Fibrinogen-mimicking, multiarm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy

Clinical use of tissue plasminogen activator (tPA) in thrombolytic therapy is limited by its short circulation time and hemorrhagic side effects. Inspired by fibrinogen binding to activated platelets, we report a fibrinogen-mimicking, multiarm nanovesicle for thrombus-specific tPA delivery and targeted thrombolysis. This biomimetic system is based on the lipid nanovesicle coated with polyethylene glycol (PEG) terminally conjugated with a cyclic RGD (cRGD) peptide. Our experiments with human blood demonstrated its highly selective binding to activated platelets and efficient tPA release at a thrombus site under both static and physiological flow conditions. Its clot dissolution time in a microfluidic system was comparable to that of free tPA. Furthermore, we report a purpose-built computational model capable of simulating targeted thrombolysis of the tPA-loaded nanovesicle and with a potential in predicting the dynamics of thrombolysis in physiologically realistic scenarios. This combined experimental and computational work presents a promising platform for development of thrombolytic nanomedicines

Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage

<p>Abstract</p> <p>Background</p> <p>Phase I/II placebo-controlled clinical trials of recombinant Factor VIIa (rFVIIa) suggested that administration of rFVIIa within 4 hours after onset of intracerebral hemorrhage (ICH) is safe, limits ICH growth, and improves outcomes. We sought to determine the cost-effectiveness of rFVIIa for acute ICH treatment, using published Phase II data. We hypothesized that rFVIIa would have a low marginal cost-effectiveness ratio (mCER) given the poor neurologic outcomes after ICH with conventional management.</p> <p>Methods</p> <p>We performed an incremental cost-effectiveness analysis from the societal perspective, considering conventional management vs. 80 ug/kg rFVIIa treatment for acute ICH cases meeting Phase II inclusion criteria. The time frame for the analysis was 1. 25 years: data from the Phase II trial was used for 90 day outcomes and rFVIIa complications – arterial thromboembolic events (ATE). We assumed no substantial cost differences in care between the two strategies except: 1) cost of rFVIIa (for an 80 mcg/kg dose in an 80 kg patient, assumed cost of $6,408); 2) cost of ATE side effects from rFVIIa (which also decrease quality of life and increase the chance of death); and 3) differential monetary costs of outcomes and their impact on quality of life, including disposition (home vs. nursing home), and outpatient vs. inpatient rehabilitation. Sensitivity analyses were performed to explore uncertainty in parameter estimates, impact of rFVIIa cost, direct cost of neurologic outcomes, probability of ATE, and outcomes after ATE.</p> <p>Results</p> <p>In the "base case", treating ICH with rFVIIa dominates the usual care strategy by being more effective and less costly. rFVIIa maintained a mCER <$50,000/QALY over a wide range of sensitivity analyses. Sensitivity analyses showed that the cost of rFVIIa must exceed $14,500, or the frequency of ATE exceed 29$50,000/QALY. Varying the cost and/or reducing the utility of health states following ATE did not impact results.</p> <p>Conclusion</p> <p>Based on data from preliminary trials, treating selected ICH patients with rFVIIa results in lower cost and improved clinical outcomes. This potential cost-effectiveness must be considered in light of the Phase III trial results.</p

Singularities and Topology of Meromorphic Functions

We present several aspects of the "topology of meromorphic functions", which we conceive as a general theory which includes the topology of holomorphic functions, the topology of pencils on quasi-projective spaces and the topology of polynomial functions.Comment: 21 pages, 1 figur

An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy

It remains a major challenge to develop a selective and effective fibrinolytic system for thrombolysis with minimal undesirable side effects. Herein, we report a multifunctional liposomal system (164.6 ± 5.3 nm in diameter) which can address this challenge through targeted delivery and controlled release of tissue plasminogen activator (tPA) at the thrombus site. The tPA-loaded liposomes were PEGylated to improve their stability, and surface coated with a conformationally-constrained, cyclic arginine-glycine-aspartic acid (cRGD) to enable highly selective binding to activated platelets. The in vitro drug release profiles at 37 °C showed that over 90% of tPA was released through liposomal membrane destabilization involving membrane fusion upon incubation with activated platelets within 1 h, whereas passive release of the encapsulated tPA in pH 7.4 PBS buffer was 10% after 6 h. The release of tPA could be readily manipulated by changing the concentration of activated platelets. The presence of activated platelets enabled the tPA-loaded, cRGD-coated, PEGylated liposomes to induce efficient fibrin clot lysis in a fibrin-agar plate model and the encapsulated tPA retained 97.4 ± 1.7% of fibrinolytic activity as compared with that of native tPA. Furthermore, almost complete blood clot lysis was achieved in 75 min, showing considerably higher and quicker thrombolytic activity compared to the tPA-loaded liposomes without cRGD labelling. These results suggest that the nano-sized, activated-platelet-sensitive, multifunctional liposomes could facilitate selective delivery and effective release of tPA at the site of thrombus, thus achieving efficient clot dissolution whilst minimising undesirable side effects

