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The electrical resistivity ρ and Hall coefficient RH of the tetragonal single-layer cuprate La1.6-xNd0.4SrxCuO4 were measured in magnetic fields up to H=37.5 T, large enough to access the normal state at T→0, for closely spaced dopings p across the pseudogap critical point at p☆=0.23. Below p☆, both coefficients exhibit an upturn at low temperature, which gets more pronounced with decreasing p. Taken together, these upturns show that the normal-state carrier density n at T=0 drops upon entering the pseudogap phase. Quantitatively, it goes from n=1+p at p=0.24 to n=p at p=0.20. By contrast, the mobility does not change appreciably, as revealed by the magnetoresistance. Our data are in excellent agreement with recent high-field data on YBa2Cu3Oy and La2-xSrxCuO4. The quantitative consistency across three different cuprates shows that a drop in carrier density from 1+p to p is a universal signature of the pseudogap transition at T=0. We discuss the implication of these findings for the nature of the pseudogap phase. [ABSTRACT FROM AUTHOR]

We report a sudden reversal in the pressure dependence of Tc in the iron-based superconductor similar to that discovered recently in KFe2As2 [Tafti et ai, Nat. Phys. 9, 349 (2013)]. As in KFe2As2, we observe no change in the Hall coefficient at T → 0, again ruling out a Lifshitz transition across the critical pressure Pc. We interpret the Tc reversal in the two materials as a phase transition from one pairing state to another, tuned by pressure, and we investigate which parameters control this transition. Comparing samples of different residual resistivity p0, we find that a sixfold increase in impurity scattering does not shift Pc. From a study of x-ray diffraction on KFe2As2 under pressure, we report the pressure dependence of lattice constants and As-Fe-As bond angle. The pressure dependence of the various lattice parameters suggests that Pc should be significantly higher in CsFe2As2 than in KFe2As2, but we find on the contrary that Pc is lower in CsFe2As2, indicating that other factors control Tc. Resistivity measurements under pressure reveal a change of regime across Pc, suggesting a possible link between inelastic scattering and pairing symmetry. [ABSTRACT FROM AUTHOR]

Background: Tidal volume (Vt) delivery during mechanical ventilation is influenced by gas compression, humidity, and temperature., Objectives: This bench study aimed at assessing the accuracy of Vt delivery by paediatric intensive care ventilators according to the humidification system. Secondary objectives were to assess the following: (i) the accuracy of Vt delivery in ventilators with an integrated Y-piece pneumotachograph and (ii) the ability of ventilators to deliver and maintain a preset positive end-expiratory pressure., Methods: Six latest-generation intensive care ventilators equipped with a paediatric mode were tested on the ASL5000 test lung in four simulated paediatric bench models (full-term neonate, infant, preschool-age chile, and school-age child), under volume-controlled mode with a heated humidifier (HH) or a heat moisture exchanger, with various loading conditions. Three ventilators equipped with a Y-piece pneumotachograph were tested with or without the pneumotachograph in the neonatal and infant models. "Accurate Vt" delivery was defined as a volume error (percentage of the preset Vt under body temperature and pressure and saturated water vapour conditions) being ≤10 % of the absolute preset value., Results: Vt accuracy varied significantly across ventilators but was acceptable in almost all the ventilators and all the models, except the neonatal model. The humidification system had an impact on Vt delivery in the majority of the tested conditions (p < 0.05). The use of an HH was associated with a better Vt accuracy in four ventilators (V500, V800, R860, and ServoU) and allowed to achieve an acceptable level of volume error in the neonatal model as compared to the use of heat moisture exchanger. The use of an integrated pneumotachograph was associated with lower volume error in only one ventilator (p < 0.01). All the tested ventilators were able to maintain adequate positive end-expiratory pressure levels., Conclusion: The humidification system affects Vt accuracy of paediatric intensive care ventilators, especially in the youngest patients for whom the HH should be preferred., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Continuous venovenous hemodiafiltration (CVVHDF) is one of the treatments of critically ill children presenting severe acute liver failure. This affliction might be induced by HSV infection requiring a treatment by acyclovir. Continuous kidney replacement therapy (CKRT) can alter its pharmacokinetics, according to its physicochemical properties and CVVHDF settings., Case-Diagnosis/treatment: The patient was a 21-month-old female presenting liver failure with hyperammonemia treated by acyclovir with presumed HSV infection. CKRT was initiated on day 1 with substantial replacement and dialysate flow rates (respectively 75 and 220 mL/kg/h). Acyclovir was intravenously administered every 8 h with a 1-h infusion of 500 mg/m 2 . Plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry assay to estimate the area under a curve (AUC) and CKRT clearance by 2 methods (one based on pre- and post-filter concentrations and the other one on dialysate flow rates). Clearance was estimated between 19.2 and 26.3 mL/min with the first method and between 27.6 and 44.3 mL/min with the second one. Concentrations were highly above the therapeutic index (peak concentration was measured at 28 mg/L), but AUC was appropriate., Conclusions: This case describes acyclovir pharmacokinetics during CKRT in a pediatric patient treated by acyclovir. The patient was treated with adapted exposure with the usual dosing, but lower dosing should be investigated with complementary studies., Trial Registration: ClinicalTrials.gov NCT02539407., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Objectives: To assess if noninvasive positive pressure ventilation (NIPPV) is associated with a greater reduction in respiratory effort as compared to continuous positive airway pressure (CPAP) during severe acute bronchiolitis, with both supports set either clinically or physiologically., Methods: Twenty infants (median [IQR] age 1.2 [0.9; 3.2] months) treated <24 h with noninvasive respiratory support (CPAP Clin, set at 7 cmH 2 O, or NIPPV Clin) for bronchiolitis were included in a prospective single-center crossover study. Esogastric pressures were measured first with the baseline support, then with the other support. For each support, recordings were performed with the clinical setting and a physiological setting (CPAP Phys and NIPPV Phys), aiming at normalising respiratory effort. Patients were then treated with the optimal support. The primary outcome was the greatest reduction in esophageal pressure-time product (PTP ES /min). Other outcomes included improvement of the other components of the respiratory effort., Results: NIPPV Clin and Phys were associated with a lower PTP ES /min (164 [105; 202] and 106 [78; 161] cmH 2 O s/min, respectively) than CPAP Clin (178 [145; 236] cmH 2 O s/min; p = 0.01 and 2 × 10 -4 , respectively). NIPPV Clin and Phys were also associated with a significant reduction of all other markers of respiratory effort as compared to CPAP Clin. PTP ES /min with NIPPV (Clin or Phys) was not different from PTP ES /min with CPAP Phys. There was no significant difference between physiological and clinical settings., Conclusion: NIPPV is associated with a significant reduction in respiratory effort as compared to CPAP set at +7 cmH 2 O in infants with severe acute bronchiolitis. CPAP Phys performs as well as NIPPV Clin., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Purpose: To confirm the overall benignity of fat-containing soft tissue tumors (STT) on a pediatric cohort and to define the clinical and imaging features that warrant a biopsy., Methods: A retrospective monocentric study was conducted on patients aged less than 25 years consecutively referred for fat-containing STT to our Comprehensive Cancer Center between 1998 and 2022. Tumor imaging characteristics at diagnosis (US, CT, or MRI) were correlated with pathology., Results: The database extraction identified 63 fat-containing tumors with clinical, histologic, and imaging data available for review. In total, 58 (92%) were benign tumors: 36 lipoblastomas and lipomas, 12 fibrous hamartomas of infancy (FHI), 5 lipofibromatosis, 2 lipomas arborescens, 2 lipomatosis and 1 spindle-cell lipoma. Five patients (8%) were diagnosed with liposarcoma. Factors significantly correlated with malignancy were age >10 years old ( p < 0.001), having a cancer-predisposing condition ( p < 0.001), a percentage of fat <25% ( p = 0.002), and a presence of myxoid zones ( p < 0.001) on imaging., Conclusion: Most fat-containing STT in children may be classified as benign tumors based on clinics and imaging. The indication for biopsy could be limited to patients aged 10 years or more with either a cancer-predisposing condition or imaging features demonstrating either a low-fat component (<25%) or the presence of myxoid zones.

