Efficacy, safety and pharmacokinetics of a new high-purity factor X concentrate in subjects with hereditary factor X deficiency.

IntroductionHereditary factor X (FX) deficiency is a rare bleeding disorder affecting 1:500 000 to 1:1 000 000 of individuals. Until recently, no specific replacement factor concentrate was available.AimThe aim of this study was to assess safety and efficacy of a new, high‐purity plasma‐derived FX concentrate (pdFX) in subjects with hereditary FX deficiency.MethodsSubjects aged ≥12 years with moderate or severe FX deficiency (plasma FX activity <5 IU dL−1) received 25 IU kg−1 pdFX as on‐demand treatment or short‐term prophylaxis for 6 months to 2 years. Subjects assessed pdFX efficacy for each bleed; at end‐of‐study, investigators assessed overall pdFX efficacy. Blood samples for pharmacokinetic analysis were obtained at baseline and ≥6 months. Safety was assessed by adverse events (AEs), inhibitor development and changes in laboratory parameters.ResultsSixteen enrolled subjects (six aged 12–17 years; 10 aged 18–58 years) received a total of 468 pdFX infusions. In the 187 analysed bleeds, pdFX efficacy was categorized as excellent, good, poor or unassessable in 90.9%, 7.5%, 1.1% and 0.5% of bleeds respectively; 83% of bleeds were treated with one infusion. For pdFX, mean (median; interquartile range) incremental recovery and half‐life were 2.00 (2.12; 1.79–2.37) IU dL−1 per IU kg−1 and 29.4 (28.6; 25.8–33.1) h respectively. No serious AEs possibly related to pdFX or evidence of FX inhibitors were observed, and no hypersensitivity reactions or clinically significant trends were detected in laboratory parameters.ConclusionThese results demonstrate that a dose of 25 IU kg−1 pdFX is safe and efficacious for on‐demand treatment and short‐term prophylaxis in subjects with moderate or severe hereditary FX deficiency

Investigation of the Interaction between the Large and Small Subunits of Potato ADP-Glucose Pyrophosphorylase

ADP-glucose pyrophosphorylase (AGPase), a key allosteric enzyme involved in higher plant starch biosynthesis, is composed of pairs of large (LS) and small subunits (SS). Current evidence indicates that the two subunit types play distinct roles in enzyme function. Recently the heterotetrameric structure of potato AGPase has been modeled. In the current study, we have applied the molecular mechanics generalized born surface area (MM-GBSA) method and identified critical amino acids of the potato AGPase LS and SS subunits that interact with each other during the native heterotetrameric structure formation. We have further shown the role of the LS amino acids in subunit-subunit interaction by yeast two-hybrid, bacterial complementation assay and native gel. Comparison of the computational results with the experiments has indicated that the backbone energy contribution (rather than the side chain energies) of the interface residues is more important in identifying critical residues. We have found that lateral interaction of the LS-SS is much stronger than the longitudinal one, and it is mainly mediated by hydrophobic interactions. This study will not only enhance our understanding of the interaction between the SS and the LS of AGPase, but will also enable us to engineer proteins to obtain better assembled variants of AGPase which can be used for the improvement of plant yield

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Background: Congenital fibrinogen deficiency is an ultra-rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. Methods: Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA\uae, Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four-point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. Results: Twenty-five afibrinogenemia patients were treated with HFC: 24 for on-demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92-0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95-0.999). Mean&nbsp;\ub1&nbsp;standard deviation (SD) increase in MCF was 5.8&nbsp;\ub1&nbsp;2.5&nbsp;mm one hour after the first HFC infusion (mean&nbsp;\ub1&nbsp;SD dose, 61.88&nbsp;\ub1&nbsp;11.73&nbsp;mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80&nbsp;mg/kg [34.09-225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82-1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. Conclusions: Human fibrinogen concentrate was efficacious for on-demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia

Microcantilever based disposable viscosity sensor for serum and blood plasma measurements