Computational simulations of thrombolysis in acute stroke: Effect of clot size and location on recanalisation

Acute ischaemic stroke can be treated by intravenous thrombolysis whereby tissue plasminogen activator (tPA) is infused to dissolve clots that block blood supply to the brain. In this study, we aim to examine the influence of clot location and size on lysis pattern and recanalisation by using a recently developed computational modelling framework for thrombolysis under physiological flow conditions. An image-based patient-specific model is reconstructed which consists of the internal carotid bifurcation with the A1 segment of anterior cerebral arteries and M1 segment of middle cerebral arteries, and the M1 bifurcation containing the M2 segments. By varying the clot size and location, 7 scenarios are simulated mimicking thrombolysis of M1 and M2 occlusions. Our results show that initial breakthrough always occurs along the inner curvature of the occluded cerebral artery, due to prolonged tPA residence time in the recirculation zone. For a given occlusion site, lysis completion time appears to increase almost quadratically with the initial clot volume; whereas for a given clot volume, the simulated M2 occlusions take up to 30% longer for complete lysis compared to the corresponding M1 occlusions

Predicting the development of stress urinary incontinence 3 years after hysterectomy

We aimed to develop a prediction rule to predict the individual risk to develop stress urinary incontinence (SUI) after hysterectomy. Prospective observational study with 3-year follow-up among women who underwent abdominal or vaginal hysterectomy for benign conditions, excluding vaginal prolapse, and who did not report SUI before surgery (n = 183). The presence of SUI was assessed using a validated questionnaire. Significant prognostic factors for de novo SUI were BMI (OR 1.1 per kg/m(2), 95% CI 1.0-1.2), younger age at time of hysterectomy (OR 0.9 per year, 95% CI 0.8-1.0) and vaginal hysterectomy (OR 2.3, 95% CI 1.0-5.2). Using these variables, we developed the following rule to predict the risk of developing SUI: 32 + BMI-age + (7.5 × route of surgery). We defined a prediction rule that can be used to counsel patients about their individual risk on developing SUI following hysterectom

The GAIA theory: from Lovelock to Margulis. From a homeostatic to a cognitive autopoietic worldview

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Hyperbaric oxygen therapy for late radiation-induced tissue toxicity: Prospectively patient-reported outcome measures in breast cancer patients

__Introduction:__ This study examines patient reported outcome measures of women undergoing hyperbaric oxygen treatment (HBOT) after breast-conserving therapy. __Method:__ Included were 57 women treated with HBOT for late radiation-induced tissue toxicity (LRITT) referred in the period January 2014-December 2015. HBOT consisted of (on average) 47 sessions. In total, 80 min of 100 % O2 was administered under increased pressure of 2.4 ATA. Quality of life was assessed before and after treatment using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BR23, and a NRS pain score. __Results:__ Fifty-seven women were available for evaluation before and after treatment. Before HBOT, patients had severe complaints of pain in the arm/shoulder (46 %), swollen arm/hand (14 %), difficulty to raise arm or move it sideways (45 %), pain in the area of the affected breast (67 %), swollen area of the affected breast (45 %), oversensitivity of the affected breast (54 %), and skin problems on/in the area of the affected breast (32 %); post HBOT, severe complaints were still experienced in 17, 7, 22, 15, 13, 15, and 11 % of the women, respectively. Differences were all significant. The NRS pain score improved at least 1 point (range 0-10) in 81 % of the patients (p < 0.05). __Conclusion:__ In these breast cancer patients treated with HBOT for LRITT, the patient-reported outcomes were positive and improvements were observed. HBOT was a well-tolerated treatment for LRITT and its side-effects were both minimal and reversible

Measurement of Lifetime and Decay-Width Difference in B0s -> J/psi phi Decays

We measure the mean lifetime, tau=2/(Gamma_L+Gamma_H), and the width difference, DeltaGamma=Gamma_L-Gamma_H, of the light and heavy mass eigenstates of the B0s meson, B0sL and B0sH, in B0s -> J/psi phi decays using 1.7 fb^-1 of data collected with the CDF II detector at the Fermilab Tevatron ppbar collider. Assuming CP conservation, a good approximation for the B0s system in the Standard Model, we obtain DeltaGamma = 0.076^+0.059_-0.063 (stat.) +- 0.006 (syst.) ps^-1 and tau = 1.52 +- 0.04 (stat.) +- 0.02 (syst.) ps, the most precise measurements to date. Our constraints on the weak phase and DeltaGamma are consistent with CP conservation. Dedicated to the memory of our dear friend and colleague, Michael P. Schmid