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Estimates of the spatiotemporal distribution of different mosquito vector species and the associated risk of transmission of arboviruses are key to design adequate policies for preventing local outbreaks and reducing the number of human infections in endemic areas. In this study, we quantified the abundance of Aedes albopictusand Aedes aegyptiand the local transmission potential for three arboviral infections at an unprecedented spatiotemporal resolution in areas where no entomological surveillance is available.

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE). Methods: The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries. Planned Outcomes: The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue. Trial Registration: NCT04540497.

Frequency conversion in nonlinear materials is an extremely useful solution to the generation of new optical frequencies. Often, it is the only viable solution to realize light sources highly relevant for applications in science and industry. In particular, supercontinuum generation in waveguides, defined as the extreme spectral broadening of an input pulsed laser light, is a powerful technique to bridge distant spectral regions based on single-pass geometry, without requiring additional seed lasers or temporal synchronization. Owing to the influence of dispersion on the nonlinear broadening physics, supercontinuum generation had its breakthrough with the advent of photonic crystal fibers, which permitted an advanced control of light confinement, thereby greatly improving our understanding of the underlying phenomena responsible for supercontinuum generation. More recently, maturing in fabrication of photonic integrated waveguides has resulted in access to supercontinuum generation platforms benefiting from precise lithographic control of dispersion, high yield, compact footprint, and improved power consumption. This Review aims to present a comprehensive overview of supercontinuum generation in chip-based platforms, from underlying physics mechanisms up to the most recent and significant demonstrations. The diversity of integrated material platforms, as well as specific features of waveguides, is opening new opportunities, as will be discussed here.

Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and PNPLA3p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis, P< 10−10; advanced fibrosis/hepatocellular carcinoma, P= 0.034) and in the general population (P< 10−7for alanine transaminase levels). In individuals with obesity, hepatic PNPLA3expression was higher in women than in men (P= 0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids, PNPLA3was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a PNPLA3enhancer and demonstrated via CRISPR–Cas9 genome editing that this sequence drives PNPLA3p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and PNPLA3p.I148M variant contributes to FLD in women.

In a now classic paper, Karen Carr argues that Kierkegaard is a religious “anti-rationalist”: He holds that reason and religious truth exist in necessary tension with one another. Carr maintains that this antagonism is not a matter of the logical incoherence of Christianity, but rather the fact that genuine submission to Christ precludes approaching him through demonstration. In this essay, we argue that while Kierkegaard is in fact an anti-rationalist, the literature has failed to appreciate the full strength of his position. It is not just that reason and obedience are in tension; rather, Kierkegaard holds the stronger view that reason is actively offended by Christianity’s primary claims. Not only is reason incapable of generating anypositive evidence for the truth of Christianity, more radically, it provides evidence against it. In order to make this case, we offer a close reading of Practice in Christianity, developing a typology of Kierkegaard’s account of Christ’s “offense.” Finally, having motivated Kierkegaard’s strong anti-rationalism, we consider why, on his account, anyone would want to be a Christian.

The etiology of IgG4‐related disease (IgG4‐RD) is unknown, and there has been controversy over the significance of allergic conditions in IgG4‐RD. We examined the prevalence of lifetime allergy symptoms in IgG4‐RD and the association between these and IgG4‐RD. We identified IgG4‐RD patients and non‐IgG4‐RD controls without autoimmune conditions seen at a single center. IgG4‐RD patients were classified using the American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria. Allergy symptoms were ascertained by questionnaire. We assessed the association of IgG4‐RD features with allergy symptoms. We compared the proportion of cases and controls with allergy symptoms using conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) after matching cases and controls 1:1 by age and sex. Lifetime allergy symptoms were reported by 165 (71%) of 231 IgG4‐RD patients. Aeroallergen symptoms were most commonly reported (n = 135, 58%), followed by skin allergy symptoms (n = 97, 42%) and food allergy symptoms (n = 47, 20%). IgG4‐RD cases with a history of allergy symptoms were more likely to have head and neck involvement (OR 2.0 [95% CI 1.1–3.6]) and peripheral eosinophilia (OR 3.3 [95% CI 1.2–9.0]) than those without allergy symptoms. The prevalence of any allergy symptoms was similar between cases and controls (OR 0.7 [95% CI 0.4–1.1]); this remained consistent after stratifying by head and neck involvement. Lifetime allergy symptoms are common in IgG4‐RD but are not reported more often in IgG4‐RD compared to non‐IgG4‐RD patients without autoimmune conditions. These findings suggest that allergies are not uniquely associated with the pathogenesis or presentation of IgG4‐RD.

