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Es gibt keinen Konsens über die Beschreibung und Schweregradeinteilung allergischer Nebenwirkungen bei Immuntherapien, obwohl zumindest hinsichtlich der Verwendung der Klassifikationssysteme der World Allergy Organisation (WAO) zur Beschreibung lokaler unerwünschter Ereignisse bei sublingualer Immuntherapie (SLIT) und systemischer allergischer Reaktionen (SAR) bei subkutaner Immuntherapie (SCIT) ein Konsens zwischen den wichtigsten nationalen/regionalen Allergiegesellschaften zu bestehen scheint. In diesem Artikel wird eine Modifikation des bestehenden WAO-Klassifikationssystems für SAR vorgeschlagen, die mit der neu vorgeschlagenen Klassifikationsskala des Consortium for Food Allergy Research (CoFAR) für systemische allergische Reaktionen bei Lebensmittelallergien (Version 3.0) übereinstimmt. Wir hoffen, dass damit ein einheitliches Klassifikationssystem zur Verfügung steht, das für Berichte über unerwünschte Reaktionen auf eine Allergen-Immuntherapie unabhängig vom Allergen und Verabreichungsweg sowohl in der klinischen Praxis als auch in der Forschung geeignet ist.

The work aims to biosynthesize and characterize titanium dioxide nanoparticles (TiO2-NPs) to evaluate antimicrobial activity, cytotoxicity, and photocatalytic activity (under visible irradiation). X-ray diffraction (XRD), N2adsorption/desorption, zeta potential (ZP), field emission gun scanning electron microscopy (FEG-SEM), and scanning electron microscopy with energy-dispersive X-ray analysis (SEM–EDX) were used to characterize. The antibacterial potential was evaluated by minimal inhibitory activity (MIC) against S. aureusand P. aeruginosa. Central composite rotational design (CCRD 23) was used for experimental design. XRD diffractogram and FEG-SEM micrograph showed characteristic peaks of TiO2-NPs (about 32 nm) and spherical shapes, respectively. TiO2-NPs had a negative charge surface (− 4.9 mV) with type V and H1 hysteresis and SBET= 118 m2g−1, Dp = 9.2 nm and Vp = 0.2 cm3g−1. EDX results indicated the presence of TiO2-NPs and the effectiveness of the green synthesis. The antimicrobial activity showed that there was no inhibition of any pathogen. About the safety profile, there was no reduction in cell viability in the 293 T, MDBK, and HaCat cell lines, and reactive oxygen species (ROS) generation did not cause significant differences about the untreated control, indicating biocompatibility. The photocatalytic activity showed degradation of 90% of RhB dye using the ideal condition ([RhB] = 10 mg L−1, [TiO2-NPs] = 3.5 g L−1, and pH = 7.0) by CCRD under visible irradiation with a pseudo-first-order kinetic model (k= 0.0146 min−1). Therefore, TiO2-NPs present applications as alternative metallic nanoparticles for wastewater treatment and show potential for antimicrobial activity.

AbstractWe consider a Poisson autoregressive process whose parameters depend on the past of the trajectory. We allow these parameters to take negative values, modelling inhibition. More precisely, the model is the stochastic process $(X_n)_{n\ge0}$ with parameters $a_1,\ldots,a_p \in \mathbb{R}$ , $p\in\mathbb{N}$ , and $\lambda \ge 0$ , such that, for all $n\ge p$ , conditioned on $X_0,\ldots,X_{n-1}$ , $X_n$ is Poisson distributed with parameter $(a_1 X_{n-1} + \cdots + a_p X_{n-p} + \lambda)_+$ . This process can be regarded as a discrete-time Hawkes process with inhibition and a memory of length p. In this paper we initiate the study of necessary and sufficient conditions of stability for these processes, which seems to be a hard problem in general. We consider specifically the case $p = 2$ , for which we are able to classify the asymptotic behavior of the process for the whole range of parameters, except for boundary cases. In particular, we show that the process remains stochastically bounded whenever the solution to the linear recurrence equation $x_n = a_1x_{n-1} + a_2x_{n-2} + \lambda$ remains bounded, but the converse is not true. Furthermore, the criterion for stochastic boundedness is not symmetric in $a_1$ and $a_2$ , in contrast to the case of non-negative parameters, illustrating the complex effects of inhibition.