Within the life-cycle assessment of health technologies, real-world data (RWD) have until now been of secondary importance to clinical trial data. The availability of massive, better quality RWD, particularly with the emergence of connected devices, the improvement of methods for characterizing populations, make it possible to have a better insight into the effects of treatment, sometimes on a national scale the importance of RWD is likely to progress in the eyes of health technology assessors, going from being traditionally complementary to possibly replacing clinical trial data. This is the fundamental question that the round table, involving experts from the academic and/or hospital, institutional, and industrial worlds, set out to answer. This work served first to establish the current role of RWD in health technology assessment, by distinguishing the main purposes of RWD, the timing of the evaluation in relation to the life cycle of the technology, and then according to the party commissioning or receiving the outcomes of RWD-based studies. Secondly, the round table proposed six general recommendations for more intensive and decisive use of RWD in the assessment and decision-making process., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Monkeypox (MPX) is a zoonotic infectious disease caused by Monkeypox virus (MPXV), an enveloped DNA virus belonging to the Poxviridae family and the Orthopoxvirus genus. Since early May 2022, a growing number of human cases of Monkeypox have been reported in non-endemic countries, with no history of contact with animals imported from endemic and enzootic areas, or travel to an area where the virus usually circulated before May 2022. This qualitative risk assessment aimed to investigate the probability that MPXV transmission occurs through food during its handling and consumption. The risk assessment used "top-down" (based on epidemiological data) and "bottom-up" (following the agent through the food chain to assess the risk of foodborne transmission to human) approaches, which were combined. The "top-down" approach first concluded that bushmeat was the only food suspected as a source of contamination in recorded cases of MPXV, by contact or ingestion. The "bottom-up" approach then evaluated the chain of events required for a human to become ill after handling or consuming food. This approach involves several conditions: (i) the food must be contaminated with MPXV (naturally, by an infected handler or after contact with a contaminated surface); (ii) the food must contain viable virus when it reaches the handler or consumer; (iii) the person must be exposed to the virus and; (iv) the person must be infected after exposure. Throughout the risk assessment, some data gaps were identified and highlighted. The conclusions of the top-down and bottom-up approaches are consistent and suggest that the risk of transmission of MPXV through food is hypothetical and that such an occurrence was never reported. In case of contamination, cooking ( e.g., 12 min at 70°C) could be considered effective in inactivating Poxviridae in foods. Recommendations for risk management are proposed. To our knowledge, this is the first risk assessment performed on foodborne transmission of MPXV., Competing Interests: The authors declare no conflict of interest. This paper was prepared thanks to the collective expertise carried out by the ANSES emergency collective expert appraisal group (GECU) “Monkeypox – Food”. ANSES analyses interests declared by experts before they are appointed and throughout the work, in order to prevent risk of conflicts of interest in relation to the points addressed in expert appraisals. The experts’ declarations of interests are made public via the website: https://dpi.sante.gouv.fr/., (© 2022 Elsevier B.V. All rights reserved.)

