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

Early Steps of HIV-1 Fusion Define the Sensitivity to Inhibitory Peptides That Block 6-Helix Bundle Formation

The HIV envelope (Env) glycoprotein mediates membrane fusion through sequential interactions with CD4 and coreceptors, followed by the refolding of the transmembrane gp41 subunit into the stable 6-helix bundle (6HB) conformation. Synthetic peptides derived from the gp41 C-terminal heptad repeat domain (C-peptides) potently inhibit fusion by binding to the gp41 pre-bundle intermediates and blocking their conversion into the 6HB. Our recent work revealed that HIV-1 enters cells by fusing with endosomes, but not with the plasma membrane. These studies also showed that, for the large part, gp41 pre-bundles progress toward 6HBs in endosomal compartments and are thus protected from external fusion inhibitors. Here, we examined the consequences of endocytic entry on the gp41 pre-bundle exposure and on the virus' sensitivity to C-peptides. The rates of CD4 and coreceptor binding, as well as the rate of productive receptor-mediated endocytosis, were measured by adding specific inhibitors of these steps at varied times of virus-cell incubation. Following the CD4 binding, CCR5-tropic viruses recruited a requisite number of coreceptors much faster than CXCR4-tropic viruses. The rate of subsequent uptake of ternary Env-CD4-coreceptor complexes did not correlate with the kinetics of coreceptor engagement. These measurements combined with kinetic analyses enabled the determination of the lifetime of pre-bundle intermediates on the cell surface. Overall, these lifetimes correlated with the inhibitory potency of C-peptides. On the other hand, the basal sensitivity to peptides varied considerably among diverse HIV-1 isolates and ranked similarly with their susceptibility to inactivation by soluble CD4. We conclude that both the longevity of gp41 intermediates and the extent of irreversible conformational changes in Env upon CD4 binding determine the antiviral potency of C-peptides

Mammographic screening before age 50 years in the UK: comparison of the radiation risks with the mortality benefits

Mammographic screening before age 50 years is less effective than at older ages and the associated radiation risks are higher. We estimated how many breast cancer deaths could be caused and how many could be prevented by a decade of annual two-view mammographic screening starting at ages 20, 30 and 40 years, respectively, in the UK; for all women, and for women with first-degree relatives affected with breast cancer. We extrapolated from a radiation risk model to estimate the number of radiation-induced breast cancer deaths, and used results from randomised trials, which suggest a reduction in breast cancer mortality of 10–20% in women invited to screening before age 50 years, to estimate the number of deaths that could be prevented. The net change in breast cancer deaths was defined as the number of radiation-induced deaths minus the number of prevented deaths. For all women, assuming a reduction in mortality from screening of 20%, a decade of annual screening was estimated to induce more deaths than it prevents if started at age 20 years and at age 30 years (net increase=0.86 and 0.37 breast cancer deaths, respectively, per 1000 women screened). The corresponding estimate for screening starting at age 40 years was a net decrease of 0.46 deaths/1000 women screened and a zero net change assuming a 10% mortality reduction. Results for women with first-degree relatives with breast cancer were generally in the same direction but, because their background incidence rates are higher, the net increases or decreases were greater. In conclusion, our estimates suggest that a decade of annual two-view mammographic screening before age 40 years would result in a net increase in breast cancer deaths, and that starting at age 40 years could result in a material net decrease only if breast cancer mortality is reduced by about 20% or more in women screened. Although these calculations were based on a number of uncertain parameters, in general, the conclusions were not altered when these parameters were varied within a feasible range

Wind from the black-hole accretion disk driving a molecular outflow in an active galaxy

Powerful winds driven by active galactic nuclei (AGN) are often invoked to play a fundamental role in the evolution of both supermassive black holes (SMBHs) and their host galaxies, quenching star formation and explaining the tight SMBH-galaxy relations. Recent observations of large-scale molecular outflows in ultra-luminous infrared galaxies (ULIRGs) have provided the evidence to support these studies, as they directly trace the gas out of which stars form. Theoretical models suggest an origin of these outflows as energy-conserving flows driven by fast AGN accretion disk winds. Previous claims of a connection between large-scale molecular outflows and AGN activity in ULIRGs were incomplete because they were lacking the detection of the putative inner wind. Conversely, studies of powerful AGN accretion disk winds to date have focused only on X-ray observations of local Seyferts and a few higher redshift quasars. Here we show the clear detection of a powerful AGN accretion disk wind with a mildly relativistic velocity of 0.25c in the X-ray spectrum of IRAS F11119+3257, a nearby (z = 0.189) optically classified type 1 ULIRG hosting a powerful molecular outflow. The AGN is responsible for ~80% of the emission, with a quasar-like luminosity of L_AGN = 1.5x10^46 erg/s. The energetics of these winds are consistent with the energy-conserving mechanism, which is the basis of the quasar mode feedback in AGN lacking powerful radio jets.Comment: Revised file including the letter, methods and supplementary information. Published in the March 26th 2015 issue of Natur

Deconstructing the Big Valley Search Space Hypothesis

The big valley hypothesis suggests that, in combinatorial optimisation, local optima of good quality are clustered and surround the global optimum. We show here that the idea of a single valley does not always hold. Instead the big valley seems to de-construct into several valleys, also called ‘funnels’ in theoretical chemistry. We use the local optima networks model and propose an effective procedure for extracting the network data. We conduct a detailed study on four selected TSP instances of moderate size and observe that the big valley decomposes into a number of sub-valleys of different sizes and fitness distributions. Sometimes the global optimum is located in the largest valley, which suggests an easy to search landscape, but this is not generally the case. The global optimum might be located in a small valley, which offers a clear and visual explanation of the increased search difficulty in these cases. Our study opens up new possibilities for analysing and visualising combinatorial landscapes as complex networks

Breast clinic and life style study BLLISS

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A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC

Background risk of breast cancer and the association between physical activity and mammographic density

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The role of agonist and antagonist muscles in explaining isometric knee extension torque variation with hip joint angle.

PURPOSE: The biarticular rectus femoris (RF), operating on the ascending limb of the force-length curve, produces more force at longer lengths. However, experimental studies consistently report higher knee extension torque when supine (longer RF length) compared to seated (shorter RF length). Incomplete activation in the supine position has been proposed as the reason for this discrepancy, but differences in antagonistic co-activation could also be responsible due to altered hamstrings length. We examined the role of agonist and antagonist muscles in explaining the isometric knee extension torque variation with changes in hip joint angle. METHOD: Maximum voluntary isometric knee extension torque (joint MVC) was recorded in seated and supine positions from nine healthy males (30.2 ± 7.7 years). Antagonistic torque was estimated using EMG and added to the respective joint MVC (corrected MVC). Submaximal tetanic stimulation quadriceps torque was also recorded. RESULT: Joint MVC was not different between supine (245 ± 71.8 Nm) and seated (241 ± 69.8 Nm) positions and neither was corrected MVC (257 ± 77.7 and 267 ± 87.0 Nm, respectively). Antagonistic torque was higher when seated (26 ± 20.4 Nm) than when supine (12 ± 7.4 Nm). Tetanic torque was higher when supine (111 ± 31.9 Nm) than when seated (99 ± 27.5 Nm). CONCLUSION: Antagonistic co-activation differences between hip positions do not account for the reduced MVC in the supine position. Rather, reduced voluntary knee extensor muscle activation in that position is the major reason for the lower MVC torque when RF is lengthened (hip extended). These findings can assist standardising muscle function assessment and improving musculoskeletal modelling applications