Demography, baseline disease characteristics and treatment history of patients with psoriasis enrolled in a multicentre, prospective, disease-based registry (PSOLAR)*

Summary Background: Psoriasis is associated with several comorbidities and behavioural risk factors. Objectives: To evaluate demographic and disease characteristics in patients enrolled in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Methods: PSOLAR is a global, prospective, longitudinal, disease-based registry that includes a postmarketing commitment to evaluate safety in patients with psoriasis. Enrolled patients had to be receiving, or be eligible to receive, conventional systemic or biological agents. Demographic/disease characteristics, medical histories, lifestyle risk factors and previous treatments are collected at enrolment. Efficacy and safety data are collected every 6 months for 8 years, and data are extracted annually. Selected parameters are evaluated by age quartile using post hoc analyses. Results: As of 23 August 2012, 11 900 patients were enrolled at 301 sites in North America, Europe and Latin America. Over half of the PSOLAR population (54·7%) is male, with a mean age of 48·6 years and mean body mass index of 30·9 kg m−2 at enrolment. Mean duration of disease at enrolment was 17·5 years, and mean Physician's Global Assessment score was 2·0. Psoriatic arthritis (35·5%) and cardiovascular diseases (38·2%) were highly prevalent. Diabetes mellitus type II was reported in 11·4% of patients. Depression and anxiety were noted in 14·7% and 11·1% of patients, respectively; 79·0% reported any alcohol use and 56·7% reported smoking or a history of smoking. The occurrence of most comorbidities, including cardiovascular disease and risk factors, increased with age. Conclusions: In the PSOLAR population, multiple and age-appropriate comorbidities are associated with psoriasis and may affect the selection of psoriasis treatments. What's already known about this topic? Psoriasis is a complicated disorder, often accompanied by multiple comorbidities. Demographic and disease characteristics of patients with psoriasis reported from large claims datasets may be affected by misclassification bias or coding errors. In clinical trials, many patients are excluded owing to strict inclusion criteria. What does this study add? Data collected by the Psoriasis Longitudinal Assessment and Registry reveal that the demographics and disease characteristics of patients with psoriasis who are receiving, or are candidates for, systemic therapy in actual clinical care resemble those reported in clinical trials. Most comorbidities occur more frequently in older patients, who, in turn, may require more comprehensive overall medical care

Comparison between finite element and experimental evidences of innovative W lattice materials for sacrificial limiter applications

Power exhaust is a key mission for the realization of fusion electricity. Engineering challenges may arise from the extreme heat fluxes developed during plasma transients, above the limit offered by existing materials. These can reduce the lifetime of plasma-facing components (PFCs), imposing extraordinary maintenance, reactor safety issues and ultimately delayed return to normal operation. Concerning the EU DEMO reactor, discrete sacrificial limiters are being investigated as the last safety resource of the reactor's wall in case of unmitigated events. Within this context, micro-engineered tungsten (W) lattices are proposed to cope with unmitigated plasma disruptions. Unlike bulk W, lattices can be tailored to meet the operational requirements of the limiter, compromise between steady-state and off-design performances while avoiding overloading of the heat sink and delay the need for extraordinary maintenance. By calibrating an equivalent solid model originally developed and validated for open-cell aluminum (Al) foams, tailored lattices have been modelled and samples fabricated through additive manufacturing for characterization and testing, currently ongoing. In the present work, the thermal response of lattice samples during thermal shock high heat flux (HHF) tests performed at the linear facility QSPA Kh-50 facility is simulated using ANSYS and compared with available results. Enthalpy changes of W were imposed to simulate phase change. Good agreement with experiments and SDC-IC reference up to melting point was observed. Ultimately, a thermal quench of an unmitigated DEMO disruption was simulated involving an original MAPDL routine that removes mesh elements at the melting or vaporization point.s

