Search

Abstract Background The prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites. Methods SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits. Results In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks’ treatment, while 163 received ≥ 104 weeks’ treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies. In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor. Conclusions In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile. Trial registration Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517 .

Purpose: Optic nerves are part of the craniospinal irradiation (CSI) target volume. Modern radiotherapy techniques achieve highly conformal target doses while avoiding organs-at-risk such as the lens. The magnitude of eye movement and its influence on CSI target- and avoidance volumes are unclear. We aimed to evaluate the movement-range of lenses and optic nerves and its influence on dose distribution of several planning techniques. Methods: Ten volunteers underwent MRI scans in various gaze directions (neutral, left, right, cranial, caudal). Lenses, orbital optic nerves, optic discs and CSI target volumes were delineated. 36-Gy cranial irradiation plans were constructed on synthetic CT images in neutral gaze, with Volumetric Modulated Arc Therapy, pencil-beam scanning proton therapy, and 3D-conventional photons. Movement-amplitudes of lenses and optic discs were analyzed, and influence of gaze direction on lens and orbital optic nerve dose distribution. Results: Mean eye structures’ shift from neutral position was greatest in caudal gaze; −5.8±1.2 mm (±SD) for lenses and 7.0±2.0 mm for optic discs. In 3D-conventional plans, caudal gaze decreased Mean Lens Dose (MLD). In VMAT and proton plans, eye movements mainly increased MLD and diminished D98 orbital optic nerve (D98OON) coverage; mean MLD increased up to 5.5 Gy [total ΔMLD range −8.1 to 10.0 Gy], and mean D98OON decreased up to 3.3 Gy [total ΔD98OON range −13.6 to 1.2 Gy]. VMAT plans optimized for optic disc Internal Target Volume and lens Planning organ-at-Risk Volume resulted in higher MLD over gaze directions. D98OON became ≥95% of prescribed dose over 95/100 evaluated gaze directions, while all-gaze bilateral D98OON significantly changed in 1 of 10 volunteers. Conclusion: With modern CSI techniques, eye movements result in higher lens doses and a mean detriment for orbital optic nerve dose coverage of

Abstract Background There is currently no information on how different mandibular segments are affected by juvenile idiopathic arthritis. The aim of this paper is to assess volumetric differences of different mandibular segments in subjects with unilateral and bilateral JIA and to compare them with non-JIA control volumes. Materials and methods Forty subjects with unilateral TMJ involvement and 48 with bilateral TMJ involvement were selected for the case group and 45 subjects with no known rheumatic comorbidities for the control group. The mandible of each subject was divided according to a validated method into different paired volumes (hemimandible, condyle, ramus and hemibody). Results The ANOVA test revealed a statistically significant difference in all the groups for condylar and ramus volumes, and the pairwise comparison evidenced a statistically significant higher condylar and ramus volume in the control group (1444.47 mm3; 5715.44 mm3) than in the affected side in the unilateral JIA group (929.46 mm3; 4776.31 mm3) and the bilateral JIA group (1068.54 mm3; 5715.44 mm3). Moreover, there was also a higher condylar volume in the unaffected side in the unilateral JIA group (1419.39 mm3; 5566.24 mm3) than in the bilateral JIA group and the affected side in the unilateral JIA group. Conclusions The affected side of unilateral JIA patients showed statistically significant lower volumes in the hemimandible, in the condyle and in the ramus. The largest total mandibular volume was observed in the control group, followed by the unilateral JIA group and, lastly, by the bilateral JIA group.

Ribonucleoprotein (RNP) granules are responsible for mRNA transport and local translation required for neuronal and oocyte maturation. Here the authors show that loss of the Drosophila Ub ligase Hecw enlarges RNP granules, leads to a liquid to gel-like transition, and results in defective oogenesis and neuronal loss.