This paper proposes a novel method for measuring blood plasma and serum viscosity with a microcantilever-based MEMS sensor. MEMS cantilevers are made of electroplated nickel and actuated remotely with magnetic field using an electro-coil. Real-time monitoring of cantilever resonant frequency is performed remotely using diffraction gratings fabricated at the tip of the dynamic cantilevers. Only few nanometer cantilever deflection is sufficient due to interferometric sensitivity of the readout. The resonant frequency of the cantilever is tracked with a phase lock loop (PLL) control circuit. The viscosities of liquid samples are obtained through the measurement of the cantilever's frequency change with respect to a reference measurement taken within a liquid of known viscosity. We performed measurements with glycerol solutions at different temperatures and validated the repeatability of the system by comparing with a reference commercial viscometer. Experimental results are compared with the theoretical predictions based on Sader's theory and agreed reasonably well. Afterwards viscosities of different Fetal Bovine Serum and Bovine Serum Albumin mixtures are measured both at 23. °C and 37. °C, body temperature. Finally the viscosities of human blood plasma samples taken from healthy donors are measured. The proposed method is capable of measuring viscosities from 0.86. cP to 3.02. cP, which covers human blood plasma viscosity range, with a resolution better than 0.04. cP. The sample volume requirement is less than 150. μl and can be reduced significantly with optimized cartridge design. Both the actuation and sensing are carried out remotely, which allows for disposable sensor cartridges. © 2013

Perceptually guided computer-generated holography

Computer-Generated Holography (CGH) promises to deliver genuine, high-quality visuals at any depth. We argue that combining CGH and perceptually guided graphics can soon lead to practical holographic display systems that deliver perceptually realistic images. We propose a new CGH method called metameric varifocal holograms. Our CGH method generates images only at a user’s focus plane while displayed images are statistically correct and indistinguishable from actual targets across peripheral vision (metamers). Thus, a user observing our holograms is set to perceive a high quality visual at their gaze location. At the same time, the integrity of the image follows a statistically correct trend in the remaining peripheral parts. We demonstrate our differentiable CGH optimization pipeline on modern GPUs, and we support our findings with a display prototype. Our method will pave the way towards realistic visuals free from classical CGH problems, such as speckle noise or poor visual quality

Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery

Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. Summary: Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40\u201360\ua0IU\ua0kg 121, VWF ristocetin cofactor activity was measured 12\u201324\ua0h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3\ua0h before surgery, rVWF was administered alone 1\ua0h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n\ua0=\ua010), minor (n\ua0=\ua04) and oral (n\ua0=\ua01) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6\ua0h, which were sustained for 72\u201396\ua0h; 70% (n\ua0=\ua07/10) of major surgeries\ua0were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two\ua0patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery

Revisiting Goal-Oriented Requirements Engineering with a Regulation View

Goal-Oriented Requirements Engineering (GORE) is considered to be one of the main achievements that the Requirements Engineering field has produced since its inception. Several GORE methods were designed in the last twenty years in both research and industry. In analyzing individual and organizational behavior, goals appear as a natural element. There are other organizational models that may better explain human behavior, albeit at the expense of more complex models. We present one such alternative model that explains individual and organizational survival through continuous regulation. We give our point of view of the changes needed in GORE methods in order to support this alternative view through the use of maintenance goals and beliefs. We illustrate our discussion with the real example of a family practitioner association that needed a new information system

A framework for designing cloud forensic‑enabled services (CFeS)

Cloud computing is used by consumers to access cloud services. Malicious actors exploit vulnerabilities of cloud services to attack consumers. The link between these two assumptions is the cloud service. Although cloud forensics assists in the direction of investigating and solving cloud-based cyber-crimes, in many cases the design and implementation of cloud services falls back. Software designers and engineers should focus their attention on the design and implementation of cloud services that can be investigated in a forensic sound manner. This paper presents a methodology that aims on assisting designers to design cloud forensic-enabled services. The methodology supports the design of cloud services by implementing a number of steps to make the services cloud forensic-enabled. It consists of a set of cloud forensic constraints, a modelling language expressed through a conceptual model and a process based on the concepts identified and presented in the model. The main advantage of the proposed methodology is the correlation of cloud services’ characteristics with the cloud investigation while providing software engineers the ability to design and implement cloud forensic-enabled services via the use of a set of predefined forensic related task

A systematic review of protocol studies on conceptual design cognition

This paper reports the first systematic review and synthesis of protocol studies on conceptual design cognition. 47 protocol studies from the domains of architectural design, engineering design, and product de-sign engineering were reviewed towards answering the following re-search question: What is our current understanding of the cognitive processes involved in conceptual design tasks carried out by individual designers? Studies were found to reflect three viewpoints on the cognitive nature of designing, namely: design as search; design as ex-ploration; and design activities. Synthesising the findings of individual studies yielded a classification of cognitive processes involved in con-ceptual design tasks, described in different terms across different viewpoints. Towards a common terminology, these processes are posi-tioned within the cognitive psychology literature, revealing seven basic types of process that appear to be fundamental to designing across all viewpoints: memory (working and long term); visual perception; men-tal imagery; attention; semantic association; cognitive control; and higher-order processes, e.g. analysis and reasoning. The development of common cognitive models of conceptual design, grounded in a sci-entifically rigorous understanding of design cognition, is identified as an avenue for future research