This study investigated the ecotoxicity and in vitrosafety profile of novel metallic nanoparticles (silver and titanium dioxide) prepared from Aloe veraextract by biosynthesis method, evaluating the acute toxicity and bioaccumulation in soil. Samples were analyzed for phytotoxicity against Lactuca sativa, Cucumis sativusand Brassica oleracea, soil toxicity (ranging from 12.5 to 100 mg mL−1) and biocompatibility by MTT (in VERO and L929 cells ranging from 12.5 to 100 µg mL−1). Phytotoxicity assays showed that for Lactuca sativaseeds, all nanoparticles showed toxicity for all tested concentrations (12.5–100 mg mL−1), while for Cucumis sativusseeds TiO2-NPs in concentrations of 12.5, 50 and 100 mg mL−1and AgNPs in concentrations of 25 and 100 mg mL−1. For Brassica oleracea,the TiO2-NPs (100 mg mL−1), Ag/TiNPs (12.5 and 100 mg mL−1) and AgNPs (12.5 and 100 mg mL−1) demonstrated toxicity. For cytotoxicity assays, AgNPs and Ag/TiNPs showed a decrease in the cell viability for the two strains tested (99–50.7 % for VERO and 99–45.3 % for L929). Therefore, the results will contribute to understanding the main parameters of phytotoxicity, bioavailability and biocompatibility of separate metallic nanoparticles (TiO2-NPs and AgNPs) and combined (Ag/TiNPs).

The article reviews multiple performances in Paris, France, in 2024, including "La Walkyrie de Wagner" concert, on May 4, by Yannick Nezet-Seguin; theatrical performance "Le Tribut de Zamora de Gounod", on May 3 and 5, by Gilles Rico, and a piano recital by Rafal Blechacz, on May 6.

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid‐based formula with synbiotics (AAF‐S) or amino acid‐based formula without synbiotics (AAF) during a 1‐year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF‐S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p= 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition. The randomized double‐blind controlled trial PRESTO showed that infants receiving amino acid‐based formula (AAF) with or without synbiotics for 12 months in early life demonstrated effective symptom resolution.After 12 and 24 months, development of tolerance to cow's milk (CM) was in line with natural outgrowth. The randomized double‐blind controlled trial PRESTO showed that infants receiving amino acid‐based formula (AAF) with or without synbiotics for 12 months in early life demonstrated effective symptom resolution. After 12 and 24 months, development of tolerance to cow's milk (CM) was in line with natural outgrowth. This study shows that, 36 months after the start of the intervention, a high proportion of children (about three‐quarters) developed tolerance to CM.These data suggest that the consumption of AAF, with or without synbiotics, and the absence of exposure to CM peptides do not slow down CM tolerance acquisition. This study shows that, 36 months after the start of the intervention, a high proportion of children (about three‐quarters) developed tolerance to CM. These data suggest that the consumption of AAF, with or without synbiotics, and the absence of exposure to CM peptides do not slow down CM tolerance acquisition.

Single-cell data analysis can infer dynamic changes in cell populations, for example across time, space or in response to perturbation, thus deriving pseudotime trajectories. Current approaches comparing trajectories often use dynamic programming but are limited by assumptions such as the existence of a definitive match. Here we describe Genes2Genes, a Bayesian information-theoretic dynamic programming framework for aligning single-cell trajectories. It is able to capture sequential matches and mismatches of individual genes between a reference and query trajectory, highlighting distinct clusters of alignment patterns. Across both real world and simulated datasets, it accurately inferred alignments and demonstrated its utility in disease cell-state trajectory analysis. In a proof-of-concept application, Genes2Genes revealed that T cells differentiated in vitro match an immature in vivo state while lacking expression of genes associated with TNF signaling. This demonstrates that precise trajectory alignment can pinpoint divergence from the in vivo system, thus guiding the optimization of in vitro culture conditions.