The relationship between autoimmune pancreatitis (AIP) type 2 and inflammatory bowel disease (IBD) has been established and previously described within International Consensus Diagnostic Criteria. However, it is unknown if the presence of IBD changes the natural disease course of AIP type 2. Our aim was to investigate the association between AIP type 2 and IBD as well as to systematically summarize all the existing evidence in the literature. Electronic medical record analysis was conducted in two centers (in Stockholm, Sweden, and Milan, Italy; records dated between January 2001 and June 2021). Additionally, we conducted a systematic review of the literature. A total of 35 patients (18 females, 51.4%) fulfilled the diagnostic criteria of AIP type 2 and were included in the study. A diagnosis of IBD was established in 29 patients (82.8%), ulcerative colitis in 17 (58.6%) and Crohn's disease in 11 (37.9%). Median follow‐up was 54 months. AIP patients with IBD commonly presented with abdominal pain and/or acute pancreatitis at diagnosis, the latter was prevailing in concomitant and later IBD onset. These patients more frequently used steroids, but there were no differences in relapse rates. Concomitant onset of IBD was associated with the development of diabetes mellitus. There were no cases of colon or pancreatic malignancy during follow‐up. In our systematic analysis, a total of 693 AIP type 2 patients were included from 24 single‐center retrospective studies and 8 multicenter retrospective studies. A diagnosis of IBD was reported in 330 (47.8%) patients. Relapse rate was 20.0%. Clinical and radiological remission of AIP type 2 was high, while the cumulative incidence of relapse is around 20%. Our results show that concomitance of IBD imposes no obvious risk of a different disease course for AIP type 2.

Systemic sclerosis is characterized by widespread fibrosis of the skin and internal organs, vascular impairment, and dysregulation of innate and adaptive immune system. Growing evidence indicates that T-cell proliferation and cytokine secretion play a major role in the initiation of systemic sclerosis, but the role of T helper 17 cells and of interleukin-17 cytokines in the development and progression of the disease remains controversial. In particular, an equally distributed body of literature supports both pro-fibrotic and anti-fibrotic effects of interleukin-17, suggesting a complex and nuanced role of this cytokine in systemic sclerosis pathogenesis that may vary depending on disease stage, target cells in affected organs, and inflammatory milieu. Although interleukin-17 already represents an established therapeutic target for several immune-mediated inflammatory diseases, more robust experimental evidence is required to clarify whether it may become an attractive therapeutic target for systemic sclerosis as well.

Nowadays, numerical simulations play an important role during the design and optimization phase of the after-treatment system (ATS). Simulation tools, based on both simple 1D or detailed CFD approaches, are able to describe the chemical species transport through the system and the main reactions occurring in the catalytic devices. In this context, the availability of accurate kinetic schemes is of primary importance for the reliable prediction of the ATS performance. In this work, the theme of the calibration of the reaction scheme based on the available experimental measurement is investigated, with particular interest in the modeling of the three-way catalyst. Hence, a methodology for the calibration is proposed, based on a two-step calibration procedure, which exploits two different types of the experimental data set, namely, oxygen storage capacity tests and standard homologation cycles. The adoption of these two different data sets allows us to optimize separately the kinetics of the reactions occurring at high temperatures and low temperatures, with a specific focus on the oxygen storage mechanism at the basis of the operation of a three-way catalyst. The effectiveness of the developed calibration procedure is finally demonstrated, considering two different test cases.

Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.

This paper tells us a complex story on the historic evolution of preventive conservation of architectural heritage in Italy. Firstly, it introduces Cesare Brandi's Theory of Restoration, pointing out the peculiar sense of the word Restoration in Brandi's system other than the common sense in the international discourse, the limits of Brandi's theory to architectural conservation and his prophecy on preventive restoration. Then it talks about the different framework and practices of preventive conservation in the field of built heritage compared to the museum sector, the milestone of Giovanni Urbani's pilot project on programmed conservation and the leading role of the Risk Map of Cultural Heritage. Finally, based on the discussions of the durable change in the architectural conservation field after the Venice Charter, including the teaching in Milan School, the debate and re-definition of architectural conservation and the advance definitions of conservation, prevention, maintenance and restoration in the 2004 National Code of Cultural Heritage and Landscape, it gives us an agenda for future trends of planned conservation with aims to conserve the material authenticity and promote the co-evolutional strategy.

