What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies.

: Intravenous tranexamic acid (TXA) reduces death because of bleeding in patients with trauma and postpartum haemorrhage. However, in some settings intravenous injection is not feasible. To find different routes of administration, we first need to determine the minimal concentration of TXA in the blood that is required to inhibit fibrinolysis.We conducted a systematic review of in-vitro and in-vivo pharmacodynamics studies. We searched MEDLINE, EMBASE, OviSP, and ISI Web of Science from database inception to November 2017 for all in-vitro (including simulated clotting models) or in-vivo studies reporting the relationship between the TXA concentration in blood or plasma and any reliable measure of fibrinolysis.We found 21 studies of which 20 were in vitro and one was in vivo. Most in-vitro studies stimulated fibrinolysis with tissue plasminogen activator and measured fibrinolysis using viscoelastic, optical density, or immunological assays. TXA concentrations between 10 and 15 mg/l resulted in substantial inhibition of fibrinolysis, although concentrations between 5 and 10 mg/l were partly inhibitory.TXA concentrations of 10-15 mg/l may be suitable targets for pharmacokinetic studies, although TXA concentrations above 5 mg/l may also be effective

t-PA Suppresses the Immune Response and Aggravates Neurological Deficit in a Murine Model of Ischemic Stroke

Introduction: Acute ischemic stroke (AIS) is a potent trigger of immunosuppression, resulting in increased infection risk. While thrombolytic therapy with tissue-type plasminogen activator (t-PA) is still the only pharmacological treatment for AIS, plasmin, the effector protease, has been reported to suppress dendritic cells (DCs), known for their potent antigen-presenting capacity. Accordingly, in the major group of thrombolyzed AIS patients who fail to reanalyze (>60%), t-PA might trigger unintended and potentially harmful immunosuppressive consequences instead of beneficial reperfusion. To test this hypothesis, we performed an exploratory study to investigate the immunomodulatory properties of t-PA treatment in a mouse model of ischemic stroke.Methods: C57Bl/6J wild-type mice and plasminogen-deficient (plg−/−) mice were subjected to middle cerebral artery occlusion (MCAo) for 60 min followed by mouse t-PA treatment (0.9 mg/kg) at reperfusion. Behavioral testing was performed 23 h after occlusion, pursued by determination of blood counts and plasma cytokines at 24 h. Spleens and cervical lymph nodes (cLN) were also harvested and characterized by flow cytometry.Results: MCAo resulted in profound attenuation of immune activation, as anticipated. t-PA treatment not only worsened neurological deficit, but further reduced lymphocyte and monocyte counts in blood, enhanced plasma levels of both IL-10 and TNFα and decreased various conventional DC subsets in the spleen and cLN, consistent with enhanced immunosuppression and systemic inflammation after stroke. Many of these effects were abolished in plg−/− mice, suggesting plasmin as a key mediator of t-PA-induced immunosuppression.Conclusion: t-PA, via plasmin generation, may weaken the immune response post-stroke, potentially enhancing infection risk and impairing neurological recovery. Due to the large number of comparisons performed in this study, additional pre-clinical work is required to confirm these significant possibilities. Future studies will also need to ascertain the functional implications of t-PA-mediated immunosuppression for thrombolyzed AIS patients, particularly for those with failed recanalization

Management of the thrombotic risk associated with COVID-19:guidance for the hemostasis laboratory

Coronavirus disease 2019 (COVID-19) is associated with extreme inflammatory response, disordered hemostasis and high thrombotic risk. A high incidence of thromboembolic events has been reported despite thromboprophylaxis, raising the question of a more effective anticoagulation. First-line hemostasis tests such as activated partial thromboplastin time, prothrombin time, fibrinogen and D-dimers are proposed for assessing thrombotic risk and monitoring hemostasis, but are vulnerable to many drawbacks affecting their reliability and clinical relevance. Specialized hemostasis-related tests (soluble fibrin complexes, tests assessing fibrinolytic capacity, viscoelastic tests, thrombin generation) may have an interest to assess the thrombotic risk associated with COVID-19. Another challenge for the hemostasis laboratory is the monitoring of heparin treatment, especially unfractionated heparin in the setting of an extreme inflammatory response. This review aimed at evaluating the role of hemostasis tests in the management of COVID-19 and discussing their main limitations