The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury

Background & Aims: In vertebrates, canonical Hedgehog (Hh) pathway activation requires Smoothened (SMO) translocation to the primary cilium (Pc), followed by a GLI-mediated transcriptional response. In addition, a similar gene regulation occurs in response to growth factors/cytokines, although independently of SMO signalling. The Hh pathway plays a critical role in liver fibrosis/regeneration; however, the mechanism of activation in chronic liver injury is poorly understood. This study aimed to characterise Hh pathway activation upon thioacetamide (TAA)- induced chronic liver injury in vivo by defining Hh-responsive cells, namely cells harbouring Pc and Pc-localised SMO. Methods: C57BL/6 mice (wild-type or Ptc1+/_) were TAA-treated. Liver injury and Hh ligand/pathway mRNA and protein expression were assessed in vivo. SMO/GLI manipulation and SMO dependent/ independent activation of GLI-mediated transcriptional response in Pc-positive (Pc+) cells were studied in vitro. Results: In vivo, Hh activation was progressively induced following TAA. At the epithelial-mesenchymal interface, injured hepatocytes produced Hh ligands. Progenitors, myofibroblasts, leukocytes and hepatocytes were GLI2+. Pc+ cells increased following TAA, but only EpCAM+/GLI2+ progenitors were Pc+/SMO+. In vitro, SMO knockdown/hGli3-R overexpression reduced proliferation/viability in Pc+ progenitors, whilst increased proliferation occurred with hGli1 overexpression. HGF induced GLI transcriptional activity independently of Pc/SMO. Ptc1+/_ mice exhibited increased progenitor, myofibroblast and fibrosis responses. Conclusions: In chronic liver injury, Pc+ progenitors receive Hh ligand signals and process it through Pc/SMO-dependent activation of GLI-mediated transcriptional response. Pc/SMO-independent GLI activation likely occurs in Pc_/GLI2+ cells. Increased fibrosis in Hh gain-of-function mice likely occurs by primary progenitor expansion/proliferation and secondary fibrotic myofibroblast expansion, in close contact with progenitors

New aspects and strategies for methane mitigation from ruminants.

The growing demand for sustainable animal production is compelling researchers to explore the potential approaches to reduce emissions of greenhouse gases from livestock that are mainly produced by enteric fermentation. Some potential solutions, for instance, the use of chemical inhibitors to reduce methanogenesis, are not feasible in routine use due to their toxicity to ruminants, inhibition of efficient rumen function or other transitory effects. Strategies, such as use of plant secondary metabolites and dietary manipulations have emerged to reduce the methane emission, but these still require extensive research before these can be recommended and deployed in the livestock industry sector. Furthermore, immunization vaccines for methanogens and phages are also under investigation for mitigation of enteric methanogenesis. The increasing knowledge of methanogenic diversity in rumen, DNA sequencing technologies and bioinformatics have paved the way for chemogenomic strategies by targeting methane producers. Chemogenomics will help in finding target enzymes and proteins, which will further assist in the screening of natural as well chemical inhibitors. The construction of a methanogenic gene catalogue through these approaches is an attainable objective. This will lead to understand the microbiome function, its relation with the host and feeds, and therefore, will form the basis of practically viable and eco-friendly methane mitigation approaches, while improving the ruminant productivity

