parametric simulations, better qualitative understandings on the choice of non-local method as well as its parameters are obtained. The effect of Kitagawa-Takahashi can be reproduced and explained by this proposed framework of microstructure modeling-simulation. [ABSTRACT FROM AUTHOR]

• Experimental torsion and bending fatigue strengths of 90°, 45°, and 0° LPBF building direction were determined. • Kitagawa diagrams were provided in bending and torsion loading at different building directions. • Bending fatigue behavior is very sensitive to building direction compared to torsion. • Torsion fatigue behavior of LPBF 316L is not sensitive to lack-of-fusion defects. The present study aims to investigate the high cycle fatigue (HCF) performance of steel 316L fabricated by the laser powder bed fusion (LPBF) process. Bending and torsional fatigue test specimens built horizontally (0°), inclined (45°), and vertically (90°) have been prepared and tested. Stress-relieving heat treatment was carried out to reduce the residual stresses. The 90°, 45°, and 0° built near-net-shape and polished specimens have fatigue strengths between 140 and 250 MPa under bending loading and 150 and 170 MPa under torsion loading. This difference illustrates a more pronounced defect sensitivity in bending compared to torsion. Fractographical analyses revealed the fatigue failure mechanisms. As the building direction inclines from vertical to horizontal, the effective areas of inherent defects diminish contributing to improving fatigue strength under bending loading whilst the differences from building directions in torsional fatigue strengths are minor. Microstructural features are seen to compete with inherent defects to affect fatigue performance in the condition that the effective defect sizes are close to the critical fatigue crack size. [ABSTRACT FROM AUTHOR]

To describe the results of a structured literature review of real-world outcomes with ixekizumab in patients with psoriasis (PsO) and/or psoriatic arthritis (PsA). Literature databases, conference proceedings and additional sources were searched for relevant publications. Real-world studies of ≥25 ixekizumab-treated patients with PsO and/or PsA were included. Data on clinical effectiveness, treatment persistence/patterns, economic outcomes, patient-reported outcomes (PROs) and safety were extracted. Fifty-one publications were included. Most studies focused on patients with PsO, and the number of publications with a focus on PROs was low. Studies of treatment patterns found that in general, ixekizumab had similar or better persistence versus other biologics, and rates or risk of switching similar to or less than comparator drugs. Adherence to ixekizumab was high, and patients were less likely to discontinue ixekizumab than other biologics. Ixekizumab was effective in the real world, with a safety profile consistent with that reported in clinical trials. Real-world use of ixekizumab in PsO and PsA is effective and safe, with generally high treatment persistence and adherence. Further work is required to determine the impact of ixekizumab on PROs in PsO, and to gather more data on real-world use of ixekizumab in PsA. [ABSTRACT FROM AUTHOR]

Introduction: Moderate to severe atopic dermatitis (AD) is associated with a significant disease burden, impacting sleep, quality of life, and treatment needs. The aim of this study was to characterize disease burden and treatment patterns for adults with moderate to severe AD in three European countries: France, Italy, and the UK. Methods: This retrospective analysis of adult patients with moderate to severe AD in Europe used medical records and physician/patient survey data collected in August 2019 to April 2020. Demographic and baseline disease characteristics, information on current comorbidities, disease flares, and current and previous treatments were collected by the physician. Patient-perceived burden was assessed using patient-reported outcome (PRO) questionnaires, which were completed on a voluntary basis and included the following instruments: Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), EuroQol five-dimensional (EQ-5D), and Work Productivity and Activity Impairment (WPAI). Disease severity was subjectively assessed by physicians and was based on their own definition of the terms mild, moderate, and severe. Data were analyzed descriptively. Results: The physician-reported sample included 912 patients with moderate to severe disease from France (n = 314), Italy (n = 309), and the UK (n = 289); approximately 30% of patients provided PRO data. Across these countries, 22–41% of patients reported current flares; mean POEM and DLQI scores were 10.6–13.1 and 9.5–11.1, respectively, indicating a high disease burden. However, systemic therapy use was low (e.g., conventional systemics were used by 18–24% of patients). Physician-assessed disease severity did not fully align with EASI scores, indicating that factors in addition to skin signs are impacting AD severity. Conclusion: Patients with moderate to severe AD report significant disease burden, highlighting unmet treatment needs, particularly with respect to the underuse of systemic treatments despite AD being a systemic disease and the associated disease burden. [ABSTRACT FROM AUTHOR]