Immunoglobulin E (IgE)-mediated food allergy is an immune response, typically to a food protein. Accurate diagnosis reduces unnecessary dietary restrictions and economic and psychological burden on patients and caregivers but relies on a rigorous clinical history, specific IgE diagnostic tests and, where needed, oral food challenge. Increased awareness is needed around which patients to test for IgE-mediated food allergy, as well as terms commonly associated with IgE-mediated food allergy testing, in order to optimise patient diagnosis and management. Herein, we describe approaches to diagnosis of IgE-mediated food allergy, appropriate interpretation of results and risks of overtesting.

Increasing evidence indicates the involvement of B cells in the pathogenesis of multiple sclerosis (MS), but their precise roles are unclear. In this Review, we provide an overview of the development and physiological functions of B cells and the main mechanisms through which B cells are thought to contribute to CNS autoimmunity. In MS, abnormalities of B cell function include pro-inflammatory cytokine production, defective B cell regulatory function and the formation of tertiary lymphoid-like structures in the CNS, which are the likely source of abnormal immunoglobulin production detectable in the cerebrospinal fluid. We also consider the hypothesis that Epstein–Barr virus (EBV) is involved in the B cell overactivation that leads to inflammatory injury to the CNS in MS. We also review the immunological effects — with a focus on the effects on B cell subsets — of several successful therapeutic approaches in MS, including agents that selectively deplete B cells (rituximab, ocrelizumab and ofatumumab), agents that less specifically deplete lymphocytes (alemtuzumab and cladribine) and autologous haematopoietic stem cell transplantation, in which the immune system is unselectively ablated and reconstituted. We consider the insights that these effects on B cell populations provide and their potential to further our understanding and targeting of B cells in MS.

Objective: To analyze the situation of food insecurity among Haitians living in Midwest of Brazil, based on questions of the Brazilian Scale of Food Insecurity (BSFI). Methods: A survey was carried out with a probabilistic sampling proportional to sex of Haitians aged over 18 years who lived in Cuiabá and Várzea Grande, Mato Grosso. Haitian migrants were interviewed by bilingual (Haitian Creole/Portuguese) individuals, and for the analysis of the BSFI questions. Because the BSFI is not validated for Haitians, the first eight questions of the scale were assessed separately, according to sex, debts incurred for the migration project and time of residence in Brazil. Chi-square was calculated to test the differences between groups. Results: A total of 404 Haitians were evaluated, 81.9% male individuals, 60.9% aged between 18 and 36 years. Among the respondents, 64.4% were worried about running out of food before having money to buy more food, and 62.6% answered that they ran out of food before having money to buy it. Higher proportions of positive answers were observed for women and those who reported having debts to finance the migration costs to Brazil. Conclusion: The high proportion of positive answers to the BSFS questions by Haitians seems to indicate a situation of social vulnerability and food insecurity, especially among Haitian women, as well as among those who had debts to migrate to Brazil and those who have lived in the country for more than a year.

Inflammation in the bone marrow (BM) microenvironment is a constitutive component of leukemogenesis in acute myeloid leukemia (AML). Current evidence suggests that both leukemic blasts and stroma secrete proinflammatory factors that actively suppress the function of healthy hematopoietic stem and progenitor cells (HSPCs). HSPCs are also cellular components of the innate immune system, and we reasoned that they may actively propagate the inflammation in the leukemic niche. In two separate congenic models of AML we confirm by evaluation of the BM plasma secretome and HSPC-selective single-cell RNA sequencing (scRNA-Seq) that multipotent progenitors and long-lived stem cells adopt inflammatory gene expression programs, even at low leukemic infiltration of the BM. In particular, we observe interferon gamma (IFN-γ) pathway activation, along with secretion of its chemokine target, CXCL10. We show that AML-derived nanometer-sized extracellular vesicles (EVAML) are sufficient to trigger this inflammatory HSPC response, both in vitro and in vivo. Altogether, our studies indicate that HSPCs are an unrecognized component of the inflammatory adaptation of the BM by leukemic cells. The pro-inflammatory conversion and long-lived presence of HSPCs in the BM along with their regenerative re-expansion during remission may impact clonal selection and disease evolution.

