Low TF Research Articles

Freeze-Vulnerable Plastic Crystal to Cryogenic Liquid Electrolyte for Lithium Batteries by Deep Freezing-Point Depression.

Low-Tf solvents (Tf = freezing point) are considered and employed for low-temperature lithium-ion battery (LIB) electrolytes to keep electrolytes in the liquid phase at low temperatures. Unfortunately, Tf is synchronized with Tb (boiling point) so low Tf brings Tb down and therefore discourages the thermal stability of electrolytes using low-Tf solvents. In this work, 1) the hot wing of LIB-working temperature by employing a high-Tb (inevitably high-Tf) solvent and 2) the cold wing by using a significant Tf depression is secured. Sulfolane is employed as the high-Tf (therefore, high-Tb) and high-Kf (Kf = cryoscopic constant) solvent since its mesomorphic state between solid and liquid. That abnormally and significantly decreases the enthalpy of fusion, and resultantly grants extremely high Kf at 66.4Km-1. By employing sulfolane with 2m lithium bis(trifluoromethanesulfonyl)imide (LiTFSI), the liquid-phase temperature window down to <-80°C for the cold wing and simultaneously guaranteed its flash point at >+150°C for the hot wing is successfully extended. LIB cells with lithium iron phosphate and lithium metal worked in a good stand with 2m LiTFSI/sulfolane at room temperature, -30°C as an ambient cold, -74°C as a deep cold, and +80°C as a deep hot.

Effect of longitudinal ctDNA monitoring with resistance genomic signatures on prognostication in patients with EGFR-mutated advanced NSCLC.

e20507 Background: Targeted therapies against activating receptor tyrosine kinases (TKi) (EGFR, ALK, ROS) mutations have significantly improved the SOC in NSCLC. Although mutant EGFR (mEGFR) targeting TKi show survival benefits, their efficacy is contingent upon the presence of de novo or emergent TKi mutations. A comprehensive gene panel (CGP) designed to detect a multitude of actionable and resistance signatures may enhance informed treatment decisions and outcome. Additionally, longitudinal monitoring of a patient may help to monitor the dynamics (disappearance/emergence) of actionable or resistance-conferring gene alterations for timely decisions on therapy alterations. Methods: In prospective clinical trial, ctDNA was evaluated at multipoint and longitudinally in 75 advanced NSCLC patients. On average 06 samples were collected from each patient at treatment initiation (baseline) and subsequently during maturation until one year. Libraries were prepared using a hybridization-capture method based on custom-designed OncoIndx 1080 CGP and sequenced (depth 5500 X) on Illumina Nextseq 2000 in a pair-end mode (150 x2). Variant calling was performed using a proprietary bioinformatics pipeline iCare. Results: Patients with mEGFR (exon 19 deletion and L858R variants) at the baseline, 60 % were accompanied by resistance signature of one or multiple pathogenic mutations in downstream components (PIK3CA, mTOR, PTEN, BRAF) of EGFR pathway, or other receptor TKs (ROS1, ERBB3, MET and RET), while 36 % showed presence of concurrent pathogenic TP53, RB1 or NF2 variants. Nearly 58 % of patients were clinically Non-respondent (NR) while the rest were Responders (R). Patients carrying resistance signatures at the treatment initiation and subsequently during treatment maturation showed dismal PFS (median 10.4 months, P &lt; 0.0001, HR:9.4, CI:3.2-27) and OS (median 10.4 months, P = 0.0004, HR:14.8, CI:4.7-46) compared to population without resistant signatures. Prevalence of resistant signatures at the baseline was highly enriched in the NR population (90 %), compared to the R population (20 %). Multivariate analysis indicated the presence of resistant signatures as an independent bad prognosticator (HR:8.4, CI: 2.8-12.4, P &lt; 0.0001). Tumor fraction value (TF) correlated well with clinical endpoints (AUC = 0.97, &lt; 0.0001), high TF value (cutoff 0.3) showed shorter OS compared to pts with low TF (HR:10, CI: 3.8-29.4, P &lt; 0.0001, median = 21.3 months). Conclusions: Inclusion of CGP as a standard of care may help to stratify patients who are EGFR positive yet may not respond to TKi due to the presence of resistance signatures, and provide the benefit of Tx modification. Longitudinal monitoring of ctDNA in advanced NSCLC patients showed distinct mutational signatures in the R and NR populations.