Minority and mode conversion heating in (3He)-H JET plasma

Radio frequency (RF) heating experiments have recently been conducted in JET (He-3)-H plasmas. This type of plasmas will be used in ITER's non-activated operation phase. Whereas a companion paper in this same PPCF issue will discuss the RF heating scenario's at half the nominal magnetic field, this paper documents the heating performance in (He-3)-H plasmas at full field, with fundamental cyclotron heating of He-3 as the only possible ion heating scheme in view of the foreseen ITER antenna frequency bandwidth. Dominant electron heating with global heating efficiencies between 30% and 70% depending on the He-3 concentration were observed and mode conversion (MC) heating proved to be as efficient as He-3 minority heating. The unwanted presence of both He-4 and D in the discharges gave rise to 2 MC layers rather than a single one. This together with the fact that the location of the high-field side fast wave (FW) cutoff is a sensitive function of the parallel wave number and that one of the locations of the wave confluences critically depends on the He-3 concentration made the interpretation of the results, although more complex, very interesting: three regimes could be distinguished as a function of X[He-3]: (i) a regime at low concentration (X[He-3] < 1.8%) at which ion cyclotron resonance frequency (ICRF) heating is efficient, (ii) a regime at intermediate concentrations (1.8 < X[He-3] < 5%) in which the RF performance is degrading and ultimately becoming very poor, and finally (iii) a good heating regime at He-3 concentrations beyond 6%. In this latter regime, the heating efficiency did not critically depend on the actual concentration while at lower concentrations (X[He-3] < 4%) a bigger excursion in heating efficiency is observed and the estimates differ somewhat from shot to shot, also depending on whether local or global signals are chosen for the analysis. The different dynamics at the various concentrations can be traced back to the presence of 2 MC layers and their associated FW cutoffs residing inside the plasma at low He-3 concentration. One of these layers is approaching and crossing the low-field side plasma edge when 1.8 < X[He-3] < 5%. Adopting a minimization procedure to correlate the MC positions with the plasma composition reveals that the different behaviors observed are due to contamination of the plasma. Wave modeling not only supports this interpretation but also shows that moderate concentrations of D-like species significantly alter the overall wave behavior in He-3-H plasmas. Whereas numerical modeling yields quantitative information on the heating efficiency, analytical work gives a good description of the dominant underlying wave interaction physics

Early results from GLASS-JWST. X: Rest-frame UV-optical properties of galaxies at 7 < z < 9

We present the first James Webb Space Telescope/NIRCam-led determination of $7<z<9$ galaxy properties based on broadband imaging from 0.8 to 5 microns as part of the GLASS-JWST Early Release Science program. This is the deepest dataset acquired at these wavelengths to date, with an angular resolution $\lesssim0.14$ arcsec. We robustly identify 14 galaxies with S/N>8 in F444W from 8 arcmin$^2$ of data at $m_{AB}\leq 28$ from a combination of dropout and photometric redshift selection. From simulated data modeling, we estimate the dropout sample purity to be $\gtrsim90\%$. We find that the number density of these sources is broadly consistent with expectations from the UV luminosity function determined from Hubble Space Telescope data. We characterize galaxy physical properties using a Bayesian Spectral Energy Distribution fitting method, finding median stellar mass $10^{8.7}M_\odot$ and age 130 Myr, indicating they started ionizing their surroundings at redshift $z>9.5$. Their star formation main sequence is consistent with predictions from simulations. Lastly, we introduce an analytical framework to constrain main-sequence evolution at $z>7$ based on galaxy ages and basic assumptions, through which we find results consistent with expectations from cosmological simulations. While this work only gives a glimpse of the properties of typical galaxies that are thought to drive the reionization of the universe, it clearly shows the potential of JWST to unveil unprecedented details on galaxy formation in the first billion years.Comment: Submitted to ApJL. 12 pages, 3 Figure

Early Results From GLASS-JWST. XVII: Building the First Galaxies -- Chapter 1. Star Formation Histories at 5<z < 7

JWST observations of high redshift galaxies are used to measure their star formation histories - the buildup of stellar mass in the earliest galaxies. Here we use a novel analysis program, SEDz*, to compare near-IR spectral energy distributions for galaxies with redshifts 5 < z < 7 to combinations of stellar population templates evolved from z = 12. We exploit NIRCam imaging in 7 wide bands covering 1-5 mu m, taken in the context of the GLASS-JWST-ERS program, and use SEDz* to solve for well-constrained star formation histories for 24 exemplary galaxies. In this first look we find a variety of histories, from long, continuous star formation over 5 < z < 12 to short but intense starbursts - sometimes repeating, and, most commonly, contiguous mass buildup lasting ~ 0.5 Myr,possibly the seeds of today's typical, M* galaxies.Comment: ApJL in press (accepted on October 30, 2022

Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.

Rationale: Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer. Objectives: The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors. Methods: FHIT immunostaining was performed on 305 tumor samples. Themethylation status of FHIT promoterwas assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples ofwhich a subset of 187 patients had available normal/tumorDNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers. Measurements and Main Results: Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7%of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was presentwhenmethylation and LOHwere analyzed together (P5 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P , 0.0001) and in smokers (P5 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P 5 0.0415). Conclusions:Our results indicate thatdifferentmolecularmechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease