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Background Disparity in cancer survival across countries has been linked to variation in cancer policy delivery but there is lack of empirical evidence for this association. We traced the evolution of cancer policies in 20 jurisdictions in Australia, Canada, Denmark, Ireland, Norway, New Zealand and the UK since 1995 and present the findings of an exploratory analysis linking cancer policy consistency to cancer survival. Methods We systematically searched and analysed national/regional cancer plans and strategies, mapping timelines of cancer policy evolution. For 10 jurisdictions, evidence was synthesised into five categories: oversight function; cancer plan; implementation plan; budget for plan implementation; and evaluation. We assigned scores evaluating whether a category was present or absent, and weighted scores for consistency. Summed scores were correlated with trends in survival from seven cancers between 1995-2014. Results All ten jurisdictions had implemented a high-level structure overseeing, steering or delivering cancer control policies (1995 - 2014); all had also published at least one major cancer plan. There was great variation in oversight mechanisms, ranging from institutionalising cancer control (New South Wales, Ontario) to cancer steering groups or taskforces (Denmark, Northern Ireland, Wales). Frequency and consistency of cancer plans also varied, from a succession of plans that build on each other (Denmark, New South Wales, Ontario) to the publication of isolated plans (New Zealand, Northern Ireland). We found a positive, albeit weak, correlation of cancer policy consistency and improvements in survival over time for six of the seven cancers. Conclusions Jurisdictions that have implemented consistent cancer control policies over time tended to be more successful in improving survival for a wide range of cancers. Our findings can help guide policymakers seeking approaches and frameworks to improve cancer services and, ultimately, cancer outcomes. Key messages • Sustained and consistent strategic cancer planning and investment are crucial for ensuring better patient outcomes, and this requires strong and sustained commitment at all levels. • The findings can help guide policymakers seeking approaches and frameworks to improve cancer services and, ultimately, cancer outcomes.

Background Many countries are experimenting with novel ways of organising and delivering more integrated health and social care. Governance is relatively neglected as a focus of attention in this context but addressing governance challenges is key for successful collaboration. Methods Cross-country case analysis involving document review and semi-structured interviews with 27 local, regional and national level stakeholders in Italy, the Netherlands and Scotland. We used the Transparency, Accountability, Participation, Integrity and Capability (TAPIC) framework to structure our analytical enquiry to explore factors that influence the governance arrangements in each system. Results Governance arrangements ranged from informal agreements in the Netherlands to mandated integration in Scotland. Novel service models were generally participative involving a wide range of stakeholders, including the public, although integration was seen to be driven, largely, from a health perspective. In Italy and Scotland some reversion to ‘command & control’ was reported in response to the imperatives of the Covid-19 pandemic. Policies, budgets, auditing and reporting systems that are clearly aligned at all levels were seen to help with implementing innovations in service organisation. Where alignment was lacking, cooperation and integration was suboptimal, regardless of whether governance arrangements were statutory or not. There was wide recognition of the importance of buy-in. Enablers of greater engagement included visible leadership, time and long-standing working relationships. Lack of suitable indicators and openness to data sharing to measure integration hindered working relationships and thus the successful delivery of integrated services. Conclusions Our study provides important insights into how to more effectively and efficiently govern service delivery structures within care systems. We will discuss approaches to governance that help support more resilient integrated care systems. Key messages • Different governance arrangements face common challenges to greater integration of care. Enablers include strong leadership, inclusivity and openness to work across traditional boundaries. • Meeting the governance challenges of integrated health and social care requires clear lines of accountability, aligned policies, budgets and reporting systems.