This work presents a novel method to reconstruct the frequency-wavenumber spectrum of water waves based on the complex acoustic Doppler spectra of scattered sound measured with an array of microphones. The reconstruction is based on a first-order small-roughness-amplitude expansion of the acoustic wave scattering equation, which is discretized and inverted by means of a singular value decomposition. An analogy of this approach to the first-order Bragg scattering problem is demonstrated by means of a stationary phase expansion. The approach enables the reconstruction of the dispersion relation of water waves when the ratio between roughness height and acoustic wavelength is less than 0.1, and when the surface wavelength is larger than 1/2 of the acoustic wavelength. The method is validated against synthetic data and data from laboratory and field experiments, to demonstrate its applicability to 2-D and 3-D complex patterns of water waves, and specifically to the surface deformations that arise naturally in a turbulent open-channel flow. Fitting the reconstructed data with the analytical dispersion relation enables the noncontact estimate of the underlying flow velocity for hydraulic conditions where the coexistence of different types of turbulence-forced and freely propagating water waves would limit the accuracy of standard noncontact Doppler velocimetry approaches, paving the way for robust and accurate noncontact river monitoring using acoustics.

This study characterises the effects of naturally varying organic content on the compression and shear behaviour of a marine silty-clay from the Netherlands. Index properties and mechanical properties are determined through laboratory tests, including oedometer and multistage loading-unloading triaxial stress paths. The results indicate a significant impact of the organic content on the compression response, with both the loading and reloading indexes increasing as the loss on ignition increases from 3% to 7%. Additionally, the study suggests a directional response of the compression behaviour, with the loading index increasing with the stress ratio. The influence of the organic content on shear strength appears to be less significant. No brittle response is observed during shearing, and a similar ultimate stress ratio is attained by all samples. However, a unique critical state line can only be identified for samples with similar organic content, as its intercept and slope are found to increase with increasing organic content. The experimental results from stress paths at constant stress ratio reveal an anisotropic pre-failure plastic deformation mode, which depends on the previous stress history and loading direction. This suggests that the stress–dilatancy relationship cannot be formulated as a unique function of the stress ratio. The high-quality experimental data presented in the study enlarge the database on soft organic soils in view of the development of advanced constitutive models.

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system1. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug–target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+and IgA+plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.

An overview of the recent operations and the main results of cesium injection in the Source for the Production of Ions of Deuterium Extracted from Rf plasma (SPIDER) negative ion source are described in this contribution. In experiments without cesium injection, all SPIDER plants were tested to verify the basic expectations on the operational parameters (e.g., electron cooling effectiveness of magnetic filter field) and to determine its operational region. For beam properties, it was shown that the current density varies across the beam in the vertical direction. In preliminary cesium experiments, the expected increase of negative ion current and simultaneous decrease of co-extracted electrons were found, along with the influence of the control parameters (polarization of the plasma electrodes, magnetic filter field) on the SPIDER beam uniformity in the horizontal and vertical directions. It was shown that non-Gaussian tails can be identified in the angular distribution on the plane perpendicular to the beam propagation direction. Stray particles, nonhomogeneous beam and large divergence might result in unexpected heat and particle loads over ITER neutral beam injector (NBI) accelerator grids; it is the goal of SPIDER to assess and possibly to identify suitable methods for controlling these beam features. A major shutdown, planned for late 2021, to solve the issues identified during the operation and to carry out scheduled modifications, is outlined. Such improvements are expected to allow SPIDER to pursue the ITER requirements in terms of negative ion current, electron-to-ion ratio, and beam duration.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1−/− or Mavs−/− placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/− or Ifnar1+/− dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.

