Fractal dimension (df) as a new structural biomarker of clot microstructure in different stages of lung cancer

Venous thromboembolism (VTE) is common in cancer patients, and is the second commonest cause of death associated with the disease. Patients with chronic inflammation, such as cancer, have been shown to have pathological clot structures with modulated mechanical properties. Fractal dimension (df) is a new technique which has been shown to act as a marker of the microstructure and mechanical properties of blood clots, and can be performed more readily than current methods such as scanning electron microscopy (SEM). We measured df in 87 consecutive patients with newly diagnosed lung cancer prior to treatment and 47 matched-controls. Mean group values were compared for all patients with lung cancer vs controls and for limited disease vs extensive disease. Results were compared with conventional markers of coagulation, fibrinolysis and SEM images. Significantly higher values of df were observed in lung cancer patients compared with controls and patients with extensive disease had higher values than those with limited disease (p< 0.05), whilst conventional markers failed to distinguish between these groups. The relationship between df of the incipient clot and mature clot microstructure was confirmed by SEM and computational modelling: higher df was associated with highly dense clots formed of smaller fibrin fibres in lung cancer patients compared to controls. This study demonstrates that df is a sensitive technique which quantifies the structure and mechanical properties of blood clots in patients with lung cancer. Our data suggests that df has the potential to identify patients with an abnormal clot micro-structure and greatest VTE risk

The Effects of Temperature on Clot Microstructure and Strength in Healthy Volunteers

BACKGROUND: Anesthesia, critical illness, and trauma are known to alter thermoregulation, which can potentially affect coagulation and clinical outcome. This in vitro preclinical study explores the relationship between temperature change and hemostasis using a recently validated viscoelastic technique. We hypothesize that temperature change will cause significant alterations in the microstructural properties of clot. METHODS: We used a novel viscoelastic technique to identify the gel point of the blood. The gel point identifies the transition of the blood from a viscoelastic liquid to a viscoelastic solid state. Furthermore, identification of the gel point provides 3 related biomarkers: the elastic modulus at the gel point, which is a measure of clot elasticity; the time to the gel point (TGP), which is a measure of the time required to form the clot; and the fractal dimension of the clot at the gel point, df, which quantifies the microstructure of the clot. The gel point measurements were performed in vitro on whole blood samples from 136 healthy volunteers over a temperature range of 27°C to 43°C. RESULTS: There was a significant negative correlation between increases in temperature, from 27°C to 43°C, and TGP (r = −0.641, P 37°C. CONCLUSIONS: This study demonstrates that the gel point technique can identify alterations in clot microstructure because of changes in temperature. This was demonstrated in slower-forming clots with less structural complexity as temperature is decreased. We also found that significant changes in clot microstructure occurred when the temperature was ≤32°C

An investigation into the effects of in vitro dilution with different colloid resuscitation fluids on clot microstructure formation

BACKGROUND: Balancing the beneficial effects of resuscitation fluids against their detrimental effect on hemostasis is an important clinical issue. We aim to compare the in vitro effects of 3 different colloid resuscitation fluids (4.5% albumin, hydroxyethyl starch [Voluven 6%], and gelatin [Geloplasma]) on clot microstructure formation using a novel viscoelastic technique, the gel point. This novel hemorheologic technique measures the biophysical properties of the clot and provides an assessment of clot microstructure from its viscoelastic properties. Importantly, in contrast to many assays in routine clinical use, the measurement is performed using unadulterated whole blood in a near-patient setting and provides rapid assessment of coagulation. We hypothesized that different colloids will have a lesser or greater detrimental effect on clot microstructure formation when compared against each other. METHODS: Healthy volunteers were recruited into the study (n = 104), and a 20-mL sample of whole blood was obtained. Each volunteer was assigned to 1 of the 3 fluids, and the sample was diluted to 1 of 5 different dilutions (baseline, 10%, 20%, 40%, and 60%). The blood was tested using the gel point technique, which measures clot mechanical strength and quantifies clot microstructure (d f) at the incipient stages of fibrin formation. RESULTS: d f and clot mechanical strength decrease with progressive dilution for all 3 fluids. A significant reduction in d f from baseline was recorded at dilutions of 20% for albumin (P < .0001), 40% for starch (P < .0001), and 60% for gelatin (P < .0001). We also observed significant differences, in terms of d f, when comparing the different types of colloid (P < .0001). We found that albumin dilution produced the largest changes in clot microstructure, providing the lowest values of d f (= 1.41 ± 0.061 at 60% dilution) compared with starch (1.52 ± 0.081) and gelatin (1.58 ± 0.063). CONCLUSIONS: We show that dilution with all 3 fluids has a significant effect on coagulation at even relatively low dilution volumes (20% and 40%). Furthermore, we quantify, using a novel viscoelastic technique, how the physiochemical properties of the 3 colloids exert individual changes on clot microstructure