Introduction Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic pathway that negatively regulates thrombin production during coagulation. Under haemophilic conditions, where the intrinsic coagulation pathway is impaired, inhibition of TFPI may improve clotting. Aim We investigated the ex vivo effects of a human TFPI neutralizing antibody, marstacimab (previously PF-06741086), in coagulation assays including rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay, performed in haemophilic whole blood and plasmas. We compared the effects of marstacimab to the effects of recombinant coagulation factors and investigated the reproducibility of marstacimab in restoring haemostasis by comparing its effect in whole blood collected from the same study participants on differing days. Methods Citrated whole blood and plasmas obtained from haemophilia participants were supplemented ex vivo with vehicle, marstacimab, recombinant FVIII (rFVIII) or recombinant factor IX (rFIX) and analysed in ROTEM, TGA and the dPT assay using low tissue factor concentrations to trigger coagulation. Results Marstacimab induced pro-coagulant responses in ROTEM parameters including reduction in clotting times and increases in angle. Similarly, participant plasmas supplemented with marstacimab exhibited improvements in TGA parameters, including reduced lag times, increased peak thrombin concentrations and reductions in dPT clotting time. Concentrations of marstacimab tested showed activity comparable to addition of rFVIII or rFIX and were reproducible. Conclusions These studies show the ex vivo potency of marstacimab in restoring haemostasis in whole blood and plasmas from haemophilia participants and comparability to ex vivo reconstitution with recombination coagulation factors.

Introduction Tissue factor pathway inhibitor (TFPI) is an endogenous protein that inhibits the extrinsic (tissue factor) pathway and negatively regulates thrombin production during coagulation. Inhibiting TFPI may become a useful target for haemophilia drug development to allow greater thrombin generation without use of the intrinsic (contact) pathway. Aims The in vitro effects of befovacimab, a humanized TFPI neutralizing antibody, were studied in whole blood and plasma samples from patients with severe FVIII deficiency. Methods Blood and plasma obtained from participants was supplemented in vitro with befovacimab (0.5, 1, 5, 10 and 100 nM) or recombinant factor VIII (rFVIII) 5-, 10- and 40% and analysed using rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay. The in vitro coagulation effects of befovacimab were compared to samples supplemented with rFVIII. Results Befovacimab induced consistent pro-coagulant responses in ROTEM parameters including reduction in clotting times and increases in α-angle; induced reductions in dPT clotting time; and improvements in TGA parameters (reduced lag time and increased thrombin generation parameters). There was a modest concentration-dependent response generally from 0.5- to 10 nM, after which, the pharmacodynamic effect plateaued through the 100 nM concentration. Befovacimab concentrations of 5 to 10 nM showed pro-coagulant activity comparable to blood samples supplemented with rFVIII 10-40%. Conclusions Befovacimab has modest dose-response effects from 0.5 to 10 nM with minimal improvement with higher concentrations. In vitro befovacimab blood concentrations of 5 to 10 nM had pro-coagulant effects similar to blood supplemented with rFVIII 10- to 40%.

INTRODUCTION The thrombin generation assay (TGA) can be used to monitor factor replacement therapy in patients with haemophilia. The TGA assay is typically performed using tissue factor as the reaction activator; however, activating with FIXa or FXIa can enhance assay sensitivity when FVIII

The objective of the study was to evaluate the effects of feeding varying levels of sun–dried red grape pomace (DGP; Vitis vinifera L. cultivar Pinotage) on nutrient digestibility, rumen fermentation, microbial nitrogen (N) supply, N retention and efficiency of N utilization in lambs. Twenty-one Dohne Merino wether lambs (6.0 ± 1.0 months and 51.6 ± 4.70 kg initial body weight) were randomly assigned to three diets containing 0, 100 and 200 g DGP per kg of diet dry matter in pelleted total mixed rations (TMR). The experiment consisted of 14 days for adaptation to the diets and 7 days for data collection. Intake of neutral detergent fiber (aNDFom) and starch decreased linearly (P ≤ 0.05) while ether extract intake increased linearly (P ≤ 0.05) with the addition of DGP. Apparent total tract aNDFom digestibility decreased linearly (P ≤ 0.05) with increasing levels of DGP. Total volatile fatty acids (VFA) production was quadratically (P ≤ 0.05) influenced by DGP addition. Increasing levels of DGP led to a linear decrease (P ≤ 0.05) in concentrations of butyrate and valerate. Allantoin, microbial N supply, total purine derivatives excreted linearly declined (P ≤ 0.05) with DGP addition. Nitrogen retention and the efficiency of N utilization were not influenced by diet (P > 0.05). Overall, addition of DGP in the lamb finisher diets reduced carbohydrate intake, microbial N yield, total purine derivatives excreted and increased total VFA concentration but did not have adverse effect of DGP on N retention and the efficiency of N utilization.