Summary: We outline the features of the R package SparseSignatures and its application to determine the signatures contributing to mutation profiles of tumor samples. We describe installation details and illustrate a step-by-step approach to (1) prepare the data for signature analysis, (2) determine the optimal parameters, and (3) employ them to determine the signatures and related exposure levels in the point mutation dataset.For complete details on the use and execution of this protocol, please refer to Lal et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Objective:. To conduct a systematic review of the currently available literature on the use of ICG to guide surgical dissection in gastrointestinal (GI) cancer surgery. Background:. Real-time indocyanine green (ICG) fluorescence-guided surgery has the potential to enhance surgical outcomes by increasing patient-tailored oncological precision. Methods:. MEDLINE, PubMed, EMBASE, and Google Scholar were searched for publications on the use of ICG as a contrast agent in GI cancer surgery until December 2020. Perfusion studies were excluded. Quality of the studies was assessed with the Methodological Index for nonrandomized Studies or Jadad scale for randomized controlled trials. A narrative synthesis of the results was provided, with descriptive statistics when appropriate. Results:. Seventy-eight studies were included. ICG was used for primary tumor and metastases localization, for sentinel lymph node detection, and for lymph flow mapping. The detection rate for primary colorectal and gastric tumors was 100% after preoperative ICG endoscopic injection. For liver lesions, the detection rate after intravenous ICG infusion was 80% and up to 100% for lesions less than 8 mm from the liver surface. The detection rate for sentinel lymph nodes was 89.8% for esophageal, 98.6% for gastric, 87.4% for colorectal, and 83.3% for anal tumors, respectively. In comparative studies, ICG significantly increases the quality of D2 lymphadenectomy in oncological gastrectomy. Conclusion:. The use of ICG as a guiding tool for dissection in GI surgery is promising. Further evidence from high-quality studies on larger sample sizes is needed to assess whether ICG-guided surgery may become standard of care.

The most important reef of the Mediterranean is the Coralligène (Coralligenous = C), including several types of calcareous algal-invertebrate build-ups growing in normal open marine conditions. We analyzed and compared two C samples from the Ligurian Sea developed in different environmental settings: 1) off Portofino on a rocky cliff, at a depth of about 40 m and 2) in front of Bogliasco, on a sub-horizontal substrate at a depth of 10 m. The maximum AMS radiocarbon dating provided an older age for Bogliasco (about 5 ka BP) than for Portofino (about 3.6 ka BP), and the mean accumulation rate of the Portofino build-up (about 80 µm y−1) was found to be higher than the one in Bogliasco (about 65 µm y−1). The different sides of each build-up showed a remarkable heterogeneity in the dominant cover by living organisms, and the comparison between the two build-ups highlighted an evident diversity in their taxonomic composition and structure, although crustose coralline algae (CCA) are the dominant framework builder and major autogenic ecosystem engineers at both localities, in the present as in the past millennia. Other major components of the structure are bryozoans and serpulids, and an important role is played by sediment filling. In Bogliasco, extreme climate events and major peaks of fine matrix and terrigenous grains are observed, lithologically related to the drainage basin of the Poggio creek and associated with charophyte occurrence and reduced CCA abundance. The occurrence of the rare Sporolithon ptychoides was observed both in Portofino at about 750 BCE and in Bogliasco. These Sporolithon phases are likely related to warm and humid spells punctuating the Holocene climate fluctuations in the Ligurian Sea. Because coralline algae are confirmed to be the most important habitat engineer of the Mediterranean reefs, they deserve more attention in the framework of any monitoring initiative aimed at C management and conservation.