The effect of sepsis and its inflammatory response on mechanical clot characteristics: a prospective observational study

Purpose: Sepsis and its progression are known to have a major influence on the coagulation system. Current coagulation tests are of limited use when assessing coagulation in sepsis patients. This study aims to assess the potential for a new functional biomarker of clot microstructure, fractal dimension, to identify changes in the mechanical properties of clot microstructure across the sepsis spectrum (sepsis, severe sepsis and septic shock). Methods: A total of 100 patients that presented acutely to a large teaching hospital were included in this prospective observational study (50 sepsis, 20 severe sepsis and 30 septic shock) against a matched control of 44 healthy volunteers. Fractal analysis was performed, as well as standard markers of coagulation, and six plasma markers of inflammation. Results: Fractal dimension was significantly higher in the sepsis and severe sepsis groups than the healthy control (1.78 ± 0.07 and 1.80 ± 0.05 respectively vs 1.74 ± 0.03) (p < 0.001), indicating a significant increase in mechanical clot strength and elasticity consistent with a hypercoagulable state. Conversely, fractal dimension was significantly lower in septic shock (1.66 ± 0.10, p < 0.001), indicating a significant reduction in mechanical clot strength and functionality consistent with a hypocoagulable state. This corresponded with a significant increase in the inflammatory response. Conclusions: This study confirms that clot microstructure is significantly altered through the various stages of sepsis. Of particular importance was the marked change in clot development between severe sepsis and septic shock, which has not been previously reported

The UK Burden of Injury Study – a protocol. [National Research Register number: M0044160889]

<p>Abstract</p> <p>Background</p> <p>Globally and nationally large numbers of people are injured each year, yet there is little information on the impact of these injuries on people's lives, on society and on health and social care services. Measurement of the burden of injuries is needed at a global, national and regional level to be able to inform injured people of the likely duration of impairment; to guide policy makers in investing in preventative measures; to facilitate the evaluation and cost effectiveness of interventions and to contribute to international efforts to more accurately assess the global burden of injuries.</p> <p>Methods/Design</p> <p>A prospective, longitudinal multi-centre study of 1333 injured individuals, atttending Emergency Departments or admitted to hospital in four UK areas: Swansea, Surrey, Bristol and Nottingham. Specified quotas of patients with defined injuries covering the whole spectrum will be recruited. Participants (or a proxy) will complete a baseline questionnaire regarding their injury and pre-injury quality of life. Follow up occurs at 1, 4, and 12 months post injury or until return to normal function within 12 months, with measures of health service utilisation, impairment, disability, and health related quality of life. National estimates of the burden of injuries will be calculated by extrapolation from the sample population to national and regional computerised hospital in-patient, emergency department and mortality data.</p> <p>Discussion</p> <p>This study will provide more detailed data on the national burden of injuries than has previously been available in any country and will contribute to international collaborative efforts to more accurately assess the global burden of injuries. The results will be used to advise policy makers on prioritisation of preventive measures, support the evaluation of interventions, and provide guidance on the likely impact and degree of impairment and disability following specific injuries.</p

The Role of Whole Blood Impedance Aggregometry and Its Utilisation in the Diagnosis and Prognosis of Patients with Systemic Inflammatory Response Syndrome and Sepsis in Acute Critical Illness