A variety of 'strange metals' exhibit resistivity that decreases linearly with temperature as the temperature decreases to zero 1-3 , in contrast to conventional metals where resistivity decreases quadratically with temperature. This linear-in-temperature resistivity has been attributed to charge carriers scattering at a rate given by ħ/τ = αk B T, where α is a constant of order unity, ħ is the Planck constant and k B is the Boltzmann constant. This simple relationship between the scattering rate and temperature is observed across a wide variety of materials, suggesting a fundamental upper limit on scattering-the 'Planckian limit' 4,5 -but little is known about the underlying origins of this limit. Here we report a measurement of the angle-dependent magnetoresistance of La 1.6-x Nd 0.4 Sr x CuO 4 -a hole-doped cuprate that shows linear-in-temperature resistivity down to the lowest measured temperatures 6 . The angle-dependent magnetoresistance shows a well defined Fermi surface that agrees quantitatively with angle-resolved photoemission spectroscopy measurements 7 and reveals a linear-in-temperature scattering rate that saturates at the Planckian limit, namely α = 1.2 ± 0.4. Remarkably, we find that this Planckian scattering rate is isotropic, that is, it is independent of direction, in contrast to expectations from 'hotspot' models 8,9 . Our findings suggest that linear-in-temperature resistivity in strange metals emerges from a momentum-independent inelastic scattering rate that reaches the Planckian limit., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The Adjuvant System AS01 contains monophosphoryl lipid A (MPL) and the saponin QS-21 in a liposomal formulation. AS01 is included in recently developed vaccines against malaria and varicella zoster virus. Like for many other adjuvants, induction of adaptive immunity by AS01 is highly dependent on the ability to recruit and activate dendritic cells (DCs) that migrate to the draining lymph node for T and B cell stimulation. The objective of this study was to more precisely address the contribution of the different conventional (cDC) and monocyte-derived DC (MC) subsets in the orchestration of the adaptive immune response after immunization with AS01 adjuvanted vaccine. The combination of MPL and QS-21 in AS01 induced strong recruitment of CD26 + XCR1 + cDC1s, CD26 + CD172 + cDC2s and a recently defined CCR2-dependent CD64-expressing inflammatory cDC2 (inf-cDC2) subset to the draining lymph node compared to antigen alone, while CD26 - CD64 + CD88 + MCs were barely detectable. At 24 h post-vaccination, cDC2s and inf-cDC2s were superior amongst the different subsets in priming antigen-specific CD4 + T cells, while simultaneously presenting antigen to CD8 + T cells. Diphtheria toxin (DT) mediated depletion of all DCs prior to vaccination completely abolished adaptive immune responses, while depletion 24 h after vaccination mainly affected CD8 + T cell responses. Vaccinated mice lacking Flt3 or the chemokine receptor CCR2 showed a marked deficit in inf-cDC2 recruitment and failed to raise proper antibody and T cell responses. Thus, the adjuvant activity of AS01 is associated with the potent activation of subsets of cDC2s, including the newly described inf-cDC2s., Competing Interests: CC and AC are employees of the GSK group of companies. AD was an employee of GSK at the time of the study and owns GSK stocks. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bosteels, Fierens, De Prijck, Van Moorleghem, Vanheerswynghels, De Wolf, Chalon, Collignon, Hammad, Didierlaurent and Lambrecht.)

Replication-deficient chimpanzee adenovirus (ChAd) vectors represent an attractive vaccine platform and are thus employed as vaccine candidates against several infectious diseases. Since inducing effective immunity depends on the interplay between innate and adaptive immunity, a deeper understanding of innate immune responses elicited by intramuscularly injected ChAd vectors in tissues can advance the platform's development. Using different candidate vaccines based on the Group C ChAd type 155 (ChAd155) vector, we characterized early immune responses in injected muscles and draining lymph nodes (dLNs) from mice, and complemented these analyses by evaluating cytokine responses and gene expression patterns in peripheral blood from ChAd155-injected macaques. In mice, vector DNA levels gradually decreased post-immunization, but local transgene mRNA expression exhibited two transient peaks [at 6 h and Day (D)5], which were most obvious in dLNs. This dynamic pattern was mirrored by the innate responses in tissues, which developed as early as 1-3 h (cytokines/chemokines) or D1 (immune cells) post-vaccination. They were characterized by a CCL2- and CXCL9/10-dominated chemokine profile, peaking at 6 h (with CXCL10/CCL2 signals also detectable in serum) and D7, and clear immune-cell infiltration peaks at D1/D2 and D6/D7. Experiments with a green fluorescent protein-expressing ChAd155 vector revealed infiltrating hematopoietic cell subsets at the injection site. Cell infiltrates comprised mostly monocytes in muscles, and NK cells, T cells, dendritic cells, monocytes, and B cells in dLNs. Similar bimodal dynamics were observed in whole-blood gene signatures in macaques: most of the 17 enriched immune/innate signaling pathways were significantly upregulated at D1 and D7 and downregulated at D3, and clustering analysis revealed stronger similarities between D1 and D7 signatures versus the D3 signature. Serum cytokine responses (CXCL10, IL1Ra, and low-level IFN-α) in macaques were predominantly observed at D1. Altogether, the early immune responses exhibited bimodal kinetics with transient peaks at D1/D2 and D6/D7, mostly with an IFN-associated signature, and these features were remarkably consistent across most analyzed parameters in murine tissues and macaque blood. These compelling observations reveal a novel aspect of the dynamics of innate immunity induced by ChAd155-vectored vaccines, and contribute to ongoing research to better understand how adenovectors can promote vaccine-induced immunity., Competing Interests: CC, VBo, AC, NS, SM, RB, VBe, and ST are, or were at the time of the study, employees of the GSK group of companies. RB, SM, VBe, and ST report ownership of GSK shares and/or restricted shares. SC is an employee of Reithera Srl., (Copyright © 2020 Collignon, Bol, Chalon, Surendran, Morel, van den Berg, Capone, Bechtold and Temmerman.)