The high voltage Padova test facility (HVPTF) is an experimental device for the study of HV insulation in vacuum, in support of the realization of the prototype of a neutral beam injector for International Thermonuclear Experimental Reactor (ITER), named megavolt ITER injector and concept advancement (MITICA). The facility investigates the physical phenomena underlying voltage holding in vacuum, in particular the mechanisms causing breakdowns and the electrode conditioning process. At HVPTF, inside a high vacuum chamber, two stainless steel electrodes, separated by a few centimeters gap, can achieve HV values for a maximum potential difference of 800 kV. During the voltage conditioning of the electrodes, current MicroDischarges (MDs) and high-energy X-rays are observed and analyzed. In this work, we present a characterization of the MD dynamics occurring during the conditioning process, with the aim to gain information on the reason of the growing difference between the current contributions measured by the two electrodes. The analysis will be performed due to two new X-rays detectors recently installed: an lutetium yttrium orthosilicate (LYSO) and a LaBr3(Ce) scintillating crystal. The new diagnostics indeed provide the fine dynamics of a single MD, recording energy and time of each single detected X-ray. In particular, we compare the MD dynamics at the beginning and at the end of the conditioning process and try to give a preliminary interpretation of the observations.

The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications.

The article focuses on the multifaceted life and career of Friedrich Gulda, a Vienna-born pianist, composer, and jazz enthusiast known for his unconventional approach to music.

Background: Due to social and geographical isolation, indigenous people are more vulnerable to adverse conditions; however, there is a lack of data on the epidemics’ impact on these populations. Thus, this article’s objective was to describe the epidemiological situation of COVID-19 in indigenous communities in Brazil. Methods: This descriptive observational study was carried out in indigenous communities in the municipality of Amaturá (Amazonas, Brazil). Individuals from the Alto Rio Solimões Special Indigenous Sanitary District (DSEI) who met the Sars-Cov-2 infection case definitions during the period between January and August 2020 were included. For case notification, the definitions adopted by the Ministry of Health of Brazil and by the Special Secretariat for Indigenous Health were considered. Results: Out of the entire population served by the Alto Rio Solimões DSEI (n= 2890), 109 indigenous people were suspected of having been infected with Sars-Cov-R during the study period; a total of 89 cases were actually confirmed (rate: 3.08 cases/100,000 inhabitants). Most patients diagnosed with COVID-19 were female (56.2%), with a mean age of 32.4 (± 23.6) years. Predominant symptoms were fever (76.4%), dry cough (64%), and headache (60.7%). Complications occurred in 7.9% of the patients; no deaths were reported. Conclusion: These results enhance the observation that indigenous populations, even if relatively isolated, are exposed to COVID-19. The disease cases assessed showed a favorable evolution, which does not mean reducing the need for caring of this population.

Immune thrombocytopenic purpura (ITP) is characterized by the presence of autoantibodies against platelet membrane antigens, leading to immune-mediated platelet destruction. ITP is considered as a rare extraintestinal manifestation (EIM) of ulcerative colitis (UC). This report aimed to describe a rare case of UC associated with ITP and a review of the literature. A 49-year-old man was admitted to our hospital with severe acute colitis which was responsive to treatment (hydrocortisone 300 mg/day). The patient was discharged from the hospital with prednisone 60 mg/day and azathioprine 50 mg/day. During the follow-up, the dose of azathioprine was increased to 100 mg/day (1.3 mg/kg), while prednisone tapering was started. After 3 months, the patient presented with thrombocytopenia (30,000 platelets/µL) without improvement despite receiving the suspension of azathioprine; thus, a bone marrow aspirate was performed. The bone marrow analysis showed hyperplasia of the erythroid series, megaloblastosis, hyperplasia of megakaryocytes with mild dyspoiesis, and absence of cytotoxicity, a morphological finding consistent with ITP. The patient was treated with prednisone 1 mg/kg/day which resulted in partial improvement of the condition and his still being followed up as outpatient using mesalazine 3.2 g for UC and a platelet count of approximately 50,000/µL using eltrombopag. As reported, ITP is a rare EIM in patients with UC. Due to the risk of complications, such as bleeding, hematological changes in these patients should be considered. The disease should be suspected in the presence of thrombocytopenia, always excluding the side effects of medications in advance, especially immunosuppressants. The correct diagnosis of this rare manifestation and proper treatment are essential to control the condition, prevent complications, and improve the patient’s prognosis.