Processing temperature-dependent nucleation and growth behaviors of polypropylene nucleated by a bisamide nucleating agent

It has been widely reported that the processing temperature significantly influenced the effectiveness of a β-nucleating agent (β-NA) in polypropylene (PP) and thus leads to variations in the final relative content of β-phase (kβ). To comprehensively understand the changing kβ with processing temperature, PP nucleated by a bisamide β-NA, N,N′-dicyclohexylterephthalamide (DCHT), was heating-treated at different temperatures (Tf) in the range of 200–250 °C, and the impact of Tf on the nucleation and subsequent growth behaviors of the α- and β-phases were separately investigated. Under low Tf, DCHT induced a high relative density of β-nuclei to α-nuclei (Nβ/Nα) with high total nucleation density (N), and both the α- and β-phases grew competitively until the crystallization ended. Under middle Tf, the Nβ/Nα became low with middle N induced by DCHT, and the faster-growing phase dominated the subsequent growth process. Under high Tf, there was a middle Nβ/Nα with low N, and the faster-growing phase became more dominant during the growth process. Based on the observed morphology of DCHT, the decreasing N with Tf could be associated with the specific surface area, the varying Nβ/Nα could be attributed to the variations in both the energy barrier and the surface area of β-nucleation under diverse DCHT morphologies, and the varying growth behavior was probably associated with the outer surface shape of diverse DCHT morphologies. Combining the thorough analysis of the changing nucleation and growth behaviors with Tf, a possible mechanism was proposed to explain the effect of processing temperature on the final polymorphic composition.

Tissue factor pathway-related biomarkers in liver cancer: activated factor VII–antithrombin complex and tissue factor mRNA levels are associated with mortality

BackgroundTissue factor (TF), the main initiator of the coagulation cascade, plays a role in cancer progression and prognosis. Activated factor VII–antithrombin complex (FVIIa-AT) is considered an indirect marker of TF exposure by reflecting TF-FVIIa interaction. ObjectivesTo assess the link between FVIIa-AT plasma levels, TF messenger RNA (mRNA) expression, and survival in cancer. MethodsTF pathway–related coagulation biomarkers were assessed in 136 patients with cancer (52 with hepatocellular carcinoma, 41 with cholangiocarcinoma, and 43 with colon cancer) undergoing surgical intervention with curative intent. TF mRNA expression analysis in neoplastic vs nonneoplastic liver tissues was evaluated in a subgroup of 91 patients with primary liver cancer. ResultsFVIIa-AT levels were higher in patients with cancer than in 136 sex- and age-matched cancer-free controls. In patients with cancer, high levels of FVIIa-AT and total TF pathway inhibitor were associated with an increased mortality risk after adjustment for confounders, but only FVIIa-AT remained a predictor of mortality by including both FVIIa-AT and total TF pathway inhibitor in Cox regression (hazard ratio, 2.80; 95% CI, 1.23-6.39; the highest vs the lowest quartile). This association remained significant even after adjustment for extracellular vesicle–associated TF-dependent procoagulant activity. In the subgroup of patients with primary liver cancer, patients with high TF mRNA levels had an increased mortality risk compared with that for those with low TF mRNA levels (hazard ratio, 1.92; 95% CI, 1.03-3.57), and there was a consistent correlation among high FVIIa-AT levels, high TF mRNA levels, and increased risk of mortality. ConclusionHigh FVIIa-AT levels may allow the identification of patients with cancer involving high TF expression and predict a higher mortality risk in liver cancer.