This study investigated the effects of feeding graded levels of sun-dried red grape pomace (GP; 0, 5, 10, 15 and 20%) on growth, carcass and meat physico-chemical quality attributes of Dohne Merino lambs for 42 days. Dry matter intake increased quadratically with a critical value (i.e., optimum inclusion level) of 11.3% GP (P ≤ 0.05). Diet exhibited similar quadratic responses for average daily gain, live, hot and cold carcass weights with optimum inclusion levels at 9.6, 9.7, 12, 2 and 12.1, respectively (P ≤ 0.05). Overall, meat quality traits were not negatively affected by GP inclusion (P > .05). Gross profit was influenced by diet, with an optimum inclusion level at 12.2% (quadratic; P ≤ 0.05). Overall, inclusion of 12.2% GP in lamb finishing diets at the expense of oat bran and wheat bran middlings improved lamb productivity, without compromising meat quality.

Introduction The thrombomodulin (TM)/activated protein C (APC) system is a key regulator of haemostasis, limiting amplification and propagation of the formed blood clot to the injury site. Dampening APC's inhibition of factor V (FV) and factor VIII (FVIII) may be a future strategy in developing next-generation therapeutic targets for haemophilia treatment. Aims To determine ex vivo the respective concentration-dependent effects of TM and a FV-stabilizing Fab on the APC regulatory pathway in severe FVIII-deficient blood and plasma. Methods Ten severe haemophilia A subjects and one healthy control were enrolled. Blood was spiked with TM (0, 1, 2.5, 5, 10, 20.0 nmol/L) and FV-stabilizing Fab (0, 3, 15, 65, 300 nmol/L). The respective effects were compared to FVIII concentrations of 3- and 10% using rotational thromboelastometry clotting time (CT) and thrombin generation analysis (TGA). Results With 1 and 2.5 nmol/L TM, 5% FVIII resulted in CT similar to the absence of TM, suggesting it completely reversed the effect of APC. Increasing TM concentrations also reduced peak thrombin generation and ETP. The addition of 300 nmol/L FV-stabilizing Fab returned CT to nearly baseline, but for most subjects was less than the effects of 3- or 10% FVIII. The FV-stabilizing Fab produced similar or greater thrombin generation compared to samples with 3- or 10% FVIII. Conclusions The FV-stabilizing Fab resulted in enhanced CT and TGA parameters consistent with FVIII levels of 3- and 10%. Additional studies need to further characterize how modulating the APC pathway may prove beneficial in developing new haemophilia drug targets.

The study evaluated shelf-life and sensory quality of meat from lambs fed finisher diets containing increasing levels of grape pomace (GP; 0, 5, 10, 15 and 20% GP/kg DM). Color, antioxidant activity and lipid oxidation of the longissimus lumborum were evaluated on different storage times (days 1, 3, 5, 7 and 9) post-slaughter using overwrapped air-permeable packaging. Treatments 0, 10 and 20% GP/kg DM were used for evaluation of protein oxidation and microbial counts on days 1, 5 and 7, while a trained panel assessed the sensory quality on day 1. Diet neither influenced meat color nor sensory quality. Diet × day interactions were observed for antioxidant activity, lipid and protein oxidation. Overall, the 20% GP/kg-diet finished lamb meat had the highest antioxidant activity and the lowest total viable bacterial counts, lipid and protein oxidation values during the shelf-life period. The 20% GP/kg DM in lamb diets, therefore, improved lamb meat shelf-life without negatively affecting sensory quality.

