A finite element method for non-linear hyperelasticity applied for the simulation of octopus ARM motions

An implicit non-linear finite element (FE) numerical procedure for the simulation of biological muscular tissues is presented. The method has been developed for studying the motion of muscular hydrostats, such as squid and octopus arms and its general framework is applicable to other muscular tissues. The FE framework considered is suitable for the dynamic numerical simulations of three-dimensional non-linear nearly incompressible hyperelastic materials that undergo large displacements and deformations. Human and animal muscles, consisting of fibers and connective tissues, belong to this class of materials. The stress distribution inside the muscular FE model is considered as the superposition of stresses along the muscular fibers and the connective tissues. The stresses along the fibers are modeled as the sum of active and passive stresses, according to the muscular model of Van Leeuwen and Kier (1997) Philos. Trans. R. Soc. London, 352: 551-571. Passive stress distribution is an experimentally-defined function of fibers’ deformation; while active stress distribution is the product of an activation level time function, a force-stretch function and a force-stretch ratio function. The mechanical behavior of the surrounding tissues is determined adopting a Mooney-Rivlin constitutive model. The incompressibility criterion is met by enforcing large bulk modulus and by introducing modified deformation measures. Due to the non-linear nature of the problem, approximate determination of the Jacobian matrix is performed, in order to utilize the full Newton-Raphson iterative procedure within each time-step. In addition, time discretization is performed via the implicit Newmark method. We developed an open-source finite element code that is capable of simulating large deflection maneuvers of muscular hydrostats. The proposed methodology is validated by comparing the numerical results with existing measurements for the squid arm extension. The efficiency and robustness of the proposed numerical method is demonstrated through a series of octopus arm maneuvers, such as extension, compression and bending

Antiretroviral Therapy Reduces Markers of Endothelial and Coagulation Activation in Patients Infected with Human Immunodeficiency Virus Type 1

We investigated the effect of antiretroviral therapy on vascular activation in 41 human immunodeficiency (HIV)—infected patients receiving a regimen that included either at least 1 protease inhibitor (PI; n = 21) or a nonnucleoside reverse-transcriptase inhibitor (NNRTI; n = 20). Acontrol group of 21 healthy subjectswas included for comparison. Levels of endothelialmarkers (soluble vascular cell adhesion molecule [sVCAM]-1, soluble intercellular adhesionmolecule-1, and vonWillebrand factor) were higher in HIV-infected persons before treatment than in control subjects anddecreasedsignificantlyafter 5-13 months of treatment. Levels of sVCAM-1 and vonWillebrand factor correlated significantly with initial virus load. D-dimer concentrations also decreased significantly after initiation of treatment. PI- and NNRTI-containing regimens had similar effects. Therapy did not reduce levels of the soluble platelet (sP) activation markers sP-selectin and CD40 ligand. The inhibition of markers of vascular activation may counterbalance sequelae of therapy-induced dyslipidemia and potentially prevent development of atherosclerosis in HIVinfected patient

Variability between laboratories performing coagulation tests with identical platforms: a nationwide evaluation study.

BACKGROUND While the assessment of analytical precision within medical laboratories has received much attention in scientific enquiry, the degree of as well as the sources causing variation between them remains incompletely understood. In this study, we quantified the variance components when performing coagulation tests with identical analytical platforms in different laboratories and computed intraclass correlations coefficients (ICC) for each coagulation test. METHODS Data from eight laboratories measuring fibrinogen twice in twenty healthy subjects with one out of 3 different platforms and single measurements of prothrombin time (PT), and coagulation factors II, V, VII, VIII, IX, X, XI and XIII were analysed. By platform, the variance components of (i) the subjects, (ii) the laboratory and the technician and (iii) the total variance were obtained for fibrinogen as well as (i) and (iii) for the remaining factors using ANOVA. RESULTS The variability for fibrinogen measurements within a laboratory ranged from 0.02 to 0.04, the variability between laboratories ranged from 0.006 to 0.097. The ICC for fibrinogen ranged from 0.37 to 0.66 and from 0.19 to 0.80 for PT between the platforms. For the remaining factors the ICC's ranged from 0.04 (FII) to 0.93 (FVIII). CONCLUSIONS Variance components that could be attributed to technicians or laboratory procedures were substantial, led to disappointingly low intraclass correlation coefficients for several factors and were pronounced for some of the platforms. Our findings call for sustained efforts to raise the level of standardization of structures and procedures involved in the quantification of coagulation factors

Failure of recombinant factor VIIa in a patient with severe polymicrobial sepsis and postoperative uncontrolled intraabdominal bleeding

<p>Abstract</p> <p>Background</p> <p>This report discusses a case of unsuccessful treatment with recombinant factor VIIa (rFVIIa) in off-label use. The need for international guidelines concerning the off-label use of rFVIIa is outlined as well as the need for methods to control the efficacy of rFVIIa objectively.</p> <p>Case presentation</p> <p>54 year old male with severe polymicrobial sepsis due to a perforated diverticulitis of the sigmoid colon and consecutive overt disseminated intravascular coagulation. He suffered severe intraabdominal bleeding after abdominal surgery despite conventional haemostatic support. Repeated applications of factor VIIa temporarily improved coagulation essays but did not stop clinical bleeding. The patient died in multiorgan failure due to septic and haemorrhagic shock.</p> <p>Conclusion</p> <p>Off-label use of rFVIIa could result in more side effects than could be expected from literature because of a publication bias. However for most off-label applications large prospective, randomised and controlled trials to confirm the positive findings are missing. For the future, not only guidelines concerning the off-label use of rFVIIa are urgently needed but also guidelines for monitoring the efficacy of rFVIIa.</p

Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (Pinteraction=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT02866838

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial.

Background: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. Methods: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. Results: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. Conclusions: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD

Management of Antithrombotic Agents in Oral Surgery Maria Martinez and Dimitrios A. Tsakiris *

Systemic anticoagulation with intravenous or oral anticoagulants and antiplatelet agents is an efficient treatment against thromboembolic or cardiovascular disease. Invasive dental procedures or oral surgery might be associated with bleeding complications if carried out under anticoagulants. Patients on vitamin K antagonists, new direct anticoagulants or antiplatelet agents having dental interventions with low-risk for bleeding do not need interruption of anticoagulation. In case of bleeding complications local hemostatic measures, such as local surgical sutures, fibrin glue, local antifibrinolytic treatment with tranexamic acid, or e-aminocaproic acid suffice to stop bleeding. In patients with high risk of bleeding an individual assessment of the benefit/risk ratio of interrupting anticoagulation should be carried out. Bridging the long-term anticoagulation with short-term anticoagulants should be planned according to national or international guidelines. The introduction of the newer direct oral anticoagulants having more flexible pharmacokinetic properties has facilitated bridging, allowing short-term interruption without increasing the risk of relapsing thrombotic or cardiovascular events