Women with severe postpartum hemorrhage have a decreased endogenous thrombin potential before delivery

BackgroundSevere postpartum hemorrhage (PPH), defined as a blood loss ≥1000 mL, is associated with maternal morbidity and mortality. ObjectivesWe aimed at characterizing coagulation properties of predelivery plasmas from pregnant women with thrombin generation assay and hemostatic biomarkers (plasminogen activator inhibitor-1, tissue factor [TF], and thrombomodulin). MethodsA nested case-control study was conducted within the “Study of Biological Determinants of Bleeding Postpartum,” a French prospective cohort study, in order to compare women with severe PPH (cases) and controls matched for age, body mass index, term, and mode of delivery. Plasma was collected at entry in the delivery room, and blood loss was measured objectively. The predelivery endogenous thrombin generation potential (ETP) was measured in plasma using calibrated automated thrombinography and low TF concentration. Hemostatic biomarkers were measured using ELISA kits. ResultsA total of 142 women (71 cases and 71 controls) were investigated. There was no difference in the median lag phase, thrombin peak, and time to peak between cases and controls. However, median predelivery ETP was lower in cases than in controls (2170 vs 2408 nM.min, P < .0001), independently of mode of delivery and PPH etiology. Median plasminogen activator inhibitor-1 and TF levels were higher in cases compared with controls (107.4 vs 68.1 ng/mL, P = .0003; 34.4 vs 27.4 pg/mL, P = .007), whereas thrombomodulin levels did not differ between the 2 groups. ConclusionAmong thrombin generation assay parameters, predelivery ETP levels may have a predictive value for severe PPH.

A Nonflammable Organic Electrolyte with a Weak Association State for Zinc Batteries Operated at −78.5 °C

AbstractTraditional rechargeable Zn batteries fail to work in cold regions due to the high freezing point (Tf) and severe corrosivity of the aqueous electrolytes with excessive association (solvent‐solvent and solute‐solvent interactions). In this study, a nonflammable weak‐associated electrolyte (WASE) consisting of ZnCl2 salt and methanol/dichloromethane mixture as a solvent is developed to achieve high reversible Zn plating/stripping at low temperatures. The low self‐association interaction of the mixed solvent not only endures WASE with a low Tf of −119.2 °C but also facilitates the desolvation of interfacial Zn2+ and induces smooth Zn plating at low temperatures. Moreover, the water‐free WASE inhibits the hydrolysis of ZnCl2 and thus restrains the corrosion of Zn electrodes. Thanks to the above merits, the Zn||Zn, Zn||Cu, and Zn||polyaniline cells with WASE exhibit superb electrochemical performance at temperatures as low as −78.5 °C.

Rejuvenation to relaxation transition and liquid memory effect in La-based metallic glasses with different energy states

Rejuvenation of metallic glasses (MGs) under cryogenic thermal cycling (CTC) has been intensively studied due to its great theoretical and practical value. However, the relationship between energy states of MGs and rejuvenation capacity is still unclear. Here, a systematic study is performed on how the initial state of MGs affects the rejuvenation effect, and the difference in the initial state of MGs is mainly depicted by the fictive temperature Tf, as well as mechanical properties. A “rejuvenation to relaxation” transition upon Tf increasing is found among samples, and the critical energy state (Tf,c∼1.1Tg) at which the transition occurs are further determined. The transition towards relaxation above Tf,c is attributed to the first CTC intervention of the local structures that are smaller than structural units involved in slow β-relaxations. Besides, the CTC-induced recovery of MGs with a low Tf towards high temperature supercooled liquids has been found, and this behavior relates to the memory effect of MGs upon cooling process. When the liquid memory of MGs is awakened by CTC, the recovery to higher energy state (rejuvenation) occurs. This work supplements rejuvenation mechanism of MGs with different initial states, and provides a possibility to predict the evolution direction (rejuvenation or relaxation) of MGs by their energy states (or Tf).

Mechanism of accelerated concurrent flame spread over glass fiber reinforced unsaturated polyester resin composites with ATH/MH retardants under external radiation