The physical and chemical properties of nanoplastics make them potential carriers for some environmental contaminants, modifying their biological effects. Nevertheless, the change in toxicity caused by pollutant adsorption on nanoplastics is still controversial, depending on the interactions between chemical and physical pollutants, the consequent change in bioavailability, the modification of intake, transport and accumulation in the organisms and also on the characteristics of contaminants. In this context, the aim of the present study was the evaluation of combined effects made by 0.5 μm nanobeads of polystyrene and triclosan adsorbed on their surface in comparison with those caused by single contaminants. The systemic effects of 7 day exposure to nanoplastics, triclosan alone and to the nanoplastic–triclosan complex have been analyzed by employing zebrafish larvae and using a multi-tier approach from the evaluation of cellular and molecular effects to the impact at organism level. Results highlighted by confocal microscopy evidenced nanobead ingestion and translocation in several tissues and organs to guarantee the goodness of the exposure results. Behavioral assays were then conducted to highlight larval swimming defects as a ‘real-time’ readout of the potential effects on the whole organism, while a suite of several biomarkers and functional proteomics was applied to investigate the effects at both cellular and molecular levels. The whole data set pointed out a clear modification in the toxicological effects of the nanoplastic–triclosan complex in comparison with single contaminants, proved by opposite behaviours in the larval swimming activity and modulation of diverse protein classes as well as by different effects on several biochemical endpoints. This means that the interaction between chemical and physical pollutants leads to more complicated responses than additive, synergistic or antagonist models, resulting in a modification of toxicity instead of its increase or decrease.

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6–0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2–4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6–0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2–4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.

Carnitine palmitoyltransferase 2 deficiency is an inherited metabolic disorder involving a deficiency in a mitochondrial enzyme necessary for long chain fatty acid oxidation, and therefore decreased utilisation of fatty acids. The adult form of this condition leads to recurrent rhabdomyolysis triggered by exercise, fasting and infection. It is a very rare condition with only a few hundred reported cases worldwide. Here we present a case of severe rhabdomyolysis in the context of carnitine palmitoyltransferase 2 deficiency in which major organ involvement was avoided, and organ support was not needed. This prompted us to perform a systematic review of the existing case reports in the literature to ascertain the most frequent patterns of organ involvement and assess the outcomes that are seen in these patients. Our findings suggest that these patients most frequently develop isolated renal failure, often requiring renal replacement therapy; however, the outcomes following this are very good, supporting the early involvement of intensive care teams.

Background and Objective. In a previous study, we showed a new EEG processing methodology called Multi-Scale Ranked Organizing Map/Implicit Function As Squashing Time (MS-ROM/IFAST) performing an almost perfect distinction between computerized EEG of Italian children with autism spectrum disorder (ASD) and typically developing children. In this study, we assessed this system in distinguishing ASD subjects from children affected with other neuropsychiatric disorders (NPD). Methods. At a psychiatric practice in Texas, 20 children diagnosed with ASD and 20 children diagnosed with NPD were entered into the study. Continuous segments of artifact-free EEG data lasting 10 minutes were entered in MS-ROM/IFAST. From the new variables created by MS-ROM/IFAST, only 12 has been selected according to a correlation criterion. The selected features represent the input on which supervised machine learning systems (MLS) acted as blind classifiers. Results. The overall predictive capability in distinguishing ASD from other NPD cases ranged from 93% to 97.5%. The results were confirmed in further experiments in which Italian and US data have been combined. In this analysis, the best MLS reached 95.0% global accuracy in 1 out of 3 classes distinction (ASD, NPD, controls). This study demonstrates the value of EEG processing with advanced MLS in the differential diagnosis between ASD and NPD cases. The results were not affected by age, ethnicity and technicalities of EEG acquisition, confirming the existence of a specific EEG signature in ASD cases. To further support these findings, it was decided to test the behavior of already trained neural networks on 10 Italian very young ASD children (25-37 months). In this test, 9 out of 10 cases have been correctly recognized as ASD subjects in the best case. Conclusions. These results confirm the possibility of an early automatic autism detection based on standard EEG.