Objective: To assess the prognostic and diagnostic value of whole blood impedance aggregometry in patients with sepsis and SIRS and to compare with whole blood parameters (platelet count, haemoglobin, haematocrit and white cell count). Methods: We performed an observational, prospective study in the acute setting. Platelet function was determined using whole blood impedance aggregometry (multiplate) on admission to the Emergency Department or Intensive Care Unit and at 6 and 24 hours post admission. Platelet count, haemoglobin, haematocrit and white cell count were also determined. Results: 106 adult patients that met SIRS and sepsis criteria were included. Platelet aggregation was significantly reduced in patients with severe sepsis/septic shock when compared to SIRS/uncomplicated sepsis (ADP: 90.7±37.6 vs 61.4±40.6; p<0.001, Arachadonic Acid 99.9±48.3 vs 66.3±50.2; p = 0.001, Collagen 102.6±33.0 vs 79.1±38.8; p = 0.001; SD ± mean)). Furthermore platelet aggregation was significantly reduced in the 28 day mortality group when compared with the survival group (Arachadonic Acid 58.8±47.7 vs 91.1±50.9; p<0.05, Collagen 36.6±36.6 vs 98.0±35.1; p = 0.001; SD ± mean)). However haemoglobin, haematocrit and platelet count were more effective at distinguishing between subgroups and were equally effective indicators of prognosis. Significant positive correlations were observed between whole blood impedance aggregometry and platelet count (ADP 0.588 p<0.0001, Arachadonic Acid 0.611 p<0.0001, Collagen 0.599 p<0.0001 (Pearson correlation)). Conclusions: Reduced platelet aggregometry responses were not only significantly associated with morbidity and mortality in sepsis and SIRS patients, but also correlated with the different pathological groups. Whole blood aggregometry significantly correlated with platelet count, however, when we adjust for the different groups we investigated, the effect of platelet count appears to be non-significant

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

The DOE E3SM Coupled Model Version 1: Overview and Evaluation at Standard Resolution

This work documents the first version of the U.S. Department of Energy (DOE) new Energy Exascale Earth System Model (E3SMv1). We focus on the standard resolution of the fully coupled physical model designed to address DOE mission-relevant water cycle questions. Its components include atmosphere and land (110-km grid spacing), ocean and sea ice (60 km in the midlatitudes and 30 km at the equator and poles), and river transport (55 km) models. This base configuration will also serve as a foundation for additional configurations exploring higher horizontal resolution as well as augmented capabilities in the form of biogeochemistry and cryosphere configurations. The performance of E3SMv1 is evaluated by means of a standard set of Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima simulations consisting of a long preindustrial control, historical simulations (ensembles of fully coupled and prescribed SSTs) as well as idealized CO2 forcing simulations. The model performs well overall with biases typical of other CMIP-class models, although the simulated Atlantic Meridional Overturning Circulation is weaker than many CMIP-class models. While the E3SMv1 historical ensemble captures the bulk of the observed warming between preindustrial (1850) and present day, the trajectory of the warming diverges from observations in the second half of the twentieth century with a period of delayed warming followed by an excessive warming trend. Using a two-layer energy balance model, we attribute this divergence to the model’s strong aerosol-related effective radiative forcing (ERFari+aci = -1.65 W/m2) and high equilibrium climate sensitivity (ECS = 5.3 K).Plain Language SummaryThe U.S. Department of Energy funded the development of a new state-of-the-art Earth system model for research and applications relevant to its mission. The Energy Exascale Earth System Model version 1 (E3SMv1) consists of five interacting components for the global atmosphere, land surface, ocean, sea ice, and rivers. Three of these components (ocean, sea ice, and river) are new and have not been coupled into an Earth system model previously. The atmosphere and land surface components were created by extending existing components part of the Community Earth System Model, Version 1. E3SMv1’s capabilities are demonstrated by performing a set of standardized simulation experiments described by the Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima protocol at standard horizontal spatial resolution of approximately 1° latitude and longitude. The model reproduces global and regional climate features well compared to observations. Simulated warming between 1850 and 2015 matches observations, but the model is too cold by about 0.5 °C between 1960 and 1990 and later warms at a rate greater than observed. A thermodynamic analysis of the model’s response to greenhouse gas and aerosol radiative affects may explain the reasons for the discrepancy.Key PointsThis work documents E3SMv1, the first version of the U.S. DOE Energy Exascale Earth System ModelThe performance of E3SMv1 is documented with a set of standard CMIP6 DECK and historical simulations comprising nearly 3,000 yearsE3SMv1 has a high equilibrium climate sensitivity (5.3 K) and strong aerosol-related effective radiative forcing (-1.65 W/m2)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151288/1/jame20860_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151288/2/jame20860.pd