This paper reports an experimental investigation of concurrent flame spread over composites, for the first time, with combined flame retardants and external radiation factors. Glass fiber reinforced unsaturated polyester resins without flame retardants (GFUPR) as well as those containing aluminum hydroxide (ATH) and magnesium hydroxide (MH), which were utilized widely in modern high-speed train, were systematically explored. Infrared measurement was employed to track the displacement of pyrolysis front. Because of the dilution of H2O generated during the decomposition of ATH and MH, the flame temperature (Tf) of GFUPR-ATH/MH is thought to be lower than that of GFUPR. Nonetheless, the most noteworthy finding is that the flame spread rate, flame preheat length and flame height for GFUPR-ATH/MH could be larger than that of GFUPR if concurrent airflow velocity exceeds 0.5 m/s under high external radiation. To interpret this unexpected while practically important phenomena, theoretical analysis based on the heat/mass transfer theory is established to explore the general mechanism. It is concluded that in the transition from natural-convection to forced-convection, the different in the flame convection in burning zone between the sample with high Tf (i.e. GFUPR) and the sample with low Tf (i.e. GFUPR-ATH/MH), will decrease rapidly. It is primarily because the sample with low Tf is earlier to enter in the region where forced-convection is controlled as the airflow velocity increases. The critical parameter (Fr2Re)-1 = 1 could be used to characterize this transition. As a result, in forced-convection region, the role of thermal conductivity of the fuel-gas mixture (kmix) may emerge, that the sample with high kmix but low Tf (i.e. GFUPR-ATH/MH) may impart more heat to burning zone than the sample with low kmix but high Tf (i.e. GFUPR), generating more combustible gases in the burning zone hence larger flame heat feedback to preheat zone. Moreover, this effect will be reinforced by the larger flame preheat length of GFUPR-ATH/MH, due to the temperature dependency of molecular diffusivity. This mechanism analysis is well corroborated by the experimental results. This new finding may facilitate understanding of the effect of flame retardants on the heat/mass transfer mechanism in flame spread under concurrent airflow and external radiation.

Phytotoxicity and accumulation of BPS to Pistia stratiotes under the influence of microplastics

Bisphenol S (BPS) is a contaminant of emerging concern, its exposure and phytotoxicity towards plants, however, is scarce. This study aimed at revealing the BPS translocation in plants and phytotoxicity in the presence of Polystyrene (PS) microplastics. Results found that BPS and PS showed no effect on plant growth, indicating the tolerance of plants towards BPS and PS co-contamination. In addition, plants enriched BPS from soil, and a major part of absorbed BPS was accumulated in roots, as supported by the higher BCF value in roots compared with leaves. Besides, the low TF (<1) suggested the capacity of plants to accumulate BPS in roots, and less translocation to leaves. PS negatively affected the translocation of BPS in plants. PS with large size (5 μm) also increased the distribution of BPS in organelles. Exposure risk assessment suggested low concern of BPS carried in plants to human health. This study underlines the bioaccumulation of BPS in plants, and the effects of PS in the translocation process.

Expression of Transferrin Protein and Messenger RNA in Neural Cells from Mouse and Human Brain Tissue.

Iron is an essential nutrient in the body. However, iron generates oxidative stress and hence needs to be bound to carrier proteins such as the glycoprotein transferrin (Tf) in body fluids. We previously reported that cerebrospinal fluid contains Tf glycan-isoforms that are derived from the brain, but their origins at the cellular level in the brain have not yet been elucidated. In the present report, we described the localization of Tf protein and mRNA in mouse and human brain tissue. In situ hybridization of mouse brain tissue revealed that Tf mRNA is expressed by different cell types such as epithelial cells in the choroid plexus, oligodendrocyte-like cells in the medulla, and neurons in the cortex, hippocampus, and basal ganglia. In contrast, Tf protein was barely detected by immunohistochemistry in hippocampal and some cortical neurons, but it was detected in other types of cells such as oligodendrocyte-like cells and choroid plexus epithelial cells. The results showed that Tf mRNA is expressed by neural cells, while Tf protein is expressed in different brain regions, though at very low levels in hippocampal neurons. Low Tf level in the hippocampus may increases susceptibility to iron-induced oxidative stress, and account for neuron death in neurodegenerative diseases.

Advanced cell therapy with low tissue factor loaded product NestaCell® does not confer thrombogenic risk for critically ill COVID-19 heparin-treated patients

