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One-year outcomes in sepsis:a prospective multicenter cohort study in Japan
Get PDFBACKGROUND: Sepsis is a leading cause of death in intensive care units (ICU). Sepsis survivors are often left with significant morbidity, termed post-intensive care syndrome (PICS), impacting post-sepsis life. The aim was to present detailed data on the prognostic and functional long-term outcomes of ICU patients with sepsis in Japan, which is currently lacking and therefore prevents development of targeted solutions.METHODS: A multicenter prospective study, involving 21 ICUs in 20 tertiary hospitals in Japan, included all consecutive adult ICU patients between November 2020 and April 2022, and diagnosed with sepsis at ICU admission (Sepsis 3). Follow-ups were performed at 3, 6, and 12 months after hospital discharge by telephone and mail. Primary outcome was death or incidence of PICS, defined by any of physical dysfunction (Barthel Index ≤ 90), cognitive dysfunction (Short Memory Questionnaire < 40), or mental disorder (any subscales for anxiety or depression of Hospital Anxiety and Depression Scale ≥ 8, or Impact of Event Scale-Revised ≥ 25). Secondary outcomes included Quality of Life (QOL), employment, and use of hospital, emergency, rehabilitation, and psychiatric services. A multivariable analysis investigated independent factors associated with each dysfunction at each follow-up.RESULTS: A total of 339 patients were included (median age 74 [67-82] years, 60% male, 77% septic shock, and a median SOFA of 9 [6-12]). Mortality was 23% at hospital discharge, increasing to 37% at 12 months. The rate of death for those who met PICS Criteria at hospital discharge was 89%, with a death or PICS incidence of 73%, 64%, and 65% at 3, 6, and 12 months, respectively. Limited improvements in QOL and return to work (44%), high rates of hospital readmissions (40%), frequent emergency service usage (31%), and low utilization of rehabilitation and psychiatric services (15% and 7%) were identified over the first year. The incidence of any PICS-related dysfunction was consistently an independent factor for the incidence of the same dysfunction at the following follow-ups.CONCLUSIONS: This multicenter study identified the distinct realities of post-sepsis life in Japanese ICU patients, highlighting the unique challenges in improving their functions and returning to daily life. Trial Registration University Hospital Medical Information Network UMIN000041433.</p
NGOs and romanticisation of the local turn:a (re)appraisal of professional peacebuilding by NGOs in Africa
Get PDFThis article critically examines local peacebuilding programmes and approaches designed and implemented by non-governmental organisations (NGOs) in the African context. It highlights the structural and functional shortcomings inherent in peacebuilding NGOs on the continent while interrogating the implications of the romanticised ‘local turn’ paradigm in peace theory and praxis. Employing an autobiographical approach, I draw on personal experiences and both formal and informal interactions with colleagues in the sector–during and beyond my tenure as a peacebuilding practitioner–to critically assess the professionalised and project-based peacebuilding initiatives undertaken by NGOs. This methodological approach distinguishes the article from existing studies, which predominantly rely on case studies and comparative analyses. The article develops a typology of professional NGO-based peacebuilders–categorising them as ambitious, career-oriented, or sceptical–and utilises this framework to scrutinise the professionalisation and ‘NGO-isation’ of peacebuilding in Africa. In doing so, it exposes fundamental weaknesses in project-based peacebuilding programmes while also demonstrating how African peacebuilding professionals contribute to the romanticisation of the local turn in peace scholarship. Ultimately, the article underscores the urgent need to critically reassess the intertwined processes of professionalisation and ‘NGO-isation’ within peacebuilding efforts in Africa and beyond.</p
Computational analysis reveals temperature-induced stabilization of FAST-PETase