We report a simple post-process technique that harnesses a hybrid chalcogenide/silicon-germanium system for the control of waveguide dispersion. By adding a chalcogenide top cladding to a SiGe/Si waveguide, we can substantially change the dispersive properties, which underpin the generation of a supercontinuum. In our particular example, we experimentally show that a shift from anomalous to normal dispersion takes place. We numerically study the dispersion dependence on the chalcogenide thickness and show how to use this additional degree of freedom to control the position of the zero dispersion wavelengths and hence the spectral span of the supercontinuum. Finally, we compare our approach with more traditional techniques that use geometry for dispersion tailoring.

Polystyrene nanoparticles (PS NPs) are considered an upcoming threat to marine ecosystems. When NPs encounter biological fluids, they are readily covered by a biomolecular coating, named the “protein corona”, which critically drives the biological fate and toxicity of NPs. Here we provide the first attempt to identify key components of protein coronas of charged amino- and carboxyl-functionalized (PS-NH2and PS-COOH, respectively) PS NPs exposed to coelomic fluid (CF) of the Mediterranean sea urchin Paracentrotus lividus. The formation of protein coronas conferred identical colloidal features to both positively and negatively charged PS NPs, which acquired a negative ζpotential and monodisperse size distribution in sea urchin CF. Proteomic analysis revealed striking functional analogies of proteins identified from NP–coronas, especially entailing the potential to promote cell association and internalization of both NP types, as mediated by adsorbed protein species. Such basal findings strengthen the importance of the biological identity of NPs in the evaluation of the ecotoxicity potential of polymeric NPs.

The Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity-Score (ABSIS) scores have been proposed to provide an objective measure of pemphigus activity. These scores have been evaluated only on already treated patients mainly with mild to moderate activity. The objective was to assess the interrater reliability of ABSIS and PDAI scores and their correlation with other severity markers in a large international study.

In December 2012, EniServizi (the Italian multinational energy company), after the Earthquake that occurred at L’Aquila in April 2009, decided to undertake the project “Re-start from Collemaggio”, funding around 14 million Euro to restore the Basilica di Collemaggio. EniServizi, aware of the BIM potential role in the complex building and infrastructure domain in the world, required an advanced HBIM based on laser scanner and photogrammetric surveying to address decision-making processes among the different actors involved in the preservation process. The Basilica of Collemaggio has been re-opened to the public on December 2017. This paper tries to make a synthesis of the different lessons learnt, in relation to both positive and critical aspects relating HBIM feasibility, sustainability and usefulness to the challenging restoration and preservation field. The theoretical and practical HBIM approach here tackled overcomes the current BIM logic based on the sequential process adopted by the AIA and NBS Level of Development (LOD), characterized by a simple-to-complex-detailing process, working in the new construction domain and generally following the conceptualizing phase, the preliminary design, the executive design, the construction phase till to the facility management. A complex-mixed LOD approach, able to entail the richness, unicity and multiplicity of each component and to get the maximum degree of knowledge, has been experimented in order to derive informed decisions in terms of preservation, restoration and management since the starting phases of the architectural design. To this aim, a Level of Geometry (LOG) coherent to the Level of Accuracy gained by the high-resolution surveys has been adapted to the specificity of the restoration process of a historic monument and is here proposed through different Grade of Generation (GOG) protocols developed in the object modelling to support the preliminary and definitive design proposal of the conservation plan of the Basilica. Particularly, a NURBS-based parametric generative modelling process (GOG9-10) is here proposed in order to get models “BIM abled” to describe the complex geometry and to match the related information. Specific Level of Information (LOI) has been introduced to support the preservation process, to document the as-built and the management of the building after the intervention, moving HBIM toward multi-actor domain. Given the effort required by such approach, obtaining a cost-effective HBIM modelling embodying the complexity of each damaged element as acquired by the surveys (i.e. walls, pillars, vaults, beams) represents a challenging issue. The result of the overall process aims to contribute in lowering the initial HBIM modelling costs by deploying a sustainable complexity delivering protocols and specification and by boosting at the same time an interoperable cooperative HBIM habit among multi-actors across all the phases, spreading its usability after the restoration process. On the lesson learnt, the process of updating the current Codification criteria (UNI11337-2009) has been started with a draft proposal stimulating the debate for the future of HBIM adoption in the case of restoration, preservation and maintenance (UNI11337-2017): in the conviction that transferring the HBIM richness into the Life Cycle Management process will allow multi-actors to take in account the knowledge and information gained during the restoration, integrating the as-built updating and keeping updated the monument monitoring during the time being.