Since the COVID-19 pandemic started, mesenchymal stromal cells (MSC) appeared as a therapeutic option to reduce the over-activated inflammatory response and promote recovery of lung damage. Most clinical studies use intravenous injection for MSC delivery, raising several concerns of thrombogenic risk due to MSC procoagulant activity (PCA) linked to the expression of tissue factor (TF/CD142). This is the first study that demonstrated procoagulant activity of TF+ human immature dental pulp stromal cells (hIDPSC, NestaCell® product) with the percentage of TF+ cells varied from 0.2% to 63.9% in plasma of healthy donors and COVID-19 heparin-treated patients. Thrombogenic risk of TF+ hIDPSCs was evaluated by rotational thromboelastometry (in vitro) and in critically ill COVID-19 patients (clinical trial). We showed that the thromboelastography is not enough to predict the risk of TF+ MSC therapies. Using TF-negative HUVEC cells, we demonstrated that TF is not a unique factor responsible for the cell's procoagulant activity. However, heparin treatment minimizes MSC procoagulant (in vitro). We also showed that the intravenous infusion of hIDPSCs with prophylactic enoxaparin administration in moderate to critically ill COVID-19 patients did not change the values of D-dimer, neither in the PT and PTT times. Our COVID-19 clinical study measured and selected the therapeutic cells with low TF (less than 25% of TF+ hIDPSCs). Our data indicate that the concomitant administration of enoxaparin and low TF-loaded is safe even for critically ill COVID-19 patients.

Experimental study and modelling of the thermal conductivity of frozen sandy soil at different water contents

In a wide range of earthworks and engineering applications such as ground heat exchanger piles and energy piles, radioactive waste disposal in deep underground locations, installation of underground power cables, etc., a better understanding of soil thermal conductivity is required in cold regions. The thermal conductivity (λ) of frozen sandy soils in eastern Turkey was measured for five volumetric water contents (θ = 0.219, 0.230, 0.246, 0.260, and 0.320 m3/ m3) at six frozen temperatures (Tf = 4, 0, −7, −12, −20 and −25 °C). Moreover, six proposed models were analyzed to determine the λ. The results demonstrated that a decrease in the Tf increased the λ and reached a plateau at a very low Tf for all θ. Increasing the θ increases the λ at the same Tf. Also, the de Vries model provided for the highest precision, followed by the Chen, the Parallel, the Johansen, the Cote and Konrad, and the serial models, respectively. Further, the changes of volume in the soil were incorporated into the parallel and series models, and a new model was developed to estimate the λ of the frozen soil. The new model can be effectively used to estimate the λ.

High-performance colossal permittivity behaviour persists to ultralow temperature in Co+Ta co-doped SnO2: A spin-defect mediated superstable large electronic moment of defect-dipole

Recently, defect complex coupling in nonmagnetic acceptor-donor co-doped binary metal oxides is found to partially localize the donor electrons with a characteristic defect-dipolar freezing temperature (Tf) above which stable colossal permittivity (>103) persists. However, apart from a lot of co-doping cases, a clear idea of how to tailor the partial localisation behaviour is remain elusive. Here, based on phenomenological theories, we propose a spin-defect mediated partial localisation of donor electrons where the localisation behaviour can be tailored by the strength of exchange correlation between charge carrier spin and local spin. We found an ultrastable high-performance colossal permittivity behaviour over a broad frequency/temperature range in Co+Ta co-doped SnO2 with an unprecedentedly low Tf (< 2 K) compared with that reported in doped SnO2 (> 150 K) and other doped binary metal oxides (> 7 K), pointing to a superstable large electronic moment of defect-dipole. The magnetic interactions between magnetic acceptor Co and donor ion significantly change the dielectric behaviour and magnetic order state, which modify the configurations of defect-dipolar clusters and change the partial localisation behaviour of donor electrons due to the exchange correlation between local spin from Co and charge carrier spin from donor. Despite the promising application potential of the novel dielectrics in cryogenic and aerospace microelectronics, the work advances the dielectric physics and benefit the exploration of novel electronic state in metal oxides and semiconductors via defect-engineering.

In-site and Ex-site Date Palm Exposure to Heavy Metals Involved Infra-Individual Biomarkers Upregulation.