Soft tissue sarcomas in children are rare tumor, representing around 6 to 7% of children cancer. They spread mostly sporadically (90%) and therefore are rarely associated to an underlying constitutional genetic disease (10%). About half of those sarcomas are rhabdomyosarcomas and the others are a very heterogenous histologic group with various bio-pathologies and prognosis. Clinical presentation is mainly a soft tissue lump often difficult to distinguish from more frequent benign causes (malformative, infectious, benign, or pseudotumor). Inappropriate initial diagnosis work-up has a strong impact on soft tissue sarcomas' prognosis. Adapted complementary investigations (first ultrasound and MRI) are important to compile arguments for a malign origin and to indicate a biopsy. However, predictive value of imaging exams still remains imperfect, and histological analysis by percutaneous image-guided biopsy and sometimes by surgical biopsy is often necessary. Authors realize an update on optimal diagnostic pathway including molecular tests in presence of a soft tissue mass in a child., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The Wiedemann-Franz (WF) law has been tested in numerous solids, but the extent of its relevance to the anomalous transverse transport and the topological nature of the wave function, remains an open question. Here, we present a study of anomalous transverse response in the noncollinear antiferromagnet Mn 3 Ge extended from room temperature down to sub-kelvin temperature and find that the anomalous Lorenz ratio remains close to the Sommerfeld value up to 100 K but not above. The finite-temperature violation of the WF correlation is caused by a mismatch between the thermal and electrical summations of the Berry curvature and not by inelastic scattering. This interpretation is backed by our theoretical calculations, which reveals a competition between the temperature and the Berry curvature distribution. The data accuracy is supported by verifying the anomalous Bridgman relation. The anomalous Lorenz ratio is thus an extremely sensitive probe of the Berry spectrum of a solid., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Songbirds are a powerful model to study vocal learning given that aspects of the underlying behavioral and neurobiological mechanisms are analogous in many ways to mechanisms involved in speech learning. Perineuronal nets (PNNs) represent one of the mechanisms controlling the closing of sensitive periods for vocal learning in the songbird brain. In zebra finches, PNN develop around parvalbumin (PV)-expressing interneurons in selected song control nuclei during ontogeny and their development is delayed if juveniles are deprived of a tutor. However, song learning in zebra finches takes place during a relatively short period of development, and it is difficult to determine whether PNN development correlates with the end of the sensory or the sensorimotor learning period. Canaries have a longer period of sensorimotor vocal learning, spanning over their first year of life so that it should be easier to test whether PNN development correlates with the end of sensory or sensorimotor vocal learning. Here, we quantified PNN around PV-interneurons in the brain of male canaries from hatching until the first breeding season and analyzed in parallel the development of their song. PNN development around PV-interneurons specifically took place and their number reached its maximum around the end of the sensorimotor learning stage, well after the end of sensory vocal learning, and correlated with song development. This suggests that PNN are specifically involved in the termination of the sensitive period for sensorimotor vocal learning., (Copyright © 2020 Cornez et al.)