Immunoglobulin G4-related disease (IgG4-RD) promptly responds to glucocorticoids but relapses in a considerable fraction of patients. Reliable biomarkers of flare are currently lacking because the pathophysiology of IgG4-RD remains largely elusive. In the present work, we aimed to identify perturbations of B-cell subpopulations that might predict IgG4-RD relapse. Thirty patients were treated with glucocorticoids according to international guidelines. Circulating CD19+and CD20+cells, naive B cells, memory B cells, plasmablasts, and plasma cells were measured by flow cytometry at baseline and every 6 months for 2 years after the initiation of corticosteroid therapy. Patients with active untreated IgG4-RD showed significantly reduced CD19+B cells, CD20+B cells, and naive B cells compared with healthy subjects (p< 0.05), but significantly expanded plasmablasts and plasma cells (p< 0.01). After 6 months of corticosteroid treatment, all patients achieved clinical improvement. Naive B cells, plasmablasts, and plasma cells significantly decreased compared with disease onset, whereas memory B cells significantly increased compared with baseline (p< 0.01). Increase of memory B cells was observed only in patients who relapsed within 2 years of follow-up, however (HR, 12.24; 2.99 to 50.2; p= 0.0005). In these patients, the relapse rates at 12 and 24 months were 30% and 100%, respectively. No abnormalities of other B-cell subpopulations at disease onset or after 6 months of glucocorticoid treatment were found to predict IgG4-RD relapse at 2 years. Increase of circulating memory B cells after 6 months of glucocorticoid treatment might predict IgG4-RD relapse.

IgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ, leading to organ dysfunction and failure. The IgG4‐RDResponder Index (RI) was developed to help investigators assess the efficacy of treatment in a structured manner. The aim of this study was to validate the RIin a multinational investigation. The RIguides investigators through assessments of disease activity and damage in 25 domains, incorporating higher weights for disease manifestations that require urgent treatment or that worsen despite treatment. After a training exercise, investigators reviewed 12 written IgG4‐RDvignettes based on real patients. Investigators calculated both an RIscore as well as a physician's global assessment (PhGA) score for each vignette. In a longitudinal assessment, 3 investigators used the RIin 15 patients with newly active disease who were followed up over serial visits after treatment. We assessed interrater and intrarater reliability, precision, validity, and responsiveness. The 26 physician investigators included representatives from 6 specialties and 9 countries. The interrater and intrarater reliability of the RIwas strong (0.89 and 0.69, respectively). Correlations (construct validity) between the RIand PhGAwere high (Spearman's r = 0.9, P< 0.0001). The RIwas sensitive to change (discriminant validity). Following treatment, there was significant improvement in the RIscore (mean change 10.5 [95% confidence interval (95% CI) 5.4–12], P< 0.001), which correlated with the change in the PhGA. Urgent disease and damage were captured effectively. In this international, multispecialty study, we observed that the RIis a valid and reliable disease activity assessment tool that can be used to measure response to therapy.

The increasing use of nanomaterials raises several concerns regarding their potential risk for the environment and human health. In particular, the aquatic ecosystems appear highly susceptible. In this context, we investigated the interplay between carbon nanopowder (CNPW) and the common pollutant benzo(α)pyrene (B(α)P) in zebrafish embryos. CNPW was contaminated with B(α)P, and showed significant adsorption towards the hydrocarbon. Embryos were then exposed to CNPW (50 mg L−1) or B(α)P (0.2, 6, 20 μg L−1) alone, or to the CNPW doped with the three B(α)P concentrations. We demonstrated that CNPW helps B(α)P uptake by zebrafish embryos and we also demonstrated that the interaction between CNPW and the hydrocarbon affects the stress response pathways of the organism, so eliciting the toxic effect. In particular, the modulation of genes related to the cellular stress response (cyp1a, hsp70, sod1, sod2) and the measurement of oxidative stress enzyme activities allowed us to identify critical molecular events modulated by the pollutants alone and in co-exposure. Finally, to evaluate the toxic effects due to CNPW interactions with B(α)P, we analyzed biomarkers of cyto-genotoxicity. No significant genotoxicity was induced by B(α)P and CNPW alone, but the co-exposure led to an increase of cytotoxicity, and a higher incidence of necrotic and apoptotic cells. Altogether our data show that nanomaterials, even if they are not toxic per se, could help to enhance the toxicity of common pollutants.