Ruminally cannulated Rambouillet wether lambs were used in three 6 x 6 Latin square experiments (n = 6/experiment) to determine which essential AA limit N retention. Lambs (BW = 36.9 +/- 1.9 kg for Exp. 1, 35.1 +/- 1.4 kg for Exp. 2, and 46.0 +/- 1.3 kg for Exp. 3) were housed in metabolism crates and limit-fed (DMI = approx. 1.8% of BW daily) twice daily a soybean hull-based diet low in ruminally undegradable protein. Treatments for Exp. 1 were continuous abomasal infusions of a solution (500 mL/d) containing 1) no AA (CON), 2) a mixture of 10 essential AA and 2 nonessential AA (10EAA), 3) 10EAA with Met removed, 4) 10EAA with Lys removed, 5) 10EAA with His removed, and 6) 10EAA with Thr removed. Treatments for Exp. 2 were abomasal infusions of 1) CON, 2) 10EAA, 3) 10EAA with Leu, Ile, and Val removed (-BCAA), 4) 10EAA with Arg removed, 5) 10EAA with Phe removed, and 6) 10EAA with Trp removed. Treatments for Exp. 3 were abomasal infusions of 1) CON, 2) 10EAA, 3) -BCAA, 4) 10EAA with Leu removed, 5) 10EAA with Ile removed, and 6) 10EAA with Val removed. All lambs received continuous infusions of acetate and propionate into the rumen and dextrose into the abomasum to supply additional energy. Periods were 7 d: 3 d for adaptation to abomasally infused treatments and 4 d for fecal and urinary collections. Blood samples were collected 3 h after feeding on d 7. In all 3 experiments, N retention was greater (P < 0.10) for lambs receiving 10EAA vs. CON, demonstrating that the basal AA supply from CON was limiting. Removal of each of the essential AA from 10EAA decreased (P < 0.10) their concentrations in plasma (except for Trp), indicating that 10EAA supplied these AA in excess of the animal's requirement. In Exp. 1, N retention (g/d) decreased (P < 0.10) in response to the removal of Met and Thr, but was not affected by removal of Lys and His from 10EAA. In Exp. 2, N retention decreased (P < 0.10) in response to removal of all 3 branched-chain AA, Arg, and Trp, whereas the removal of Phe from 10EAA did not affect N retention. In Exp. 3, N retention decreased (P < 0.10) in response to removal of branched-chain AA and Val, but was not affected by the omission of Leu and Ile from 10EAA. The results of this research demonstrated that Met, Thr, Arg, Trp, and Val limited N retention of lambs fed a diet low in ruminally undegradable protein.

AMS with tritium is a method able to detect even very small nuclear releases. It was applied in this work to monitor the tritium concentration at nuclear power plants (CANDU-type) and at nuclear fuel reprocessing plants and to diagnose fusion experiments. Two different depth profiling measuring procedures are presented. AMS measurements of the tritium, created in D–D fusion reactions offered detailed information about the spatial distribution of Triton fluxes to the vessel wall of a Tokamak, about the plasma confinement and about the interaction of the heating neutral deuterium beam with the confined and rotating plasma.

Through his reflections on dealing with treatment for brain cancer and the resulting disabilities, the author helps to create an intriguing insight into how his experience was fashioned by the medical, emotional, and multicultural forces he faced. Prominent among the issues discussed are his coping with fear through humor, being able to accept his disabilities, and presenting a hopeful and lighter side to a personal hardship.

Before the mid-1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV-1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV-seropositive patients, age 13-88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross-sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV-1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV-1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV-1-positive participants had > or = 200 CD4+ cells microL(-1), only 59% were on HAART. HIV-1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti-HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV-1-positive than HIV-1-negative participants (85% vs. 70%, P < 0.0001). HIV-1-positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV-negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self-reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non-Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV-1, HCV or both.

The production of radioactive isotopes in scintillation detectors by muons and their secondary shower particles has been studied experimentally at the SPS muon beam at CERN. This paper shows the results obtained in cross-section measurements on liquid scintillator targets, especially on 12 C which is the most relevant target in these organic materials. Their energy dependence has been deduced from the cross-sections determined at two muon energies 100 and 190 GeV. Based on the measured cross-sections the muon-induced background rates for the forthcoming solar neutrino experiments BOREXINO and KAMLAND have been calculated for different energy regions that are relevant for solar neutrino physics.

