Digitalization of industry brings new usage perspectives of digital tools as Virtual Reality (VR) and Augmented Reality (AR). However there is still open issue for integrating their usage into ...information system workflow of the industry. Therefore the paper proposes a workflow and an ontology based on the collaborators' skills to allow the authoring of AR and VR operation guide instead of paper one. The paper gives an example based on the proposed ontology.
Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although the disease can present with ...concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets.
We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis.
We performed a genome-wide association meta-analysis of 3 North-European cohorts (n = 1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP.
We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P < 5 × 10−6) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and TH2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP.
The first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.
IMPORTANCE: High-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of ...circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab. OBJECTIVE: To evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria. EXPOSURE: Serum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES: Disease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline primary outcome), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less. RESULTS: A total of 491 patients (171 women and 320 men; mean SD age, 45.7 12.8 years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of ≤1.5). CONCLUSIONS AND RELEVANCE: This real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.
This paper presents a methodology and the associated tool for enhancing decision making in shop floor layout using collaborative virtual reality, associated to real-time performance indicators in ...Industry 4.0. It first describes the collaborative architecture of the application. Subsequently, application features like: visualization at scale one (machines, industrial environment’s top view, product flow path), 3D model interaction (setting layout), physical process flow evaluation (spaghetti diagrams, Key Performance Indicators-KPI), testing multiple configurations (via save and load). Finally, paper illustrates possible usages and benefits of how VR tool helps improve ergonomics and safety; helps reduce deliberation time and bottlenecks through machine spatial footprint, visualization, scale one experience and referring KPIs.
Senescence is a tumor suppressor mechanism triggered by oncogenic stimuli and characterized by a permanent cell cycle arrest mediated by tumor suppressors such as p53, Rb and PML. PML itself is ...critical for the formation of nuclear bodies (PML bodies) that accumulate in senescent cells rendering them suitable markers for the senescence phenotype. The mechanism of PML-induction during senescence is complex and includes increased PML gene transcription by p53 or transcription factors of the interferon/Jak/Stat pathway. In turn, PML engages both p53 and Rb, although the precise molecular processes are unknown. PML interacts with the DNA-binding domain of p53 facilitating p53 modifications. PML can also interact with Rb and may play a role in Rb-dependent gene silencing during senescence. Recent studies suggest an additional connection between PML and the senescence program. Senescence involves a constitutive activation of the DNA damage response. Intriguingly, proteins that signal DNA damage or help repairing it localize to PML bodies, suggesting that PML may play a role in the DNA damage response during senescence. We think that the discovery of factors acting upstream or downstream PML may help to understand how cells bypass senescence on their way to tumorigenesis. More importantly the PML pathway may eventually lead to novel anti-cancer therapies.
Ustekinumab is an effective treatment for psoriasis, but response varies between patients. The formation of anti-drug antibodies (ADAs) may explain part of this variation by reducing the free ...ustekinumab level. Currently, published analyses of the clinical impact of ADAs are incomplete. In this observational cross-sectional multicenter study of 340 patients, we evaluated the impact of ADAs on ustekinumab level and clinical response as assessed by the PASI. Circulating ADA levels were measured using two assays: a drug-sensitive radioimmunoassay and a drug-tolerant ELISA. Circulating ustekinumab levels were measured using an ELISA. ADAs were detected in 3.8% (95% confidence interval CI = 3.2–4.2) and in 10.6% (95% CI = 7.9–13.9) of patients using the radioimmunoassay and drug-tolerant ELISA, respectively. At least 85% of the ADAs were neutralizing. Compared with patients negative for ADAs, ADA positivity in the radioimmunoassay and drug-tolerant ELISA were associated with lower median ustekinumab levels (−0.62 μg/ml 95% CI = −1.190 to −0.30 and −0.74 μg/ml 95% CI = −1.09 to −0.47, respectively) and higher absolute PASI (6.6 95% CI = 3.0–9.9 and 1.9 95% CI = 0.4–4.0, respectively). Absence of detectable ustekinumab regardless of ADA status correlated with poor clinical outcome (median sample PASI 10.1, 6.5 95% CI = 3.9–8.8 compared with patients positive for ustekinumab). In conclusion, substantially reduced drug exposure resulting from ADAs formation is associated with impaired clinical response.
This paper proposes a modeling based multi-agent system to simulate a production workshop considered as a Cyber-Physical System (CPS). A Cyber-Physical Production System (CPPS) is a fundamental ...component of Industry 4.0, which strongly influences how workshops make production and how the entire supply chain is designed, managed and supervised. Indeed, the use of systems combining physical components with other devices of computing and data processing and storage offers intelligence to these organs and opens the field of studying several problems related to the modelling of these systems and their supervision process in production workshops. In this paper, we propose a multi-agent fractal architecture to represent the workshop and its components as well as its application to the transport task in flexible production workshops.
Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Here we perform a genome-wide association analysis in the United Kingdom, comparing severe cases of acne ...(n=1,893) with controls (n=5,132). In a second stage, we genotype putative-associated loci in a further 2,063 acne cases and 1,970 controls. We identify three genome-wide significant associations: 11q13.1 (rs478304, Pcombined=3.23 × 10(-11), odds ratio (OR) = 1.20), 5q11.2 (rs38055, P(combined) = 4.58 × 10(-9), OR = 1.17) and 1q41 (rs1159268, P(combined) = 4.08 × 10(-8), OR = 1.17). All three loci contain genes linked to the TGFβ cell signalling pathway, namely OVOL1, FST and TGFB2. Transcripts of OVOL1 and TFGB2 have decreased expression in affected compared with normal skin. Collectively, these data support a key role for dysregulation of TGFβ-mediated signalling in susceptibility to acne.
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