Songbirds learn their song during a sensitive period of development associated with enhanced neural plasticity. In addition, in open-ended learners such as canaries, a sensitive period for sensorimotor vocal learning reopens each year in the fall and leads to song modifications between successive breeding seasons. The variability observed in song production across seasons in adult canaries correlates with seasonal fluctuations of testosterone concentrations and with morphological changes in nuclei of the song control system (SCS). The sensitive periods for song learning during ontogeny and then again in adulthood could be controlled by the development of perineuronal nets (PNN) around parvalbumin-expressing interneurones (PV) which limits learning-induced neuroplasticity. However, this relationship has never been investigated in the context of adult vocal learning in adult songbirds. Here we explored PNN and PV expression in the SCS of adult male Fife Fancy canaries in relation to the seasonal variations of their singing behaviour. We found a clear pattern of seasonal variation in testosterone concentrations and song production. Furthermore, PNN expression was significantly higher in two specific song control nuclei, the robust nucleus of the arcopallium (RA) and the Area X of the basal ganglia, during the breeding season and during the later stages of sensorimotor song development compared to birds in an earlier stage of sensorimotor development during the fall. These data provide the first evidence that changes in PNN expression could represent a mechanism regulating the closing-reopening of sensitive periods for vocal learning across seasons in adult songbirds., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The 3-O-desacyl-4'-monophosphoryl lipid A (MPL) activates immunity through Toll-like receptor 4 (TLR4) signaling. The Adjuvant System AS01 contains MPL and is used in the candidate malaria vaccine and the licensed zoster vaccine. Recent studies reported that AS01 adjuvant activity depends on a transient inflammation at the site of vaccination, but the role of stromal or structural cells in the adjuvant effect is unknown. We investigated this question in mouse models by assessing the role of TLR4 on hematopoietic versus resident structural cells during immunization with AS01-adjuvanted vaccines. We first established that TLR4-deficient animals had a reduced immune response to an AS01-adjuvanted vaccine. Using bone marrow chimera, we consistently found that Tlr4 expression in radio-sensitive cells, i.e., hematopoietic cells, was required for an optimal adjuvant effect on antibody and T-cell responses. At day 1 after injection, the pro-inflammatory reaction at the site of injection was strongly dependent on TLR4 signaling in hematopoietic cells. Similarly, activation of dendritic cells in muscle-draining lymph nodes was strictly associated with the radio-sensitive cells expressing Tlr4. Altogether, these data suggest that MPL-mediated TLR4-signaling in hematopoietic cells is critical in the mode of action of AS01., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Novel adjuvant technologies have a key role in the development of next-generation vaccines, due to their capacity to modulate the duration, strength and quality of the immune response. The AS01 adjuvant is used in the malaria vaccine RTS,S/AS01 and in the licensed herpes-zoster vaccine (Shingrix) where the vaccine has proven its ability to generate protective responses with both robust humoral and T-cell responses. For many years, animal models have provided insights into adjuvant mode-of-action (MoA), generally through investigating individual genes or proteins. Furthermore, modeling and simulation techniques can be utilized to integrate a variety of different data types; ranging from serum biomarkers to large scale "omics" datasets. In this perspective we present a framework to create a holistic integration of pre-clinical datasets and immunological literature in order to develop an evidence-based hypothesis of AS01 adjuvant MoA, creating a unified view of multiple experiments. Furthermore, we highlight how holistic systems-knowledge can serve as a basis for the construction of models and simulations supporting exploration of key questions surrounding adjuvant MoA. Using the Systems-Biology-Graphical-Notation, a tool for graphical representation of biological processes, we have captured high-level cellular behaviors and interactions, and cytokine dynamics during the early immune response, which are substantiated by a series of diagrams detailing cellular dynamics. Through explicitly describing AS01 MoA we have built a consensus of understanding across multiple experiments, and so we present a framework to integrate modeling approaches into exploring adjuvant MoA, in order to guide experimental design, interpret results and inform rational design of vaccines., Competing Interests: CA, RM, AD, MC, and ST report ownership of GSK shares and/or restricted GSK shares., (Copyright © 2019 Buckley, Alden, Coccia, Chalon, Collignon, Temmerman, Didierlaurent, van der Most, Timmis, Andersen and Coles.)

Magnetic domain walls are topological solitons whose internal structure is set by competing energies which sculpt them. In common ferromagnets, domain walls are known to be of either Bloch or Néel types. Little is established in the case of Mn 3 Sn, a triangular antiferromagnet with a large room-temperature anomalous Hall effect, where domain nucleation is triggered by a well-defined threshold magnetic field. Here, we show that the domain walls of this system generate an additional contribution to the Hall conductivity tensor and a transverse magnetization. The former is an electric field lying in the same plane with the magnetic field and electric current and therefore a planar Hall effect. We demonstrate that in-plane rotation of spins inside the domain wall would explain both observations and the clockwise or anticlockwise chirality of the walls depends on the history of the field orientation and can be controlled.

Ozone (O 3 ) and drought increase tree oxidative stress. To protect forest health, we need to improve risk assessment, using metric model such as the phytotoxic O 3 dose above a threshold of y nmol·m -2 ·s -1 (PODy), while taking into account detoxification mechanisms and interacting stresses. The impact of drought events on the effect of O 3 pollution deserves special attention. Water deficit may decrease O 3 entrance into the leaves by reducing stomatal opening; however, water deficit also induces changes in cell redox homeostasis. Besides, the behaviour of the cell antioxidative charge in case of stress combination (water deficit and O 3 ) still remains poorly investigated. To decipher the response of detoxification mechanisms relatively to the Halliwell-Asada-Foyer cycle (HAF), we exposed poplar saplings (Populus nigra × deltoides) composed of two genotypes (Carpaccio and Robusta), to various treatments for 17 days, i.e. i) mild water deficit, ii) 120 ppb O 3 , and iii) a combination of these two treatments. Ozone similarly impacted the growth of the two genotypes, with an important leaf loss. Water deficit decreased growth by almost one third as compared to the control plants. As for the combined treatment, water deficit protected the saplings from leaf ozone injury, but with an inhibitory effect on growth. The pool of total ascorbate was not modified by the different treatments, while the pool of total glutathione increased with POD 0 . We noticed a few differences between the two genotypes, particularly concerning the activity of monodehydroascorbate reductase and glutathione reductase relatively to POD 0 . The expression profiles of genes coding for the dehydroascorbate reductase and glutathione reductase isoforms differed, probably in link with the putative localisation of ROS production in response to water deficit and ozone, respectively. Our result would argue for a major role of MDHAR, GR and glutathione in the preservation of the redox status., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. Previous work indicates that AS03 induces a local and transient inflammatory response that contributes to its adjuvant effect. However, the molecular mechanisms involved in its immunostimulatory properties are ill-defined. Upon intramuscular injection in mice, AS03 elicited a rapid and transient downregulation of lipid metabolism-related genes in the draining lymph node. In vitro, these modifications were associated with profound changes in lipid composition, alteration of endoplasmic reticulum (ER) morphology and activation of the unfolded protein response pathway. In vivo, treatment with a chemical chaperone or deletion of the ER stress sensor kinase IRE1α in myeloid cells decreased AS03-induced cytokine production and its capacity to elicit high affinity antigen-specific antibodies. In summary, our results indicate that IRE1α is a sensor for the metabolic changes induced by AS03 in monocytic cells and may constitute a canonical pathway that could be exploited for the design of novel vaccine adjuvants., Competing Interests: All authors have declared the following interests: R.G., C.C. and A.D. are employees of the GSK group of companies. A.M.D. reports ownership of GSK shares. The remaining authors declare no competing interests.

