Severe ocular involvement in a newborn with Langerhans Cell Histiocytosis

Abstract Langerhans Cell Histiocytosis (LCH) is a rare proliferative disease of the mononuclear phagocyte system, characterised by tissue infiltration of CD1a + CD207+ histiocytes. The clinical presentation is variable, ranging from unifocal asymptomatic bone involvement to life-threatening multisystem disease, requiring aggressive therapeutic approaches. Intraocular involvement is uncommon and associated to poor visual and general prognosis. We report a case of LCH in a newborn with severe ocular and multisystem risk-organ involvement, unresponsive to several lines of chemotherapy. Off-label administration of vemurafenib led to dramatic improvement at systemic level; however, chronic sequelae of ocular involvement resulted in poor visual prognosis. Intraocular LCH involvement may be asymptomatic and clinical signs delayed, leading to severe complications, especially in newborns and young children. Screening for ocular involvement is essential for early treatment initiation, which can possibly improve the visual outcome. Vemurafenib is effective on systemic involvement, and its role in ocular LCH needs to be evaluated

Phenotypic and functional characterisation of CCR7(+ )and CCR7(- )CD4(+ )memory T cells homing to the joints in juvenile idiopathic arthritis

The aim of the study was to characterise CCR7(+ )and CCR7(- )memory T cells infiltrating the inflamed joints of patients with juvenile idiopathic arthritis (JIA) and to investigate the functional and anatomical heterogeneity of these cell subsets in relation to the expression of the inflammatory chemokine receptors CXCR3 and CCR5. Memory T cells freshly isolated from the peripheral blood and synovial fluid (SF) of 25 patients with JIA were tested for the expression of CCR7, CCR5, CXCR3 and interferon-γ by flow cytometry. The chemotactic activity of CD4 SF memory T cells from eight patients with JIA to inflammatory (CXCL11 and CCL3) and homeostatic (CCL19, CCL21) chemokines was also evaluated. Paired serum and SF samples from 28 patients with JIA were tested for CCL21 concentrations. CCR7, CXCR3, CCR5 and CCL21 expression in synovial tissue from six patients with JIA was investigated by immunohistochemistry. Enrichment of CD4(+), CCR7(- )memory T cells was demonstrated in SF in comparison with paired blood from patients with JIA. SF CD4(+)CCR7(- )memory T cells were enriched for CCR5(+ )and interferon-γ(+ )cells, whereas CD4(+)CCR7(+ )memory T cells showed higher coexpression of CXCR3. Expression of CCL21 was detected in both SF and synovial membranes. SF CD4(+ )memory T cells displayed significant migration to both inflammatory and homeostatic chemokines. CCR7(+ )T cells were detected in the synovial tissue in either diffuse perivascular lymphocytic infiltrates or organised lymphoid aggregates. In synovial tissue, a large fraction of CCR7(+ )cells co-localised with CXCR3, especially inside lymphoid aggregates, whereas CCR5(+ )cells were enriched in the sublining of the superficial subintima. In conclusion, CCR7 may have a role in the synovial recruitment of memory T cells in JIA, irrespective of the pattern of lymphoid organisation. Moreover, discrete patterns of chemokine receptor expression are detected in the synovial tissue

Immunomodulation with romiplostim as a second-line strategy in primary immune thrombocytopenia: The iROM study.

Thrombopoietin receptor agonists (TPO-RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first-line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end-points included the sustained remission off-treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)-4, IL-9 and IL-17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor-β levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation

Hyperuniform monocrystalline structures by spinodal solid-state dewetting

Materials featuring anomalous suppression of density fluctuations over large length scales are emerging systems known as disordered hyperuniform. The underlying hidden order renders them appealing for several applications, such as light management and topologically protected electronic states. These applications require scalable fabrication, which is hard to achieve with available top-down approaches. Theoretically, it is known that spinodal decomposition can lead to disordered hyperuniform architectures. Spontaneous formation of stable patterns could thus be a viable path for the bottom-up fabrication of these materials. Here we show that mono-crystalline semiconductor-based structures, in particular Si$_{1-x}$Ge$_{x}$ layers deposited on silicon-on-insulator substrates, can undergo spinodal solid-state dewetting featuring correlated disorder with an effective hyperuniform character. Nano- to micro-metric sized structures targeting specific morphologies and hyperuniform character can be obtained, proving the generality of the approach and paving the way for technological applications of disordered hyperuniform metamaterials. Phase-field simulations explain the underlying non-linear dynamics and the physical origin of the emerging patterns.Comment: 6 pages, 3 figures, supplementary information (7 pages) enclose

