Impaired endogenous fibrinolysis at high shear using a point-of-care test in STEMI is associated with alterations in clot architecture

© The Author(s) 2019Impaired endogenous fibrinolysis is an adverse prognostic biomarker in acute coronary syndrome (ACS). Abnormally dense in vitro fibrin thrombi have been demonstrated in ACS patients and related to hypofibrinolysis using cumbersome, laboratory-based methods. We aimed to assess endogenous fibrinolysis using a point-of-care technique and relate this to clot architecture. From patients with ST-segment elevation myocardial infarction (STEMI), venous blood was drawn immediately on arrival to assess thrombotic status. Blood was assessed using the point-of-care Global Thrombosis Test which measures occlusive thrombus formation under high shear and subsequently endogenous fibrinolysis (lysis time, LT). Two samples per patient were run in parallel. In one channel, the measurement was allowed to proceed as normal. In the other, after occlusion, thrombus was extracted, washed, fixed in glutaraldehyde, dried, sputter-coated, and assessed using scanning electron microscope. Endogenous fibrinolysis was strongly associated fibrin fibre thickness (p = 0.0001). As LT increased (less efficient fibrinolysis), the fibrin network of the thrombus was significantly more compact and dense, with thinner fibrin fibres and smaller gaps. Fibrin fibre thickness correlated inversely with LT (r = - 0.89, p = 0.001). Adverse clot architecture in vitro is directly related to impaired endogenous fibrinolysis using a relatively new point-of-care technique in patients with STEMI. This may transform the relevance of fibrin clot architecture from an off-line laboratory association to being directly relevant to endogenous fibrinolysis at the patient bedside, which could be used as a near-patient test to guide prognosis and assess the effect of treatment.Peer reviewedFinal Published versio

A Comprehensive Review of Modern Cold Chain Shipping Solutions

Packaging is one of the most important factors affecting the overall cold chain efficiency. This paper aims to examine the current trends of cold chain packaging by conducting a comprehensive review on the current commercially available cold chain shipping solutions. A conceptual model of the cold chain shipping solutions including the structure, categories and components is proposed to provide analytical comparisons with the existing literature. It is found that the shipping solutions can improve the overall cold chain performance in many aspects which include improving temperature control performance, flexibility, safety, sustainability and knowledge sharing of the cold chains. Despite all the advantages, there are still limitations and challenges posed which are also discussed. This is the first paper presenting an overview of commercially available cold chain shipping solutions. It not only contributes to the literature by presenting new knowledge but is also beneficial for all the stakeholders in cold chain packaging by providing practical information and guidelines

Characteristics, Challenges, and Opportunities of Vaccine Cold Chain

Purpose: Main attention regarding vaccine supply chain has been drawn on strategic decision level with a limited concentration on tactical and operational levels. Temperature maintenance along the vaccine supply chain remains to be one of the challenging logistical problems. The purpose of this paper is to understand the characteristics, challenges and opportunities of the vaccine cold chain today and how emerging technologies (e.g. vaccine vial monitoring, thermostable vaccines and new packaging systems) affect its development and implementations that can be done before the availability of new technologies. Design/methodology/approach: Literature review is done on the topic of vaccine cold chain, with the key search word of vaccine cold chain. Supporting resources include the official websites of the World Health Organisation (WHO) and Covid-19 vaccine manufacturers. Findings: The gap between the existing literature and the potential requirements; Trend to future research on vaccine cold chain. Research limitations/implications: Contents about strategic decision level of vaccine supply chain are excluded. Practical implications: Pending for empirical studies; Does not consider cost-effectiveness and environmental impacts on the vaccine supply chain. Originality/value: The number of vaccines has expanded in the past years due to improved immunization programs across the world, and the vaccines for the Covid-19 pandemic have the nature of high demand and pressuring time requirement, posing a need for improvement on the existing cold chain. Many existing pieces of literature on this topic are case-specific or scenario-based, and more general operation management insights are important as well, which can be beneficial to the decision-makers in the vaccine supply chain

Moisture transport by Atlantic tropical cyclones onto the North American continent

Tropical Cyclones (TCs) are an important source of freshwater for the North American continent. Many studies have tried to estimate this contribution by identifying TC-induced precipitation events, but few have explicitly diagnosed the moisture fluxes across continental boundaries. We design a set of attribution schemes to isolate the column-integrated moisture fluxes that are directly associated with TCs and to quantify the flux onto the North American Continent due to TCs. Averaged over the 2004–2012 hurricane seasons and integrated over the western, southern and eastern coasts of North America, the seven schemes attribute 7 to 18 % (mean 14 %) of total net onshore flux to Atlantic TCs. A reduced contribution of 10 % (range 9 to 11 %) was found for the 1980–2003 period, though only two schemes could be applied to this earlier period. Over the whole 1980–2012 period, a further 8 % (range 6 to 9 % from two schemes) was attributed to East Pacific TCs, resulting in a total TC contribution of 19 % (range 17 to 22 %) to the ocean-to-land moisture transport onto the North American continent between May and November. Analysis of the attribution uncertainties suggests that incorporating details of individual TC size and shape adds limited value to a fixed radius approach and TC positional errors in the ERA-Interim reanalysis do not affect the results significantly, but biases in peak wind speeds and TC sizes may lead to underestimates of moisture transport. The interannual variability does not appear to be strongly related to the El Nino-Southern Oscillation phenomenon