[This corrects the article DOI: 10.1038/s41541-017-0027-3.].

Early market access of health products is associated with a larger number of requests for information by the health authorities. Compared with these expectations, the growing expansion of health databases represents an opportunity for responding to questions raised by the authorities. The computerised nature of the health system provides numerous sources of data, and first and foremost medical/administrative databases such as the French National Inter-Scheme Health Insurance Information System (SNIIRAM) database. These databases, although developed for other purposes, have already been used for many years with regard to post-registration studies (PRS). The use thereof will continue to increase with the recent creation of the French National Health Data System (SNDS [2016 health system reform law]). At the same time, other databases are available in France, offering an illustration of "product use under actual practice conditions" by patients and health professionals (cohorts, specific registries, data warehouses, etc.). Based on a preliminary analysis of requests for PRS, approximately two-thirds appeared to have found at least a partial response in existing databases. Using these databases has a number of disadvantages, but also numerous advantages, which are listed. In order to facilitate access and optimise their use, it seemed important to draw up recommendations aiming to facilitate these developments and guarantee the conditions for their technical validity. The recommendations drawn up notably include the need for measures aiming to promote the visibility of research conducted on databases in the field of PRS. Moreover, it seemed worthwhile to promote the interoperability of health data warehouses, to make it possible to match information originating from field studies with information originating from databases, and to develop and share algorithms aiming to identify criteria of interest (proxies). Methodological documents, such as the French National Authority for Health (HAS) recommendations on "Les études post-inscription sur les technologies de santé (médicaments, dispositifs médicaux et actes). Principes et méthodes" [Post-registration studies on health technologies (medicinal products, medical devices and procedures). Principles and methods] should be updated to incorporate these developments., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Combining immunostimulants in adjuvants can improve the quality of the immune response to vaccines. Here, we report a unique mechanism of molecular and cellular synergy between a TLR4 ligand, 3- O -desacyl-4'-monophosphoryl lipid A (MPL), and a saponin, QS-21, the constituents of the Adjuvant System AS01. AS01 is part of the malaria and herpes zoster vaccine candidates that have demonstrated efficacy in phase III studies. Hours after injection of AS01-adjuvanted vaccine, resident cells, such as NK cells and CD8 + T cells, release IFNγ in the lymph node draining the injection site. This effect results from MPL and QS-21 synergy and is controlled by macrophages, IL-12 and IL-18. Depletion strategies showed that this early IFNγ production was essential for the activation of dendritic cells and the development of Th1 immunity by AS01-adjuvanted vaccine. A similar activation was observed in the lymph node of AS01-injected macaques as well as in the blood of individuals receiving the malaria RTS,S vaccine. This mechanism, previously described for infections, illustrates how adjuvants trigger naturally occurring pathways to improve the efficacy of vaccines., Competing Interests: All authors have declared the following interests: M.C., C.C., C.H., A.C., P.B., S.M., N.G., R.v.d.M., D.F., R.A.v.d.B., and A.M.D. are, or were at the time of the study, employees of the GSK group of companies. S.M., P.B., R.v.d.M., and A.M.D. own GSK stocks. S.G.’s laboratory received a Public-Private Partnership grant from GlaxoSmithKline Biologicals SA and the Walloon Region (ref. “SAPOVAC”). A.K.S. was partly employed by the Academic Medical Center (AMC) of the University of Amsterdam, which has an agreement with GlaxoSmithKline Biologicals S.A. C.J.G. was supported by an appointment to the Postgraduate Research Participation Program at the Walter Reed Army Institute of Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and MRMC. The other authors report no financial conflict of interest.

Introduction: Adjuvants are used to improve vaccine immunogenicity and efficacy by enhancing antigen presentation to antigen-specific immune cells with the aim to confer long-term protection against targeted pathogens. Adjuvants have been used in vaccines for more than 90 years. Combinations of immunostimulatory molecules, such as in the Adjuvant System AS01, have opened the way to the development of new or improved vaccines. Areas covered: AS01 is a liposome-based vaccine adjuvant system containing two immunostimulants: 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and the saponin QS-21. Here we describe studies investigating the mode of action of AS01, and consider the role of AS01 in enhancing specific immune responses to the antigen for selected candidate vaccines targeting malaria and herpes zoster. The effects of AS01 are rapid and transient, being localized to the injected muscle and draining lymph node. AS01 is efficient at promoting CD4 +  T cell-mediated immune responses and is an appropriate candidate adjuvant for inclusion in vaccines targeting viruses or intracellular pathogens. Expert commentary: AS01 activity to enhance adaptive responses depends on synergistic activities of QS-21 and MPL. AS01 adjuvantation shows good prospects for use in new vaccines targeted to populations with challenging immune statuses and against diseases caused by complex pathogens.