The article looks at the architectural design of the Academy for Architecture of the University of Italian Switzerland in Mendrisio, Switzerland, with details of the structural layout and cultural influence on design.

The cosmic rays propagation inside the heliosphere is well described by a transport equation introduced by Parker in 1965. To solve this equation, several approaches were followed in the past. Recently, a Monte Carlo approach became widely used in force of its advantages with respect to other numerical methods. In this approach the transport equation is associated to a fully equivalent set of stochastic differential equations (SDE). This set is used to describe the stochastic path of quasi‐particle from a source, e.g., the interstellar space, to a specific target, e.g., a detector at Earth. We present a comparison of forward‐in‐time and backward‐in‐time methods to solve the cosmic rays transport equation in the heliosphere. The Parker equation and the related set of SDE in the several formulations are treated in this paper. For the sake of clarity, this work is focused on the one‐dimensional solutions. Results were compared with an alternative numerical solution, namely, Crank‐Nicolson method, specifically developed for the case under study. The methods presented are fully consistent each others for energy greater than 400 MeV. The comparison between stochastic integrations and Crank‐Nicolson allows us to estimate the systematic uncertainties of Monte Carlo methods. The forward‐in‐time stochastic integrations method showed a systematic uncertainty <5%, while backward‐in‐time stochastic integrations method showed a systematic uncertainty <1% in the studied energy range. Quantitative comparison of backward‐forward‐in‐time cosmic rays transport Monte Carlo methodsEstimation of systematic error of both methods for spectra at 1 AU for energies above 1 GVBackward‐in‐time method is suited for predicting modulated spectra for high‐precision experiments

Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα) mediates the broad effects of ERα on the hepatic lipid metabolism.

We investigate, in terms of production from pulsars and their nebulae, the cosmic ray positron and electron fluxes above ∼10 GeV, observed by the AMS-02 experiment up to 1 TeV. We concentrate on the Vela-X case. Starting from the gamma-ray photon spectrum of the source, generated via synchrotron and inverse Compton processes, we estimated the electron and positron injection spectra. Several features are fixed from observations of Vela-X and unknown parameters are borrowed from the Crab nebula. The particle spectra produced in the pulsar wind nebula are then propagated up to the Solar System, using a diffusion model. Differently from previous works, the omnidirectional intensity excess for electrons and positrons is obtained as a difference between the AMS-02 data and the corresponding local interstellar spectrum. An equal amount of electron and positron excess is observed and we interpreted this excess (above ∼100 GeV in the AMS-02 data) as a supply coming from Vela-X. The particle contribution is consistent with models predicting the gamma-ray emission at the source. The input of a few more young pulsars is also allowed, while below ∼100 GeV more aged pulsars could be the main contributors.

AbstractBackground:The prevalence of overweight and obesity among children and adolescents has increased worldwide and has reached alarming proportions. Currently, sugar-sweetened beverages (SSBs) are the primary source of added sugar in the diet of children and adolescents. Contradictive findings from studies and reviews have fueled an endless debate on the role of SSBs in the development of childhood obesity.Objectives:The primary aim of the present review of reviews was to assess how review- and study-level methodological factors explain conflicting results across reviews and meta-analyses by providing an up-to-date synthesis of recent evidence regarding the association between SSB consumption and weight gain, overweight, and obesity in a population of 6-month-old to 19-year-old children and adolescents. The secondary aim was to assess the quality of included reviews using the Assessment of Multiple SysTemAtic Reviews (AMSTAR) measurement tool.Methods:Systematic literature reviews and meta-analyses were included. The literature search was performed through the platforms Pubmed/Medline, Cinahl, and Web of Knowledge.Results:Thirteen reviews and meta-analyses were included. Nine reviews concluded that there was a direct association between SSBs and obesity in children and adolescents and four others did not. The quality of the included reviews was low to moderate, and the two reviews with the highest quality scores showed discrepant results.Conclusions:The majority of reviews concluded that there was a direct association between SSB consumption and weight gain, overweight, and obesity in children and adolescents. However, recent evidence from well-conducted meta-analyses shows discrepant results regarding the association between SSB and weight gain, overweight, and obesity among children and adolescents. Improving methodological quality of studies and reviews as well as ensuring responsible conduct of research and scientific integrity is essential for the provision of objective results.