Introduction: This study evaluated patient characteristics and treatment patterns according to weight in pediatric patients with psoriasis in a real-world setting. Methods: Primary care and specialist physicians treating pediatric patients with psoriasis aged 6–17 years in five European countries were surveyed in the 2019–2020 Adelphi Real World Pediatric Psoriasis Disease Specific Programme. At least two patients with current or previous biologic use were included per physician. Patient characteristics and treatment patterns were analyzed overall and for patients weighing 25–50 kg or more than 50 kg. Results: Data from 772 patients weighing 25–50 kg and 1147 weighing more than 50 kg were analyzed. Median age at diagnosis was significantly less in lighter than heavier patients (10.0 vs. 14.0 years; p < 0.001), as was median disease duration (2.2 vs. 3.0 years; p < 0.001). Topical treatments were prescribed in 59.0% of patients overall (70.3% of lighter and 51.4% of heavier patients; p < 0.001), and were used to treat mild rather than moderate-to-severe psoriasis. Conventional systemic use was low (10.8% of patients overall) and predominantly for moderate-to-severe psoriasis. In this biologic-enriched sample, most biologics (78.2%) were prescribed in older (> 13 years) patients. Biologic use increased with line of therapy (6.6% of first-line, 18.0% of second-line, 33.7% of third-line, 44.7% of fourth-line treatments). Conclusion: Biologics are predominantly prescribed in older (> 13 years) and heavier (> 50 kg) patients, with little first- or second-line use. The low use of biologics in European pediatric patients with psoriasis may represent an unmet treatment need, as topical or conventional systemic agents remain the main treatment option for moderate or severe psoriasis in these patients through the treatment pathway. Plain Language Summary: This study looked into types of treatments according to body weight in children with psoriasis, since approved dosing regimens for some treatments are based on body weight. Primary care and specialist physicians treating children with psoriasis aged 6–17 years in five European countries completed a survey. Patient information for those receiving specific types of psoriasis treatments were collected. Of the children included, 772 weighed 25–50 kg and 1147 weighed more than 50 kg. Most children received treatments applied to the skin, such as creams and ointments; this occurred in 70% of lighter patients and in 51% of heavier patients. Conventional treatments taken via the mouth were prescribed in a few patients (11% [overall]), while newer biologic drugs were taken to a greater extent in heavier (30%) than lighter (16%) patients. Most biologics (78%) were prescribed in older (> 13 years) patients. Biologic use increased with the number of failed previous treatments, comprising 7%, 18%, 34%, and 45% of first, second, third, and fourth treatments, respectively. We conclude that children with psoriasis who are treated with biologic drugs are predominantly older and heavier, and have more severe psoriasis. Prescriptions for biologics are given after many other treatments have been tried. [ABSTRACT FROM AUTHOR]

• Torsion fatigue limit is found higher than bending fatigue limit for LPBF 316L. • Effect of lack-of-fusion defect dominates over the effect of stress gradient. • Skipping contouring introduces clustering defects without increasing surface roughness. • Clustering surface defects act synergistically as one to initiate the fatigue crack. The mechanical performances of additive manufactured (AM) material are highly dependent on the fabrication process which inevitably results in surface imperfection as well as porosity. In the present study, the high cycle fatigue (HCF) behavior of an AM stainless steel 316L is experimentally investigated to characterize and evaluate the effect of the inherent surface defects. Profilometry and Computed Tomography are used. A series of fatigue experiments is carried out under different loading modes including tension, bending, and torsion fatigue tests. For each loading condition, different surface preparations are used to investigate the effect of surface state. Fatigue tests reveal that surface treatment can improve fatigue performances, the improvements observed being higher under tension/bending loading than under torsion loading. The fractographic analysis is performed for all the available tested specimens to reveal the mechanism of fatigue crack initiation. Lack-of-fusion (LoF) defects play the predominant role in the fatigue performance of SS 316L fabricated by laser powder bed fusion (LPBF). The presence of multiple LoF defects at the surface or subsurface is detrimental to the endurance under cyclic loading. By using Murakami approach modeling the relationship between fatigue strength and defect size, it is found that the multiple clustering defects act synergistically as one large virtual crack to initiate the fatigue crack. [ABSTRACT FROM AUTHOR]

Multiaxial high cycle fatigue modeling of materials is an issue that concerns many industrial domains (automotive, aerospace, nuclear, etc.) and in which many progress still remains to be achieved. Several approaches exist in the literature: invariants, energy, integral and critical plane approaches all of them having their advantages and drawbacks. These different formulations are usually based on mechanical quantities at the micro or mesoscales using localization schemes and strong assumptions to propose simple analytical forms. This study aims to revisit these formulations using a numerical approach based on crystal plasticity modeling coupled with explicit description of microstructure (morphology and texture) and proposes a statistical procedure for the analyses of numerical results in the HCF context. This work has three steps: First, 2.5D periodic digital microstructures based on a random grain sizes distribution are generated. Second, multiaxial cyclic loading conditions corresponding to the fatigue strength at 106 cycles are applied to these microstructures. Third, the mesoscopic Fatigue Indicator Parameters (FIPs), formulated from the different criteria existing in the literature, are identified using the finite element calculations of the mechanical fields. These mesoscopic FIP show the limits of the original criteria when it comes to applying them at the grain scale. A statistical method based on extreme value probability is used to redefine the thresholds of these criteria. These new thresholds contain the sensitivity of the HCF behavior to microstructure attributes. Finally, the biaxiality and phase shift effects are discussed at the grain scale and the loading paths of some critical grains are analyzed. [ABSTRACT FROM AUTHOR]