Chronic inflammatory airway diseases, including asthma, chronic rhinosinusitis, eosinophilic COPD and allergic rhinitis are a global health concern. Despite the coexistence of these diseases and their common pathophysiology, they are often managed independently, resulting in poor asthma control, continued symptoms and poor quality of life. Understanding disease pathophysiology is important for best treatment practice, reduced disease burden and improved patient outcomes. The pathophysiology of type 2 inflammation is driven by both the innate immune system triggered by pollutants, viral or fungal infections involving type 2 innate lymphoid cells (ILC2) and the adaptive immune system, triggered by contact with an allergen involving type 2 T-helper (Th2) cells. Both ILC2 and Th2 cells produce the type-2 cytokines (interleukin (IL)-4, IL-5 and IL-13), each with several roles in the inflammation cascade. IL-4 and IL-13 cause B-cell class switching and IgE production, release of pro-inflammatory mediators, barrier disruption and tissue remodelling. In addition, IL-13 causes goblet-cell hyperplasia and mucus production. All three interleukins are involved in trafficking eosinophils to tissues, producing clinical symptoms characteristic of chronic inflammatory airway diseases. Asthma is a heterogenous disease; therefore, identification of biomarkers and early targeted treatment is critical for patients inadequately managed by inhaled corticosteroids and long-acting β-agonists alone. The Global Initiative for Asthma guidelines recommend add-on biological (anti IgE, IL-5/5R, IL-4R) treatments for those not responding to standard of care. Targeted therapies, including omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab and tezepelumab, were developed on current understanding of the pathophysiology of type 2 inflammation. These therapies offer hope for improved management of type 2 inflammatory airway diseases.

We report a simple and efficient strategy to enhance the fluorescence of biocompatible biindole diketonates (bdks) in the visible spectrum through difluoroboronation (BF2bdks complexes). Emission spectroscopy testifies an increase in the fluorescence quantum yields from a few percent to as much as >0.7. This massive increment is essentially independent of substitutions at the indole (-H, -Cl, and -OCH3) and corresponds to a significant stabilization of the excited state with respect to non-radiative decay mechanisms: the non-radiative decay rates are reduced by as much as an order of magnitude, from 109 s−1 to 108 s−1, upon difluoroboronation. The stabilization of the excited state is large enough to enable sizeable 1O2 photosensitized production. Different time-dependent (TD) density functional theory (DFT) methods were assessed in their ability to model the electronic properties of the compounds, with TD-B3LYP-D3 providing the most accurate excitation energies. The calculations associate the first active optical transition in both the bdks and BF2bdks electronic spectra to the S0 → S1 transition, corresponding to a shift in the electronic density from the indoles to the oxygens or the O-BF2-O unit, respectively.

Introduction: The study of facial profiles in the dental field is very important for the diagnosis and the dental and orthodontic treatment plan. The aim of this study is to analyze the three-dimensional morphology of the faces of 269 growing patients with Class I and II occlusions, focusing on children aged between 6 and 9 years old. The analysis was conducted using a non-invasive computerized system, which allowed for the automatic collection of facial landmarks and the subsequent reconstruction of three-dimensional coordinates. Materials and methods: The sample comprised 269 children within the specified age range. Each child's facial features were captured using the non-invasive computerized system, which utilized two infrared CCD cameras, real-time hardware for label recognition, and software for three-dimensional landmark reconstruction. Sixteen cutaneous facial landmarks were automatically collected for each participant. From these landmarks, 10 angular and 15 linear measurements, as well as five direct distance rates, were derived. The mean values for each age class were calculated separately for children with bilateral Angle Class I occlusion and compared with those for children with bilateral Class II occlusion. In all children, the left and right occlusal classes were measured as suggested by Katz. Results: The analysis revealed notable differences, primarily in the three-dimensional angular measurements between children with Class I and II occlusions. Specifically, Class II children exhibited more convex faces in the sagittal plane and a less prominent lower jaw compared to Class I children. However, no significant differences were observed in linear measurements, except for the lower facial height rate, which varied inconsistently across age groups between the two occlusion types. Discussion and Conclusions: the findings of this research highlight distinct three-dimensional facial morphological differences between children with Class I and II occlusions. While Class II children tended to have more convex facial profiles and less prominent lower jaws, linear measurements showed minimal variation between the two occlusion types. These results underscore the importance of three-dimensional analysis in understanding facial morphology in growing patients with different occlusal patterns. [ABSTRACT FROM AUTHOR]