Objective:The objective of this report is to characterize IgG4-related disease (IgG4-RD) as it is manifested in the head and neck and describe a series of patients with a rarely described presentation in laryngopharyngeal subsites.Methods:Here, we illustrate the presentation and clinical course of 3 patients with laryngopharyngeal manifestations of IgG4-RD, including the manner of diagnosis and effective treatment.Results:Three patients with laryngopharyngeal lesions were ultimately diagnosed with IgG4-RD after lengthy work-up. The diagnostic criteria and treatment protocols are explained.Conclusion:IgG4-related disease is a fibroinflammatory disorder now described in almost every organ system. The head and neck regions are among the most common areas of involvement, however, reports of laryngopharyngeal involvement are rare. We also summarize current knowledge of this entity and discuss established diagnostic criteria and clinical findings.

A rare anatomic anomaly of the second cervical vertebra involving the odontoid process was first described in 1863 in a post-mortem specimen and then was called “Os Odontoideum” (OO) by Giacomini that coined this term in 1886. The etiology of the OO is still controversial and it focuses mainly on two theories: acquired and congenital. In this scientific paper, we present the case of a patient admitted to our ward following a displaced fracture of the jaw and with a radiological diagnosis of a cervical spine fracture. Only a careful clinical and instrumental evaluation allowed us to detect the presence of OO anomaly, thus modifying prognosis and treatment protocol.

The widespread use of engineered nanomaterials (ENMs) in a variety of technologies and consumer products inevitably causes their release into aquatic environments and final deposition into the oceans. In addition, a growing number of ENM products are being developed specifically for marine applications, such as antifouling coatings and environmental remediation systems, thus increasing the need to address any potential risks for marine organisms and ecosystems. To safeguard the marine environment, major scientific gaps related to assessing and designing ecosafe ENMs need to be filled. In this Nano Focus, we examine key issues related to the state-of-the-art models and analytical tools being developed to understand ecological risks and to design safeguards for marine organisms.

IMPORTANCE IgG4-related hypertrophic pachymeningitis (IgG4-RHP) is an increasingly recognized manifestation of IgG4-related disease, a fibroinflammatory condition that can affect virtually any organ. It is estimated that IgG4-RHP may account for a high proportion of cases of hypertrophic pachymeningitis once considered idiopathic. OBJECTIVE To summarize the current knowledge on IgG4-RHP including its pathological, clinical, and radiological presentations. Particular emphasis is placed on diagnostic and therapeutic implications. EVIDENCE REVIEW This review is based on 21 reports published in the English medical literature since 2009. PubMed was searched with the following terms: IgG4, pachymeningitis, IgG4-related pachymeningitis, IgG4-related disease, IgG4-related, and IgG4 meningitis. Only cases with biopsy-proven IgG4-RHP were considered and included in this review. FINDINGS Little is known with certainty regarding the pathogenesis of IgG4-RHP. The presence of oligoclonally restricted IgG4-positive plasma cells within inflammatory meningeal niches strongly suggests a specific response against a still unknown antigen. Clinical presentation of IgG4-RHP is not distinguishable from other forms of hypertrophic pachymeningitis and reflects mechanical compression of vascular or nerve structures, leading to functional deficits. Signs of systemic IgG4-related disease may concomitantly be present. Diagnostic process should rely primarily on magnetic resonance imaging, cerebrospinal fluid analysis, and meningeal biopsy. In particular, hallmark histopathological features of IgG4-RHP are a lymphoplasmacytic infiltration of IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. High-dose glucocorticoids are still the treatment of choice for IgG4-RHP because immunosuppressive agents have shown variable efficacy in reducing the meningeal hypertrophy. Rituximab is a promising therapeutic approach but experience with B-cell depletion strategies remains limited. CONCLUSIONS AND RELEVANCE IgG4-related disease accounts for an increasing proportion of cases of idiopathic hypertrophic pachymeningitis. Clinicians should become familiar with this alternative differential diagnosis because a prompt, specific therapeutic approach may avoid long-term neurological complications.