Get PDFMore than 10 % of global solid waste consists of poly(ethyleneterephthalate) (PET). Among other techniques, PET hydrolases (PETases) can be used to depolymerize this plastic. However, wildtype PETases exhibit poor specific activities and insufficient thermostability, limiting their use in depolymerization processes which require high temperatures. In 2022, machine learning-aided enzyme engineering of a PETase stemming from the bacterium Ideonella sakaiensis (IsPETase) resulted in a more functional, active, stable, and tolerant variant (FAST-PETase). To rationalize the molecular basis of FAST-PETase’s improved thermal stability, we performed comparative Constraint Network Analysis (CNAnalysis) and Molecular Dynamics (MD) simulations of wildtype IsPETase (WT-PETase) and FAST-PETase at 30°C and 50°C identifying thermolabile sequence stretches in the wildtype enzyme. Further analysis of the backbone flexibility revealed that all mutations of FAST-PETase affected these critical regions. Counterintuitively, the in-silico analyses additionally highlighted that the flexibility of these regions decreased at 50°C in FAST-PETase, instead of exhibiting increased flexibility at higher temperature as would be expected from thermodynamic considerations. This effect was confirmed by physical energy calculations, which suggest that temperature-dependent conformational changes of FAST-PETase decrease the free energy of unfolding (ΔG(stability)) and rigidify the enzyme at elevated temperatures enhancing stability. Looking forward, these findings might help guide the rational engineering of protein thermostability and contribute to our understanding of the thermal adaptation of thermophilic enzymes
Effect of Heat Treatments on the Microstructure, Corrosion Resistance and Wear Behaviour of Bainitic/Martensitic Ductile Iron Under Dry Sliding Friction
Get PDFThe development of high-strength cast irons with multiphase metal matrix structures is one of the new areas of modern materials science and mechanical engineering. This is so because of the high dissipative properties of such materials, which, in turn, ensure an improvement in their functional characteristics. It is known that one of the effective methods for obtaining alloys with a heterogeneous structure is a multi-stage heat treatment. Therefore, this study aimed to enhance the corrosion and friction properties of high-strength cast irons by combining different processing methods to create a bainite-martensitic matrix. High-strength cast irons with high ductility micro-alloyed with boron were chosen as the object for research. The experiments studied the effect of various types of multi-stage heat treatment on the structural features, tribological properties, hardness and corrosion resistance. The cast irons were quenched in water or liquid nitrogen after a controlled duration of isothermal exposure at different temperatures. It was established that cooling of isothermally hardened samples in liquid nitrogen makes it possible to effectively engineer the morphology and amount of the formed martensitic phase. It was observed that the high-strength cast irons with 10–15% lower bainite, residual austenite and martensite have the best frictional characteristics. This innovative method allowed the quenching of cast iron directly into liquid nitrogen without violent cracking
Design of peptide-based PAC1 antagonists combining molecular dynamics simulations and a biologically relevant cell-based assay
No full textThe PACAP receptor PAC1 is a Gs-coupled family B1 GPCR for which the highest-affinity endogenous peptide ligands are the pituitary adenylate cyclase-activating peptides PACAP38 and PACAP27, and whose most abundant endogenous ligand is PACAP38. PACAP action at PAC1 is implicated in neuropsychiatric disorders, atherosclerosis, pain chronification, and protection from neurodegeneration and ischemia. As PACAP also interacts with two related receptors, VPAC1 and VPAC2, highly selective ligands, both agonists and antagonists, for PAC1 have been sought. To date, the peptide PACAP(6-38) and polypeptide M65, which is related to maxadilan, a sandfly vasodilator peptide, have been identified as selective for PAC1. Several non-peptide small molecule compounds (SMOLs) have been reported to be specific antagonists at PAC1, albeit their specificities have not been rigorously documented. Here, we present a platform of cellular assays for the screening of biologically relevant antagonists at PAC1 and show that some currently proposed SMOL antagonists do not have activity in this cell reporter assay, while we confirm that PACAP(6-38) and M65 are competitive antagonists. We have used this assay system to explore other peptide antagonists at PAC1, guided by molecular dynamics analysis of the PACAP-PAC1 interaction based on cryo-EM structural models of PAC1 complexed with a number of biologically active ligands. The affinity-trap model for the PAC1-ligand interaction successfully predicts the engagement behavior of PACAP27 and PACAP38 peptide-based PAC1 inhibitors. In particular, C-terminal deletants of PACAP(6-38) that maintain equipotency to PACAP(6-38) allow the shorter sequence to function as a scaffold for further peptide-based antagonist exploration