As a tree of considerable importance in arid regions—date palm, Phoenix dactylifera L. survival in contaminated areas of Sfax city has drawn our attention. Leaf samples of the plants grown in the study area showed high levels of cadmium (Cd), copper (Cu), and chromium (Cr). On the basis of this finding, the cellular mechanisms that explain these metal accumulations were investigated in controlled conditions. After four months of exposure to Cd, Cr, or Cu, high bioconcentration and translocation factor (TF > 1) have been shown for date palm plantlets exposed to Cd and low TF values were obtained for plantlets treated with Cr and Cu. Moreover, accumulation of oxidants and antioxidant enzyme activities occurred in exposed roots to Cu and Cd. Secondary metabolites, such as polyphenols and flavonoids, were enhanced in plants exposed at low metal concentrations and declined thereafter. Accumulation of flavonoids in cells may be correlated with the expression of the gene encoding Pdmate5, responsible for the transport of secondary metabolites, especially flavonoids. Other transporter genes responded positively to metal incorporation, especially Pdhma2, but also Pdabcc and Pdnramp6. The latter would be a new candidate gene sensitive to metallic stress in plants. Expressions of gene coding metal chelators were also investigated. Pdpcs1 and Pdmt3 exhibited a strong induction in plants exposed to Cr. These modifications of the expression of some biochemical and molecular based-markers in date palm helped to better understand the ability of the plant to tolerate metals. They could be useful in assessing heavy metal contaminations in polluted soils and may improve accumulation capacity of other plants.

Azithromycin Reduction to Reach Elimination of Trachoma (ARRET): study protocol for a cluster randomized trial of stopping mass azithromycin distribution for trachoma

BackgroundThe World Health Organization (WHO) recommends annual mass azithromycin distribution until districts drop below 5% prevalence of trachomatous inflammation—follicular (TF). Districts with very low TF prevalence may have little or no transmission of the ocular strains of Chlamydia trachomatis that cause trachoma, and additional rounds of mass azithromycin distribution may not be useful. Here, we describe the protocol for a randomized controlled trial designed to evaluate whether mass azithromycin distribution can be stopped prior to the current WHO guidelines.MethodsThe Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) study is a 1:1 community randomized non-inferiority trial designed to evaluate whether mass azithromycin distribution can be stopped in districts with baseline prevalence of TF under 20%. Communities in Maradi, Niger are randomized after baseline assessment either to continued annual mass azithromycin distribution or stopping annual azithromycin distribution over a 3-year period. We will compare the prevalence of ocular C. trachomatis (primary outcome), TF and other clinical signs of trachoma, and serologic markers of trachoma after 3 years. We hypothesize that stopping annual azithromycin distribution will be non-inferior to continued annual azithromycin distributions for all markers of trachoma prevalence and transmission.DiscussionThe results of this trial are anticipated to provide potentially guideline-changing evidence for when mass azithromycin distributions can be stopped in low TF prevalence areas.Trial registration numberThis study is registered at clinicaltrials.gov (NCT04185402). Registered December 4, 2019; prospectively registered pre-results.

Prevalence and abundance of 9 periodontal pathogens in the saliva of periodontally healthy adults and patients undergoing supportive periodontal therapy.

PurposeThis study aimed to examine the prevalence and abundance of 9 representative periodontal pathogens in the saliva samples of periodontally healthy subjects (PH) and patients with periodontitis who underwent supportive periodontal therapy (SPT). The age-specific distribution of these pathogens in periodontally healthy individuals was also analyzed.MethodsOne hundred subjects (aged >35 years) were recruited (50 each in the PH and SPT groups) between August 2016 and April 2019. The prevalence and abundance of periodontal pathogens in the PH group were compared with those in periodontally healthy young subjects (94 subjects; aged <35 years), who were included in our previous study. DNA copy numbers of Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), Treponema denticola (Td), Prevotella intermedia (Pi), Fusobacterium nucleatum (Fn), Campylobacter rectus (Cr), Peptostreptococcus anaerobius (Pa), and Eikenella corrodens (Ec) were analyzed using real-time polymerase chain reaction.ResultsThe detection frequencies of all pathogens, except Aa, were high in the PH and SPT groups. The ranking order of pathogen DNA copy numbers was similar in both groups. In both groups, Fn had the highest abundance, Aa had the lowest abundance. Additionally, Td was significantly more abundant in men than in women in both groups (P<0.05). Compared with the PH group, the SPT group exhibited significantly lower total bacteria and Fn abundance and higher Pg abundance (P<0.05). The age-specific pathogen distribution analysis revealed a significantly low Aa abundance and high Tf and Cr abundance in the PH group.ConclusionsThe clinical parameters and microbial profiles were similar between the SPT and PH groups. However, patients with periodontitis require supportive care to prevent recurrence. As the abundance of some bacteria varied with age, future studies must elucidate the correlation between age-related physiological changes and periodontal bacterial composition.