Fungal trunk disease (FTD) poses a significant threat to hazelnut (Corylus avellana L.) production worldwide. In Chile, the fungus Diplodia mutila, from the Botryosphaeriaceae family, has been frequently identified causing this disease in the Maule and Ñuble Regions. However, control measures for D. mutila remain limited. This research aimed to evaluate the effectiveness of chemical and biological fungicides against D. mutila under in vitro, controlled pot experiment, and field conditions. An in vitro screening of 30 fungicides was conducted. The effectiveness was assessed by measuring the length of vascular lesions in hazelnut branches inoculated with D. mutila mycelium disks under controlled and field conditions. Field trials were conducted in a hazelnut orchard in Ñiquén, Ñuble Region, Chile. The results showed that three biological and five chemical fungicides were selected in vitro with >31% inhibition after 14 days. In pot experiments, all fungicides reduced necrotic lesions on branches by 32% to 61%. In field experiments, the most effective systemic fungicides were fluopyram/tebuconazole, fluxapyroxad/pyraclostrobin, and tebuconazole, while the effectiveness of antagonists Pseudomonas protegens ChC7 and Bacillus subtilis QST713 varied with seasonal temperatures. Effective conventional and biological fungicides against D. mutila could be integrated into disease management programs to protect hazelnut wounds from infections. [ABSTRACT FROM AUTHOR]

The fabrication and integration of high‐quality structures of Yttrium Iron Garnet (YIG) is critical for magnonics. Films with excellent properties are obtained only on single crystal Gadolinium Gallium Garnet (GGG) substrates using high‐temperature processes. The subsequent realization of magnonic structures via lithography and etching is not straightforward as it requires a tight control of the edge roughness, to avoid magnon scattering, and planarization in case of multilayer devices. In this work a different approach is described based on local laser annealing of amorphous YIG films, avoiding the need for subjecting the entire sample to high thermal budgets and for physical etching. Starting from amorphous and paramagnetic YIG films grown by pulsed laser deposition at room temperature on GGG, a 405 nm laser is used for patterning arbitrary shaped ferrimagnetic structures by local crystallization. In thick films (160 nm) the laser induced surface corrugation prevents the propagation of spin‐wave modes in patterned conduits. For thinner films (80 nm) coherent propagation is observed in 1.2 µm wide conduits displaying an attenuation length of 5 µm that is compatible with a damping coefficient of ≈5 × 10−3. Possible routes to achieve damping coefficients compatible with state‐of‐the art epitaxial YIG films are discussed. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate through analysis using CBCT the transverse and axial diameters of the mandibular condyles in subjects affected by juvenile idiopathic arthritis (JIA) and compare them with those of healthy subjects. Methods: The study was conducted on CBCT scans from the digital archive of the Department of Biomedical Surgical and Dental Sciences, University of Milan, including patients with JIA and using healthy subjects as controls. Inclusion criteria: aged between 7 and 25 years old at the time of the CBCT examination; Caucasian ethnicity; diagnosis of JIA according to the International League of Associations for Rheumatology (ILAR) criteria documented in patients' records; TMJ involvement; good quality CBCTs covering our region of interest (ROI), from the glabella to the mandibular inferior border; no previous orthodontic/orthopedic treatment; no history of craniofacial trauma or congenital birth defects involving the craniofacial area. Each CBCT scan underwent examination using 3Diagnosys® software. Since data were normally distributed, parametric tests were used for analysis. The sample was divided into three groups: (1) bilateral JIA subjects, (2) unilateral JIA subjects, and (3) healthy controls. Results: We found a statistically significant reduction (p < 0.0001) in the transverse diameter (TR-Diam) of the affected condyles by an average of 1.7 mm, while the axial diameter (AX-Diam) again showed a slight reduction, on average by 0.1 mm, with a non-statistically significant value. Another comparison was made between the unaffected condyles of patients with unilateral JIA and the healthy condyles of the control group. The unilateral unaffected condyles were found to be slightly smaller than those of healthy patients, but without statistically significant differences. We found that in both JIA males and females, the condylar growth tends to stop earlier than the healthy ones. Conclusions: The transverse diameter was found to be more affected than the axial one, causing typical bone resorption and condylar shape. Moreover, we showed that the pathology, in the case of unilateral JIA, does not compromise only the affected condyles; the corresponding condyle that seems to be healthy is actually partially compromised. In addition, we observed that the growth of affected condyles of JIA subjects tends to stop earlier than the condyles of the healthy controls. [ABSTRACT FROM AUTHOR]