The health education and promotion profession is facing a series of teacher preparation challenges related to the delivery of quality school health education/promotion programmes. The challenges occurring in the United States are also present in a variety of other regions as the education structure attempts to ensure that students receive a sound preparation in health education and promotion during their school experience. The challenges can be categorised into the following areas: • Quality and quantity of professional preparation for teachers during their preservice university training; • Need for in-service of teachers already in the K-1 2 workforce (in the USA grades K -12 are broadly equivalent to ages five to 17 years); • University faculty workforce professional development needs; • Research to provide baseline data for future standards development. Because there is a direct connection between community and school and parents and teachers at the K-1 2 level of education, the demand for highly skilled teachers and professional development is playing out at that level much more rapidly than at the university level. The relative isolation of some university faculty and programmes has developed an interesting situation in which many administrators and master teachers at the K-12 level of education have a better grasp and understanding of new teaching and learning strategies and tools than professors at the university level. This has happened at the same time when there is also a shortage of university professors entering school health education/promotion teacher education. This confluence of realities may predicate the need for a radical change in university based teacher preparation in health education/promotion. The overwhelming challenge for many countries including the United States remains the large number of teachers in the current workforce who must be provided professional development experiences. Currently both the National Health Education Standards for K-1 students and teacher preparation standards in health education reflect best practice theory only. There is no national data to support the standards. During the next ten years it is imperative that nationwide data be collected, compiled and analysed on actual learning outcomes for both K-12 students and health education teacher candidates. This will allow the next set of standards at both of the above-mentioned levels to reflect the knowledge and skills that have been actually attained and demonstrated. It will also be a basis for creating revisions and expansions in such a way that national standards can be an actual measure by which student performance can be judged. It is hoped that the rising tide of both national and international interest in having an increasingly health literate population will inspire members of the profession to be creative in the development of educational approaches, strategic partnerships, and funding to put strong systems of teacher preparation in place for the future.

Summary Secondary factor VIII (FVIII) prophylaxis converts severe haemophiliacs (FVIII:C

Two cases of spontaneous arterial dissection occurring in young, multiparous women shortly after delivery of uncomplicated pregnancies are described. Histologic analysis of arterial tissue samples obtained in both cases at points near and remote from the dissection sites shows evidence of significant arterial degeneration and loss of integrity, with changes similar to those observed in pregnant women, women using oral contraceptives, and animals given female sex hormones. The types of arterial lesions associated with pregnancy and their sites of predilection and the etiologic roles of the hemodynamic stresses of pregnancy and hormones are discussed. (J VASC SURG 1995;21:515-20.)

In this paper measurements of the radionuclides of 36Cl, 41Ca, 60Co, 152Eu and 154Eu in samples from Hiroshima, which were exposed to neutrons of the A-bomb explosion, are interpreted. In order to calculate the neutron spectrum at the sample site, neutron transport calculations using Monte Carlo techniques were carried out. Activation profiles in a granite mock-up irradiated with reactor neutrons could be reproduced by this method using DS86 input parameters. The calculated neutron spectrum at the sample site for non-thermal neutrons is identical to that obtained in DS86, but contains some 50% more thermal neutrons. The influence of parameters like soil composition, source terms and air humidity on the activation of these radioisotopes is discussed. The granite-covered earth at the sample site, for example, hardens the spectrum in comparison with DS86 values. Even when using a fission spectrum pointing downward and neglecting air humidity one cannot explain our 36Cl measurements. If the effective thermal neutron fluences, that have a similar ratio of resonance integral to thermal neutron capture cross sections obtained from 36Cl, 41Ca and 152Eu, are averaged, a bomb yield of about 16 kt is deduced in agreement with a bomb yield of (15 +/- 3) kt estimated in DS86.

The antiretroviral drugs azidothymidine (AZT) and 9-(-2-phosphonyl-methoxyethyl)adenine (PMEA) were individually tested for prevention of simian immunodeficiency virus (SIVmne) infection in macaques (Macaca fascicularis). Macaques were pretreated with either drug before inoculation with SIVmne, and drug treatment was continued for four weeks. The virus, antibody, and clinical status of the macaques was monitored for up to 36 weeks following inoculation. While AZT prophylaxis resulted in reduced virus load in some macaques, PMEA prophylaxis was highly efficacious in preventing acute SIVmne infection.