Thrombin generation in vivo and ex vivo in sickle cell disease patients

Activation of coagulation is an important hallmark of sickle cell disease (SCD) and it is believed that hypercoagulability plays a role to the disease pathophysiology. Studies have sought to identify how hemostatic biomarkers are expressed in SCD, however, the results are inconclusive. In this context, our objective was to evaluate the thrombin generation in vivo and ex vivo in SCD patients and the association between these biomarkers and the use of HU. This cross-sectional study was carried out with patients diagnosed with SCD, users or not of Hydroxyurea (HU), and healthy individuals as controls. D dimer (D-Di) was evaluated by ELISA and (TGT) thrombin generation test by CAT method. D-Di plasma levels were significantly higher in SCD patients when compared to the controls. TGT parameters such as peak, ETP and normalized ETP at low TF concentration and time-to-peak, peak, ETP and normalized ETP values at high TF concentration were lower in SCD patients than in controls. In contrast, the normalized activated protein C sensitivity ratio (nAPCsr) was higher in patients compared to controls, indicating resistance to the action of this natural anticoagulant. Regarding the use of HU, comparing users and non-users of this drug, no difference was observed in D-Di levels and in most TGT parameters. Our data analyzed together allow us to conclude that patients with SCD present a state of hypercoagulability in vivo due to the higher levels of D-Di and resistance to APC assessed ex vivo which is consistent with the coagulation imbalance described in SCD patients.

Spatiotemporal Contrast Sensitivity of Brown-Norway Rats under Scotopic and Photopic Illumination

Rats are a popular animal model for vision research and for investigating disorders of the visual system. The study aimed to quantify the spatiotemporal contrast sensitivity function (CSF) of healthy adult Brown-Norway rats under scotopic and photopic illumination. Animals were trained to jump onto the one of two adjacent platforms behind which was displayed a sinewave grating pattern. Contrast thresholds of light- and dark-adapted rats were determined using a staircase method of adjustment for gratings that varied in spatial frequency (sf) and temporal frequency (tf) and ranged several log-units in mean luminance. Photopic CSFs showed strong bandpass spatial tuning, consistent with prior measurements, and weak bandpass temporal tuning. CSFs were parameterized by a truncated log-parabola model, yielding a peak contrast sensitivity of 52 ± 9, peak sf of 0.17 ± 0.05 cycles/degree, sf limit of 1.6 ± 0.3 cycles/degree, low sf attenuation of 85 ± 9%, peak tf of 1.7 ± 1.1 Hz, extrapolated tf limit of 166 ± 44 Hz, and low tf attenuation of 55 ± 12%. CSFs became more lowpass and decreased systematically in contrast sensitivity and spatiotemporal acuity as mean luminance was reduced. CSFs were also measured via the visual head-tracking reflex. Photopic contrast sensitivity, spatial acuity, and temporal acuity were all markedly below that of the grating detection task and optomotor findings for other rat strains. The CSF data provide a comprehensive and quantitative description of rat spatial and temporal vision and a benchmark for evaluating effects of ocular diseases on their ability to see.