Influence of storage conditions and packaging materials on some quality attributes of water yam flour

The study investigated some quality attributes of water yam flour stored in three packaging materials [high and low density polyethylene and plastic container] under different storage conditions [relative humidity (36%, 56%, 75% and 96%), temperature (25±2, 35±2 and 45±2 °C)] for 24 weeks. The functional properties, proximate composition and microbial load of the samples were evaluated at 4 weeks interval. Significant differences (p<0.01) were observed for proximate composition, functional properties and microbial load of the samples during storage. The interactive effect of storage conditions and packaging materials was significant (p<0.01) on proximate composition and pasting properties (except trough viscosity). The yam flour samples were still shelf stable after the 24 weeks of storage

Outcomes of patients with COVID-19 on kidney replacement therapy: a comparison among modalities in England.

BACKGROUND: Chronic kidney disease is a recognized risk factor of poor outcomes from coronavirus disease 2019 (COVID-19). METHODS: This retrospective cohort study used the UK Renal Registry database of people on kidney replacement therapy (KRT) at the end of 2019 in England and who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between 1 March 2020 and 31 August 2020 to analyse the incidence and outcomes of COVID-19 among different KRT modalities. Comparisons with 2015-2019 mortality data were used to estimate excess deaths. RESULTS: A total of 2783 individuals on KRT tested positive for SARS-CoV-2. Patients from more-deprived areas {most deprived versus least deprived hazard ratio [HR] 1.20 [95% confidence interval (CI) 1.04-1.39]} and those with diabetes compared with those without [HR 1.51 (95% CI 1.39-1.64)] were more likely to test positive. Approximately 25% of in-centre haemodialysis and transplanted patients died within 28 days of testing positive compared with 36% of those on home therapies. Mortality was higher in those ≥80 years of age compared with those 60-79 years [odds ratio (OR) 1.71 (95% CI 1.34-2.19)] and much lower in those listed for transplantation compared with those not listed [OR 0.56 (95% CI 0.40-0.80)]. Overall, excess mortality in 2020 for people on KRT was 36% higher than the 2015-2019 average. Excess deaths peaked in April 2020 at the height of the pandemic and were characterized by wide ethnic and regional disparities. CONCLUSIONS: The impact of COVID-19 on the English KRT population highlights their extreme vulnerability and emphasizes the need to protect and prioritize this group for vaccination. COVID-19 has widened underlying inequalities in people with kidney disease, making interventions that address health inequalities a priority

Search for supersymmetry with a dominant R-parity violating LQDbar couplings in e+e- collisions at centre-of-mass energies of 130GeV to 172 GeV

A search for pair-production of supersymmetric particles under the assumption that R-parity is violated via a dominant LQDbar coupling has been performed using the data collected by ALEPH at centre-of-mass energies of 130-172 GeV. The observed candidate events in the data are in agreement with the Standard Model expectation. This result is translated into lower limits on the masses of charginos, neutralinos, sleptons, sneutrinos and squarks. For instance, for m_0=500 GeV/c^2 and tan(beta)=sqrt(2) charginos with masses smaller than 81 GeV/c^2 and neutralinos with masses smaller than 29 GeV/c^2 are excluded at the 95% confidence level for any generation structure of the LQDbar coupling.Comment: 32 pages, 30 figure

Search for the glueball candidates f0(1500) and fJ(1710) in gamma gamma collisions

Data taken with the ALEPH detector at LEP1 have been used to search for gamma gamma production of the glueball candidates f0(1500) and fJ(1710) via their decay to pi+pi-. No signal is observed and upper limits to the product of gamma gamma width and pi+pi- branching ratio of the f0(1500) and the fJ(1710) have been measured to be Gamma_(gamma gamma -> f0(1500)). BR(f0(1500)->pi+pi-) < 0.31 keV and Gamma_(gamma gamma -> fJ(1710)). BR(fJ(1710)->pi+pi-) < 0.55 keV at 95% confidence level.Comment: 10 pages, 3 figure