In a previous pharmacokinetic/pharmacodynamic study in nonbleeding hemophilia patients, variability in laboratory response to recombinant factor VIIa (rFVIIa) 90 μg/kg was noted, and the patients were described as delayed or rapid laboratory responders based on time to clot formation. The current study determined whether in-vitro experiments could reproduce previous in-vivo findings; whether the delayed laboratory response to rFVIIa 90 μg/kg is improved by spiking with high-dose rFVIIa or rFVIIa analogue (vatreptacog alfa); whether a dose-response is observed with our method. In-vitro experiments were conducted in our previous patient cohort using rFVIIa 1.28 and 3.84 μg/ml and vatreptacog alfa 0.28 and 0.56 μg/ml. Whole blood studies were conducted using the Hemodyne Hemostasis Analysis System (platelet contractile force, clot elastic modulus, force onset time) and rotational thromboelastometry (clotting time, maximum clot firmness). Spiking with rFVIIa 1.28 μg/ml showed the same distribution of delayed and rapid laboratory response as observed previously. Increasing in-vitro rFVIIa concentrations improved the coagulation parameters; however, there remained delayed and rapid responders. Vatreptacog alfa improved the coagulation parameters at all concentrations tested, and the 0.56 μg/ml concentration normalized the force onset time, platelet contractile force, clot elastic modulus and clotting time parameters. A dose-response was observed with both assays. There was good agreement between the laboratory responses obtained after intravenous administration of rFVIIa 90 μg/kg and in-vitro spiking studies. Escalating rFVIIa and vatreptacog alfa concentrations improved coagulation parameters in all patients compared to rFVIIa 1.28 μg/ml. Vatreptacog alfa produced more pronounced coagulation effects at lower concentrations than rFVIIa; and the 0.56 μg/ml concentration completely normalized responses in all patients. (Less)

Recombinant FVIIa is a haemostatic agent administered to patients with severe FVIII or FIX deficiency with inhibitors. Although rFVIIa is effective at stopping bleeding, a reliable assay to monitor its effect is lacking. To characterize the pharmacokinetics and global coagulation effects of rFVIIa for 6 h following a IV dose of 90 μg kg⁻¹. Ten non-bleeding subjects with severe FVIII or FIX deficiency were infused with a single-dose of rFVIIa 90 μg k⁻¹ body weight and blood was collected before and at 0.5, 1, 2, 4 and 6 h postdose. Global haemostasis was characterized throughout the study utilizing whole blood analyses (Hemodyne HAS, TEG, ROTEM). The clearance and half-life of factor FVII:C was estimated as 39.0 ± 8.8 mL h⁻¹ kg⁻¹ and 2.1 ± 0.2 h respectively. There was good inter-assay agreement with respect to clot initiation parameters (R, CT and FOT) and these parameters all fell to a mean of approximately 9 min following rFVIIa dosing. The platelet contractile force (PCF) and clot elastic modulus (CEM) were positively correlated to FVII:C (P0.0001), and these parameters were dynamic throughout the 6-h period. The MA and MCF did not correlate to FVII:C nor did they significantly change during the study. Prothrombin F1 + 2 significantly increased following rFVIIa dosing (P0.001), but remained steady throughout the study. There was no change in D-dimer concentrations over time. The FOT, R and CT characterized clot initiation following rFVIIa dosing. The PCF and CEM were correlated to FVII:C and characterized the dynamics of platelet function and clot strength over the rFVIIa dosing interval. The clinical significance of these findings needs additional study.