Simple Summary: Ischemia-reperfusion injury (IRI) is the source of significant graft inflammation in liver transplantation. Such injuries can lead to increased recurrence of both benign and malignant diseases of the biliary tree after transplant. Herein, we review the mechanisms and risk factors for the link between IRI and biliary recurrence, as well as evidence for strategies to mitigate this damage. Liver transplantation is known to generate significant inflammation in the entire organ based on the metabolic profile and the tissue's ability to recover from the ischemia-reperfusion injury (IRI). This cascade contributes to post-transplant complications, affecting both the synthetic liver function (immediate) and the scar development in the biliary tree. The new occurrence of biliary strictures, and the recurrence of malignant and benign liver diseases, such as cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC), are direct consequences linked to this inflammation. The accumulation of toxic metabolites, such as succinate, causes undirected electron flows, triggering the releases of reactive oxygen species (ROS) from a severely dysfunctional mitochondrial complex 1. This initiates the inflammatory IRI cascade, with subsequent ischemic biliary stricturing, and the upregulation of pro-tumorigenic signaling. Such inflammation is both local and systemic, promoting an immunocompromised status that can lead to the recurrence of underlying liver disease, both malignant and benign in nature. The traditional treatment for CCA was resection, when possible, followed by cytotoxic chemotherapy. Liver transplant oncology is increasingly recognized as a potentially curative approach for patients with intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma. The link between IRI and disease recurrence is increasingly recognized in transplant oncology for hepatocellular carcinoma. However, smaller numbers have prevented similar analyses for CCA. The mechanistic link may be even more critical in this disease, as IRI causes the most profound damage to the intrahepatic bile ducts. This article reviews the underlying mechanisms associated with biliary inflammation and biliary pathology after liver transplantation. One main focus is on the link between transplant-related IRI-associated inflammation and the recurrence of cholangiocarcinoma and benign liver diseases of the biliary tree. Risk factors and protective strategies are highlighted. [ABSTRACT FROM AUTHOR]

Inkjet printing is a versatile and cheap technique for the fabrication of films, offering unique advantages in terms of scalability, precision, and customization. In recent years, there has been a growing interest in utilizing inkjet printing technology for the deposition of magnetic films with tailored properties. Cobalt ferrite (CoFe2O4) stands out due to its exceptional magnetic properties, including high coercivity, saturation magnetization, and excellent chemical stability. This paper presents a comprehensive study on the inkjet printing of cobalt ferrite magnetic films, focusing on the manufacturing process, especially on the different factors that could lead to stable multilayer depositions to achieve high thicknesses: ink solid loading, drop spacing, substrate temperature, and interlayers drying. Finally, the microstructure of the samples is investigated to identify the occurring defects after sintering between 800 and 1000 °C. The magnetic properties of the films are determined, revealing a maximum coercivity of 1.98 kOe and a magnetic saturation of 78.25 emu cm−3. [ABSTRACT FROM AUTHOR]

Summary: A key task of genomic surveillance of infectious viral diseases lies in the early detection of dangerous variants. Unexpected help to this end is provided by the analysis of deep sequencing data of viral samples, which are typically discarded after creating consensus sequences. Such analysis allows one to detect intra-host low-frequency mutations, which are a footprint of mutational processes underlying the origination of new variants. Their timely identification may improve public-health decision-making with respect to traditional approaches exploiting consensus sequences. We present the analysis of 220,788 high-quality deep sequencing SARS-CoV-2 samples, showing that many spike and nucleocapsid mutations of interest associated to the most circulating variants, including Beta, Delta, and Omicron, might have been intercepted several months in advance. Furthermore, we show that a refined genomic surveillance system leveraging deep sequencing data might allow one to pinpoint emerging mutation patterns, providing an automated data-driven support to virologists and epidemiologists.