Exploring the Utilization of a Bayesian Network-Based Risk Management System for Cold Chain Packaging

This paper presents a comprehensive risk management model for cold chain packaging, as there is still a lack of systematic approaches to address this industry-wide issue. The proposed Bayesian network model is based on literature review and expert opinions of existing cold chain packaging systems to identify various risks and factors. The model includes various components related to the cold chain packaging system. This model can be used by stakeholders such as logistic managers and consultants to weigh the impact of each risk factor and identify potential risks that may affect the effectiveness of the cold chain system. In addition, the model can be used to evaluate the overall effectiveness of the cold chain system and suggest ways to further improve the system. The model will provide valuable insights for industry practitioners to better plan and manage cold chain packaging operations

Fatigue evaluation in maintenance and assembly operations by digital human simulation

Virtual human techniques have been used a lot in industrial design in order to consider human factors and ergonomics as early as possible. The physical status (the physical capacity of virtual human) has been mostly treated as invariable in the current available human simulation tools, while indeed the physical capacity varies along time in an operation and the change of the physical capacity depends on the history of the work as well. Virtual Human Status is proposed in this paper in order to assess the difficulty of manual handling operations, especially from the physical perspective. The decrease of the physical capacity before and after an operation is used as an index to indicate the work difficulty. The reduction of physical strength is simulated in a theoretical approach on the basis of a fatigue model in which fatigue resistances of different muscle groups were regressed from 24 existing maximum endurance time (MET) models. A framework based on digital human modeling technique is established to realize the comparison of physical status. An assembly case in airplane assembly is simulated and analyzed under the framework. The endurance time and the decrease of the joint moment strengths are simulated. The experimental result in simulated operations under laboratory conditions confirms the feasibility of the theoretical approach

Magnetic stimulation for non-homogeneous biological structures

BACKGROUND: Magnetic stimulation has gained relatively wide application in studying nervous system structures. This technology has the advantage of reduced excitation of sensory nerve endings, and hence results in quasi-painless action. It has become clinically accepted modality for brain stimulation. However, theoretical and practical solutions for assessment of induced current distribution need more detailed and accurate consideration. Some possible analyses are proposed for distribution of the current induced from excitation current contours of different shape and disposition. Relatively non-difficult solutions are shown, applicable for two- and three-dimensional analysis. METHODS: The boundary conditions for field analysis by the internal Dirichlet problem are introduced, based on the vector potential field excited by external current coils. The feedback from the induced eddy currents is neglected. Finite element modeling is applied for obtaining the electromagnetic fields distribution in a non-homogeneous domain. RESULTS: The distributions were obtained in a non-homogeneous structure comprised of homogeneous layers. A tendency was found of the induced currents to follow paths in lower resistivity layers, deviating from the expected theoretical course for a homogeneous domain. Current density concentrations occur at the boundary between layers, suggesting the possibility for focusing on, or predicting of, a zone of stimulation. CONCLUSION: The theoretical basis and simplified approach for generation of 3D FEM networks for magnetic stimulation analysis are presented, applicable in non-homogeneous and non-linear media. The inconveniences of introducing external excitation currents are avoided. Thus, the possibilities are improved for analysis of distributions induced by time-varying currents from contours of various geometry and position with respect to the medium

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site

We introduce a novel method to screen the promoters of a set of genes with shared biological function, against a precompiled library of motifs, and find those motifs which are statistically over-represented in the gene set. The gene sets were obtained from the functional Gene Ontology (GO) classification; for each set and motif we optimized the sequence similarity score threshold, independently for every location window (measured with respect to the TSS), taking into account the location dependent nucleotide heterogeneity along the promoters of the target genes. We performed a high throughput analysis, searching the promoters (from 200bp downstream to 1000bp upstream the TSS), of more than 8000 human and 23,000 mouse genes, for 134 functional Gene Ontology classes and for 412 known DNA motifs. When combined with binding site and location conservation between human and mouse, the method identifies with high probability functional binding sites that regulate groups of biologically related genes. We found many location-sensitive functional binding events and showed that they clustered close to the TSS. Our method and findings were put to several experimental tests. By allowing a "flexible" threshold and combining our functional class and location specific search method with conservation between human and mouse, we are able to identify reliably functional TF binding sites. This is an essential step towards constructing regulatory networks and elucidating the design principles that govern transcriptional regulation of expression. The promoter region proximal to the TSS appears to be of central importance for regulation of transcription in human and mouse, just as it is in bacteria and yeast.Comment: 31 pages, including Supplementary Information and figure

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research