Summary. Recombinant FVIIa is a haemostatic agent administered to patients with severe FVIII or FIX deficiency with inhibitors. Although rFVIIa is effective at stopping bleeding, a reliable assay to monitor its effect is lacking. To characterize the pharmacokinetics and global coagulation effects of rFVIIa for 6 h following a IV dose of 90 μg kg(-1) . Ten non-bleeding subjects with severe FVIII or FIX deficiency were infused with a single-dose of rFVIIa 90 μg kg(-1) body weight and blood was collected before and at 0.5, 1, 2, 4 and 6 h postdose. Global haemostasis was characterized throughout the study utilizing whole blood analyses (Hemodyne HAS, TEG, ROTEM). The clearance and half-life of factor FVII:C was estimated as 39.0 ± 8.8 mL h(-1) kg(-1) and 2.1 ± 0.2 h respectively. There was good inter-assay agreement with respect to clot initiation parameters (R, CT and FOT) and these parameters all fell to a mean of approximately 9 min following rFVIIa dosing. The platelet contractile force (PCF) and clot elastic modulus (CEM) were positively correlated to FVII:C (P < 0.0001), and these parameters were dynamic throughout the 6-h period. The MA and MCF did not correlate to FVII:C nor did they significantly change during the study. Prothrombin F1 + 2 significantly increased following rFVIIa dosing (P < 0.001), but remained steady throughout the study. There was no change in D-dimer concentrations over time. The FOT, R and CT characterized clot initiation following rFVIIa dosing. The PCF and CEM were correlated to FVII:C and characterized the dynamics of platelet function and clot strength over the rFVIIa dosing interval. The clinical significance of these findings needs additional study. (Less)

Plasmacytoid urothelial carcinomas (PUC) along with micropapillary urothelial carcinoma (MPC), small cell cancer, and nested-typed tumors are among the rare variations of urothelial carcinomas. The molecular characterization of PUC and MPC is currently the focus of our research on bladder cancer which we are conducting in cooperation with the Institute of Pathology in Erlangen. PUCs account for approximately 0.9% of all urothelial carcinomas. The diagnosis of these rare variants has acquired increasing importance since this may have prognostic and possibly therapeutic consequences for the patients. By analysis of 32 PUCs we were able to demonstrate the most comprehensive results available to date on the underlying molecular and clinical characteristics of these variants. Micropapillary cancers have already been described in multiple organs. Micropapillary breast cancer represent an individual entity with characteristic genomic aberrations and corresponding clinical and pathological features.

To evaluate the hemostatic effects of NN1731 and rFVIIa, an ex-vivo study in hemophilia patients used the Hemodyne Hemostasis Analysis System (HAS) to measure platelet contractile force (PCF), clot elastic modulus (CEM), and force onset time (FOT), and the Haemoscope Thrombelastograph (TEG) to measure reaction time (R), kinetics time (K), and maximum amplitude (MA). Blood samples from 10 healthy volunteers and 10 Factor VIII-deficient patients of varying severity (mild, moderate, severe), were spiked with rFVIIa and NN1731 (both 0.64 and 1.28 microg/ml, respectively) and analyzed to characterize platelet function and clot kinetics. There was wide variability in the rFVIIa response. NN1731 had greater and more consistent effects on PCF, CEM, FOT, R, and K relative to rFVIIa, in all hemophilia groups. The lowest NN1731 concentration (0.64 microg/ml) shortened R and FOT, and increased CEM and PCF more than rFVIIa 1.28 microg/ml. NN1731 normalized clotting parameters equivalent to values obtained in healthy volunteers. FOT and R were highly correlated (r = 0.96). No correlation was observed between CEM and MA. NN1731 produced less variable, more pronounced and predictable ex-vivo hemostatic effects on PCF, CEM, FOT, R and K than rFVIIa in all hemophilia groups. HAS and TEG assays provided similar estimates of FOT and R, however CEM appeared to be more sensitive than MA to changes in clot firmness.

Type 3 von Willebrand disease (VWD) is a rare bleeding disorder with markedly decreased or absent von Willebrand factor (VWF) protein, accompanied by a parallel decrease in VWF function and factor VIII (FVIII) activity. The goal of this study was to describe the population of patients enrolled in the USA Centers for Disease Control Universal Data Collection (UDC) study with type 3 VWD, defined as a VWF:Ag of