Microfluidic hemophilia models using blood from healthy donors

BackgroundMicrofluidic clotting assays permit drug action studies for hemophilia therapeutics under flow. However, limited availability of patient samples and Inter‐donor variability limit the application of such assays, especially with many patients on prophylaxis. ObjectiveTo develop approaches to phenocopy hemophilia using modified healthy blood in microfluidic assays. MethodsCorn trypsin inhibitor (4 µg/mL)‐treated healthy blood was dosed with either anti–factor VIII (FVIII; hemophilia A model) or a recombinant factor IX (FIX) missense variant (FIX‐V181T; hemophilia B model). Treated blood was perfused at 100 s−1 wall shear rate over collagen/tissue factor (TF) or collagen/factor XIa (FXIa). ResultsAnti‐FVIII partially blocked fibrin production on collagen/TF, but completely blocked fibrin production on collagen/FXIa, a phenotype reversed with 1 µmol/L bispecific antibody (emicizumab), which binds FIXa and factor X. As expected, emicizumab had no significant effect on healthy blood (no anti‐FVIII present) perfused over collagen/FXIa. The efficacy of emicizumab in anti‐FVIII‐treated healthy blood phenocopied the action of emicizumab in the blood of a patient with hemophilia A perfused over collagen/FXIa. Interestingly, a patient‐derived FVIII‐neutralizing antibody reduced fibrin production when added to healthy blood perfused over collagen/FXIa. For low TF surfaces, reFIX‐V181T (50 µg/mL) fully blocked platelet and fibrin deposition, a phenotype fully reversed with anti‐TFPI. ConclusionTwo new microfluidic hemophilia A and B models demonstrate the potency of anti‐TF pathway inhibitor, emicizumab, and a patient‐derived inhibitory antibody. Using collagen/FXIa‐coated surfaces resulted in reliable and highly sensitive hemophilia models.

Procoagulant Microparticles Derived from Myeloma Plasma Cells Have a Determinant Role in the Hypercoagulable State Associated with Multiple Myeloma. a Modelization in Vitro Study

Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by bone marrow infiltration leading to multiple lytic bone lesions, renal failure, anemia and increased rate of thrombotic events. The cross-talk between cancer cells, plasma clotting mechanism, platelets and endothelial cells enhances hypercoagulability. The mechanisms by which myeloma plasma cells (MPCs) interfere with their microenvironment during the blood coagulation process have been poorly investigated. Several studies have established a link between levels of cancer cell derived procoagulant microparticles, cancer aggressiveness, response to anticancer treatments well as with the risk of cancer associated thrombosis., The mechanisms by which myeloma plasma cells interfere to blood coagulation process in their microenvironment have been poorly investigated. Aim: Set up an experimental model that allows the identification of the procoagulant fingerprint of MPCs and myeloma cell-derived microparticles (MC-dMPs) as well as their impact on thrombin generation of normal plasma. In addition, we evaluated the relative impact of TF-pathway and the intrinsic clotting pathway on thrombin generation triggered by myeloma plasma cells and MC-dMPs. Finally, we performed a simulation of thrombin generation process in the presence of myeloma plasma cells and MC-dMPs as well as in the presence of varying concentrations of TF and procoagulant phopsholipids, mimicking some of the conditions that potentially exist in MPCs. Methods. TF and annexin V expression by MPCs (MPC-dMPs) were analyzed by flow cytometry, TF activity (TFa) and TF gene expression was also determined. Thrombin Generation (TG) in the presence of MPCs or MPC-dMPs was assessed with the Calibrated Automated Thrombogram assay (CAT®) in normal human PPP. TG was also assessed in plasma spiked with MPCs and MPC-dMPs or variable concentrations of TF and procoagulant phospholipids. Results: MPC-dMPs expressed about 8-fold higher levels of TF as compared to MPCs. TFa expressed by MPC- dMPs was significantly higher as compared to that expressed by MPC cells. MPCs and PC- dMPs enhanced thrombin generation of human plasma. Thrombin generation was significantly higher with MPC-dMPs compared to MPCs. MPCs and MPC-dMPs, when concomitantly present in normal PPP, significantly amplified thrombin generation as compared to that observed in the presence of MPCs alone. Presence of TF and procoagulant phospholipids in the microenvironment resulted in significant amplification of thrombin generation induced by MPCs. Conclusion: This study support the concept that hypercoagulability induced by myeloma plasma cells is the result of the combination of the procoagulant properties of myeloma cells with the procoagulant elements of the plasma microenvironment which consist of procoagulant phospholipids and low TF concentration. Following this concept we assume that MPC-dMPs released by myeloma plasma cells into the microenvironment enhance the weak procoagulant activity of myeloma plasma cells. Whereas this combined effect of MPCs and MPC-dMPs on thrombin generation has an impact on the formation of local fibrin network their critical role into the hypercoagulablity, procoagulant MC-dMP could be a potential target for the evaluation of the aggressivity of MPCs and of their response to anti-myeloma treatment. Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Elalamy:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; LEO Pharma: Honoraria, Research Funding; Aspen: Honoraria, Research Funding; Bayer Healthcare: Honoraria, Research Funding.