FASER: ForwArd Search ExpeRiment at the LHC

FASER, the ForwArd Search ExpeRiment, is a proposed experiment dedicated to searching for light, extremely weakly-interacting particles at the LHC. Such particles may be produced in the LHC's high-energy collisions in large numbers in the far-forward region and then travel long distances through concrete and rock without interacting. They may then decay to visible particles in FASER, which is placed 480 m downstream of the ATLAS interaction point. In this work, we describe the FASER program. In its first stage, FASER is an extremely compact and inexpensive detector, sensitive to decays in a cylindrical region of radius R = 10 cm and length L = 1.5 m. FASER is planned to be constructed and installed in Long Shutdown 2 and will collect data during Run 3 of the 14 TeV LHC from 2021-23. If FASER is successful, FASER 2, a much larger successor with roughly R ~ 1 m and L ~ 5 m, could be constructed in Long Shutdown 3 and collect data during the HL-LHC era from 2026-35. FASER and FASER 2 have the potential to discover dark photons, dark Higgs bosons, heavy neutral leptons, axion-like particles, and many other long-lived particles, as well as provide new information about neutrinos, with potentially far-ranging implications for particle physics and cosmology. We describe the current status, anticipated challenges, and discovery prospects of the FASER program.Comment: 13 pages, 4 figures, submitted as Input to the European Particle Physics Strategy Update 2018-2020 and draws on FASER's Letter of Intent, Technical Proposal, and physics case documents (arXiv:1811.10243, arXiv:1812.09139, and arXiv:1811.12522

Comprehensive space-time hydrometeorological simulations for estimating very rare floods at multiple sites in a large river basin

Estimates for rare to very rare floods are limited by the relatively short streamflow records available. Often, pragmatic conversion factors are used to quantify such events based on extrapolated observations, or simplifying assumptions are made about extreme precipitation and resulting flood peaks. Continuous simulation (CS) is an alternative approach that better links flood estimation with physical processes and avoids assumptions about antecedent conditions. However, long-term CS has hardly been implemented to estimate rare floods (i.e. return periods considerably larger than 100 years) at multiple sites in a large river basin to date. Here we explore the feasibility and reliability of the CS approach for 19 sites in the Aare River basin in Switzerland (area: 17 700 km2) with exceedingly long simulations in a hydrometeorological model chain. The chain starts with a multi-site stochastic weather generator used to generate 30 realizations of hourly precipitation and temperature scenarios of 10 000 years each. These realizations were then run through a bucket-type hydrological model for 80 sub-catchments and finally routed downstream with a simplified representation of main river channels, major lakes and relevant floodplains in a hydrologic routing system. Comprehensive evaluation over different temporal and spatial scales showed that the main features of the meteorological and hydrological observations are well represented and that meaningful information on low-probability floods can be inferred. Although uncertainties are still considerable, the explicit consideration of important processes of flood generation and routing (snow accumulation, snowmelt, soil moisture storage, bank overflow, lake and floodplain retention) is a substantial advantage. The approach allows for comprehensively exploring possible but unobserved spatial and temporal patterns of hydrometeorological behaviour. This is of particular value in a large river basin where the complex interaction of flows from individual tributaries and lake regulations are typically not well represented in the streamflow observations. The framework is also suitable for estimating more frequent floods, as often required in engineering and hazard mapping

Comprehensive space–time hydrometeorological simulations for estimating very rare floods at multiple sites in a large river basin

Estimates for rare to very rare floods are limited by the relatively short streamflow records available. Often, pragmatic conversion factors are used to quantify such events based on extrapolated observations, or simplifying assumptions are made about extreme precipitation and resulting flood peaks. Continuous simulation (CS) is an alternative approach that better links flood estimation with physical processes and avoids assumptions about antecedent conditions. However, long-term CS has hardly been implemented to estimate rare floods (i.e. return periods considerably larger than 100 years) at multiple sites in a large river basin to date. Here we explore the feasibility and reliability of the CS approach for 19 sites in the Aare River basin in Switzerland (area: 17 700 km2) with exceedingly long simulations in a hydrometeorological model chain. The chain starts with a multi-site stochastic weather generator used to generate 30 realizations of hourly precipitation and temperature scenarios of 10 000 years each. These realizations were then run through a bucket-type hydrological model for 80 sub-catchments and finally routed downstream with a simplified representation of main river channels, major lakes and relevant floodplains in a hydrologic routing system. Comprehensive evaluation over different temporal and spatial scales showed that the main features of the meteorological and hydrological observations are well represented and that meaningful information on low-probability floods can be inferred. Although uncertainties are still considerable, the explicit consideration of important processes of flood generation and routing (snow accumulation, snowmelt, soil moisture storage, bank overflow, lake and floodplain retention) is a substantial advantage. The approach allows for comprehensively exploring possible but unobserved spatial and temporal patterns of hydrometeorological behaviour. This is of particular value in a large river basin where the complex interaction of flows from individual tributaries and lake regulations are typically not well represented in the streamflow observations. The framework is also suitable for estimating more frequent floods, as often required in engineering and hazard mapping