A Causal Analysis of the Plots of Intelligent Adversaries
No full textIn this paper we demonstrate a new advance in causal Bayesian graphical modelling combined with Adversarial Risk Analysis. This research aims to support strategic analyses of various defensive interventions to counter the threat arising from plots of an adversary. These plots are characterised by a sequence of preparatory phases that an adversary must necessarily pass through to achieve their hostile objective. To do this we first define a new general class of plot models. Then we demonstrate that this is a causal graphical family of models - albeit with a hybrid semantic. We show this continues to be so even in this adversarial setting. It follows that this causal graph can be used to guide a Bayesian decision analysis to counter the adversary's plot. We illustrate the causal analysis of a plot with details of a decision analysis designed to frustrate the progress of a planned terrorist attack
Navigating the EU AI Act: A Practical Guide for Global Manufacturing and Engineering Leaders
No full textThis book is an essential guide for manufacturers and engineers navigating AI compliance and governance. Artificial intelligence is revolutionising manufacturing and engineering, but with rapid progress, comes greater levels of responsibility and regulatory scrutiny. The EU AI Act is a landmark regulation shaping how businesses develop and deploy AI. Written by Professor Marcos Kauffman, an expert in technology and innovation management, this book provides a practical roadmap to achieving compliance while driving innovation. It covers:AI Risk Classification: Understanding prohibited, high-risk, limited-risk, and minimal-risk AI applications.Regulatory Alignment: Implementing conformity assessments, governance frameworks, and human oversight mechanisms.Industry Case Studies: Lessons from AI in automotive, aerospace, and industrial automation.Technology-Driven Compliance: Leveraging AI auditing tools and compliance dashboards.With step-by-step strategies, real-world examples, and insights from industry leaders, this book transforms compliance from a regulatory burden into an opportunity for innovation and competitive advantage. Whether you are a CTO, engineer, or just starting to apply AI in your business context, this book equips you with the tools to responsibly integrate AI into manufacturing and engineering
Interaction between 3-SNP genetic risk score and dietary fats intake on inflammatory markers among overweight and obese women
No full textThis study, for the first time, sought to investigate whether the interaction between the GRS consists of three SNPs (CAV-1, CRY-1, MC4R) and fat intake is associated with inflammatory markers among Iranian overweight and obese women. This cross-sectional study was conducted with 246 overweight and obese women, aged 18-48 years. Three SNPs, including CAV-1 rs3807992, CRY-1 rs2287161, and MC4R rs17782313, were genotyped using PCR-RFLP to calculate the genetic risk score (GRS) for each participant. Dietary fat intake was measured using a validated semi-quantitative food frequency questionnaire (FFQ). C-reactive protein (CRP), interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and Galectin-3 (Gal-3) were assessed as the primary outcomes of the study. After controlling for confounding variables, a significant interaction between high total fat intake and high GRS, compared to the reference group, was found for TGF-β level ( -value: 0.028). A significant positive interaction between high GRS and high intakes of SFA intake ( -value: 0.013). A significant interaction between high GRS and high intakes of MUFA, compared to the reference group, was found for ghrelin level ( -value: 0.040) and MCP-1 level ( -value: 0.075). There was a significant interaction between high GRS and intakes of DHA, compared to the reference group, for Gal-3 level ( -value: 0.013) MCP-1 level ( -value: 0.020). Consuming different types of fats can influence the interaction between GRS and inflammatory markers, suggesting further research is needed to fully understand this relationship. The online version contains supplementary material available at 10.1007/s40200-024-01542-z. [Abstract copyright: © The Author(s), under exclusive licence to Tehran University of Medical Sciences 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.