Saponins represent a promising class of vaccine adjuvant. Together with the TLR4-ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the malaria and zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169 + resident macrophages of the draining lymph node where it elicited a local innate immune response. Depletion of these cells abrogated QS-21-mediated innate cell recruitment to the lymph node, dendritic cell (DC) phenotypic maturation as well as the adjuvant effect on T-cell and antibody responses to co-administered antigens. DCs rather than lymph node-resident macrophages were directly involved in T-cell priming by QS-21, as revealed by the decrease in antigen-specific T-cell response in Batf3 -/- mice. Further analysis showed that the adjuvant effect of QS-21 depended on the integration of Caspase-1 and MyD88 pathways, at least in part through the local release of HMGB1. Taken together, this work unravels the key role of lymph node sentinel macrophage in controlling the adjuvant effect of a molecule proven to improve vaccine response in humans., Competing Interests: All authors have declared the following interests. C.C., S.W., M.C., A.E., A.M.D. are employees of the GSK group of companies. S.W., A.E. and A.M.D. own GSK. stocks. The other authors report no financial conflicts of interest.

The liposome-based adjuvant AS01 incorporates two immune stimulants, 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01 is under investigation for use in several vaccines in clinical development. i.m. injection of AS01 enhances immune cell activation and dendritic cell (DC) Ag presentation in the local muscle-draining lymph node. However, cellular and Ag trafficking in the lymphatic vessels that connect an i.m. injection site with the local lymph node has not been investigated. The objectives of this study were: 1) to quantify the in vivo cellular immune response induced by AS01 in an outbred ovine model, 2) to develop a lymphatic cannulation model that directly collects lymphatic fluid draining the muscle, and 3) to investigate the function of immune cells entering and exiting the lymphatic compartments after s.c. or i.m. vaccination with AS01 administered with hepatitis B surface Ag (HBsAg). We show that HBsAg-AS01 induces a distinct immunogenic cellular signature within the blood and draining lymphatics following both immunization routes. We reveal that MHCII(high) migratory DCs, neutrophils, and monocytes can acquire Ag within muscle and s.c. afferent lymph, and that HBsAg-AS01 uniquely induces the selective migration of Ag-positive neutrophils, monocytes, and an MHCII(high) DC-like cell type out of the lymph node via the efferent lymphatics that may enhance Ag-specific immunity. We report the characterization of the immune response in the lymphatic network after i.m. and s.c. injection of a clinically relevant vaccine, all in real time using a dose and volume comparable with that administered in humans., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background and Purpose: A substantial part of ischemic strokes is attributed to atrial fibrillation (AF). We hypothesized that patients with ischemic stroke without prior diagnosed AF were at higher risk of having a subsequent diagnosis of AF, and this was associated with multiple risk factors., Methods: This French longitudinal cohort study was based on the national database covering hospital care from 2008 to 2012 for the entire population., Results: Of 65 807 patients with ischemic stroke in 2009, 48 992 did not have AF at baseline. A total of 4828 of these patients were diagnosed as having AF during a follow-up of 15±15 months (incidence rate 7.9 per 100 person-years). By comparison, the yearly rate of new-onset AF for the 826 416 patients with a cardiac hospitalization was 5.9%. CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack) and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack [doubled], vascular disease, age 65-75 years, and sex category [female]) scores were both associated with the risk of new-onset AF during follow-up (CHADS2: hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.66-1.75; CHA2DS2-VASc: HR 1.45, 95% CI 1.42-1.48). The c statistics were 0.700 (95% CI 0.696-0.706) for CHADS2 and 0.706 (95% CI 0.702-0.710) with CHA2DS2-VASc (P=0.003 for comparison of the 2 scores). Independent predictors of subsequent diagnosis of AF were age 65 to 74 years (HR 2.29, 95% CI 2.06-2.54), age ≥75 years (HR 3.31, 95% CI 3.02-3.64), hypertension (HR 1.22, 95% CI 1.13-1.32), heart failure (HR 2.56, 95% CI 2.41-2.72), and vascular disease (HR 1.10, 95% CI 1.04-1.17)., Conclusions: Ischemic stroke was associated with a substantially increased risk of incident AF, particularly among individuals with higher CHADS2 or CHA2DS2-VASc scores. These risk scores seem to be simple tools for identifying patients at higher risk of incident AF after ischemic stroke., (© 2015 American Heart Association, Inc.)

Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCII(high) dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCII(high) dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells., (Copyright © 2014 by The American Association of Immunologists, Inc.)

The adenosine monophosphate-activated protein kinase (AMPK) activators 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) and metformin (MET) inhibit resumption of meiosis in porcine cumulus-enclosed oocytes. The objective of this study was to characterize the inhibitory effect of MET on porcine oocyte meiosis by: (1) determining the effects of an AMPK inhibitor and of inhibitors of signalling pathways involved in MET-induced AMPK activation in other cell types on MET-mediated meiotic arrest in porcine cumulus-enclosed oocytes; (2) determining whether MET and AICAR treatments lead to increased activation of porcine oocyte and/or cumulus cell AMPK as measured by phosphorylation of its substrate acetyl-CoA carboxylase; and (3) determining the effects of inhibition of the AMPK kinase, Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), and Ca2+ chelation on oocyte meiotic maturation and AMPK activation in porcine oocytes and cumulus cells. The AMPK inhibitor compound C (CC; 1 μM) did not reverse the inhibitory effect of AICAR (1 mM) and MET (2 mM) on porcine oocyte meiosis. Additionally, CC had a significant inhibitory effect on its own. eNOS, c-Src and PI-3 kinase pathway inhibitors did not reverse the effect of metformin on porcine oocyte meiosis. The level of acetyl-CoA carboxylase (ACC) phosphorylation in oocytes and cumulus cells did not change in response to culture in the presence of MET, AICAR, CC, the CaMKK inhibitor STO-609 or the Ca2+ chelator BAPTA-AM for 3 h, but STO-609 increased the percentage of porcine cumulus-enclosed oocytes (CEO) that remained at the germinal vesicle (GV) stage after 24 h of culture. These results indicate that the inhibitory effect of MET and AICAR on porcine oocyte meiosis was probably not mediated through activation of AMPK.

Unlike farmland, forests growing on acidic soils are among the terrestrial ecosystems that are the least influenced or amended by man. Forests which developed on acidic soils are characterized by an important stock of inorganic nutrients entrapped in poorly weatherable soil minerals. In this context, the mineral-weathering process is of great importance, since such minerals are not easily accessible to tree roots. To date, several bacterial genera have been noted for their ability to weather minerals and, in the case of some of them, to improve tree nutrition. Nevertheless, few studies have focused their analyses on mineral-weathering bacterial communities in relation to geochemical cycles and soil characteristics, their ecological origin, associated tree species and forest management practices. Here we discuss the heterogeneity of the mineral-weathering process in forest soils and present what is known concerning the taxonomic and functional characteristics of mineral-weathering bacteria, as well as the different locations where they have been isolated in forest soils. We also discuss the biotic and abiotic factors that may influence the distribution of these bacteria, such as the effect of tree species or forest management practices., (Copyright © 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

In this study, we tested experimentally the influence of plant and bacterial activities on the calcium (Ca) isotope distribution between soil solutions and plant organs. Abiotic apatite weathering experiments were performed under two different pH conditions using mineral and organic acids. Biotic experiments were performed using either apatite or Ca-enriched biotite substrates in the presence of Scots pines, inoculated or not with the rhizosphere bacterial strain Bulkholderia glathei PML1(12), or the B. glathei PML1(12) alone. For each experiment, the percolate was collected every week and analyzed for Ca concentrations and Ca isotopic ratios. No Ca isotopic fractionation was observed for the different abiotic experimental settings. This indicates that no Ca isotopic fractionation occurs during apatite dissolution, whatever the nature of the acid (mineral or organic). The main result of the biotic experiments is the 0.22 ‰ (44)Ca enrichment recorded for a solution in contact with Scots pines grown on the bacteria-free apatite substrate. In contrast, the presence of bacteria did not cause Ca isotopic fractionation of the solution collected after 14 weeks of the experiments. These preliminary results suggest that bacteria influence the Ca isotopic signatures by dissolving Ca from apatite more efficiently. Therefore, Ca isotopes might be suitable for detecting bacteria-mediated processes in soils., (Copyright © 2011 John Wiley & Sons, Ltd.)

The antimicrobial activity of the disinfectant formulation UMONIUM38 (Isopropyl-tridecyl-dimethyl-ammonium; Huckert's International, Nivelles, Belgium) planned for the low temperature disinfection of critical and semi-critical medical equipment and surfaces was evaluated under clean and dirty experimental conditions (high and low concentrations of organic material). The formulation was obtained by a synergic combination of three different active compounds, two alcohols and a quaternary ammonium. The anti-mycobacterial (Mycobacterium avium and Mycobacterium terrae), and antiviral (Poliovirus type 1, Adenovirus type 5, hepatitis B virus, and human immunodeficiency virus type 1) activities of this formulation were addressed using suspension assays. In addition, surface assays were also used to test the antibacterial (Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Enterococcus hirae) and antimycotic (Candida albicans and Aspergillus niger) activities. The data document the dynamics of the antimicrobial activity under in vitro controlled conditions and highlight the relatively low influence of organic material on its activity.

Thirteen laboratories characterized a coded panel of 10 MAbs to SIVmac251 envelope protein in a collaboration organized by the National Institute of Allergy and Infectious Diseases (NIAID). The MAbs were examined against SIV isolates in neutralization and radioimmune precipitation, immunoblot, enzyme-linked immunosorbent, and radioimmune assays. Although laboratories employed diverse neutralization assays that varied in sensitivity there was agreement on the relative ability of the MAbs to neutralize SIVmac251. Additionally, even though the quantity of any single MAb required to neutralize SIVmac251 varied between laboratories, there was agreement on the rank-order strength fo the five neutralizing MAbs. Based on the data from this study, the MAbs were classified according to their neutralization potential as high efficiency (MAb concentration, < 5 micrograms/ml), low efficiency (MAb concentration, 5-100 micrograms/ml), or nonneutralizing (MAb concentration, > 100 micrograms/ml). The MAbs could be assigned to four serological groups based on ability to cross-neutralize and bind different SIV isolates. The distinction between groups I, II, and III were based on the limited neutralization data obtained with the sooty mangabey isolate.

Eighteen monoclonal antibodies (MAb) to simian immunodeficiency virus (SIV) envelope have been characterized. All MAb were shown to bind to viral antigens on the surface of unfixed SIV-infected cells and to precipitate surface glycoproteins of SIVmac251. In Western blot 11 MAb bound to gp160 and gp120, five bound to gp160 and the transmembrane protein gp41 and two MAb did not react with denatured antigen. Preliminary competition assays identified the existence of six competition groups; two groups were within gp41 and four were within gp120. Of the latter four groups, three contained MAb with neutralizing activity. Two of the neutralizing MAb (KK5 and KK9) did not react with denatured antigen in Western blot suggesting that they may recognize conformational epitopes. Enzyme-linked immunosorbent-assay titres of MAb against SIVmac251 ranged from 10(2.4) to 10(5.6) and although similar titres were obtained with some MAb against other SIV and HIV antigens, the presence of isolate specific and shared group epitopes was demonstrated.