Evolution of National Guidelines on Medicines Used to Treat COVID-19 in Pregnancy in 2020-2022: A Scoping Review.

The lack of inclusion of pregnant women in clinical trials evaluating the effectiveness of medicines to treat COVID-19 has made it difficult to establish evidence-based treatment guidelines for pregnant women. Our aim was to provide a review of the evolution and updates of the national guidelines on medicines used in pregnant women with COVID-19 published by the obstetrician and gynecologists' societies in thirteen countries in 2020-2022. Based on the results of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial, the national societies successively recommended against prescribing hydroxychloroquine, lopinavir-ritonavir and azithromycin. Guidelines for remdesivir differed completely between countries, from compassionate or conditional use to recommendation against. Nirmatrelvir-ritonavir was authorized in Australia and the UK only in research settings and was no longer recommended in the UK at the end of 2022. After initial reluctance to use corticosteroids, the results of the RECOVERY trial have enabled the recommendation of dexamethasone in case of severe COVID-19 since mid-2020. Some societies recommended prescribing tocilizumab to pregnant patients with hypoxia and systemic inflammation from June 2021. Anti-SARS-CoV-2 monoclonal antibodies were authorized at the end of 2021 with conditional use in some countries, and then no longer recommended in Belgium and the USA at the end of 2022. The gradual convergence of the recommendations, although delayed compared to the general population, highlights the importance of the inclusion of pregnant women in clinical trials and of international collaboration to improve the pharmacological treatment of pregnant women with COVID-19

Technical Proposal for FASER: ForwArd Search ExpeRiment at the LHC

FASER is a proposed small and inexpensive experiment designed to search for light, weakly-interacting particles during Run 3 of the LHC from 2021-23. Such particles may be produced in large numbers along the beam collision axis, travel for hundreds of meters without interacting, and then decay to standard model particles. To search for such events, FASER will be located 480 m downstream of the ATLAS IP in the unused service tunnel TI12 and be sensitive to particles that decay in a cylindrical volume with radius R=10 cm and length L=1.5 m. FASER will complement the LHC's existing physics program, extending its discovery potential to a host of new, light particles, with potentially far-reaching implications for particle physics and cosmology. This document describes the technical details of the FASER detector components: the magnets, the tracker, the scintillator system, and the calorimeter, as well as the trigger and readout system. The preparatory work that is needed to install and operate the detector, including civil engineering, transport, and integration with various services is also presented. The information presented includes preliminary cost estimates for the detector components and the infrastructure work, as well as a timeline for the design, construction, and installation of the experiment.Comment: 82 pages, 62 figures; submitted to the CERN LHCC on 7 November 201

Modified strain and elastic energy behavior of Ge islands formed on high-miscut Si(0 0 1) substrates

Abstract We investigate here the influence of Si substrate miscut on the strain and elastic energy of Ge islands. We show how the morphology, composition and the elastic energy for 4 and 13 monolayers (ML) Ge islands grown at 600 °C and 730 °C on vicinal Si(0 0 1) surfaces change with miscut angles ranging between 0° and 10°. Scanning Tunneling Microscopy is used to determine the island morphology. Resonant x-ray diffraction near the Ge-K absorption edge allows the determination of the Ge concentration as well as the elastic energy stored on such structures from their dependency on the lattice parameter. Simulations using the Finite Elements Method indicate that the enlargement of the SiGe broad peak retrieved from the x-ray diffraction measurements is actually caused by the asymmetrical faceting induced by large miscut angles. Such faceting has a strong effect on island density and elastic energy, producing differences that are proportional to those observed in conditions with distinct SiGe content