Observation of Andreev Reflection Enhanced Shot Noise

We have experimentally investigated the quasiparticle shot noise in NbN/MgO/NbN superconductor - insulator - superconductor tunnel junctions. The observed shot noise is significantly larger than theoretically expected. We attribute this to the occurrence of multiple Andreev reflection processes in pinholes present in the MgO barrier. This mechanism causes the current to flow in large charge quanta (Andreev clusters), with a voltage dependent average value of m = 1+ 2 Delta/eV times the electron charge. Because of this charge enhancement effect, the shot noise is increased by the factor m.Comment: 4 pages, 5 figures include

Population pharmacokinetics of the von Willebrand factor-factor VIII interaction in patients with von Willebrand disease

Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may improve dosing and quality of care. In total, 695 VWF:Act and 894 FVIII level measurements from 118 patients (174 surgeries) who were treated perioperatively with the VWF/FVIII concentrate were used to develop this population PK model using nonlinear mixed-effects modeling. VWF:Act and FVIII levels were analyzed simultaneously using a turnover model. The protective effect of VWF:Act on FVIII clearance was described with an inhibitory maximum effect function. An average perioperative VWF:Act level of 1.23 IU/mL decreased FVIII clearance from 460 mL/h to 264 mL/h, and increased FVIII half-life from 6.6 to 11.4 hours. Clearly, in the presence of VWF, FVIII clearance decreased with a concomitant increase of FVIII half-life, clarifying the higher FVIII levels observed after repetitive dosing with this concentrate. VWF:Act and FVIII levels during perioperative treatment were described adequately by this newly developed integrated population PK model. Clinical application of this model may facilitate more accurate targeting of VWF:Act and FVIII levels during perioperative treatment with this specific VWF/FVIII concentrate (Humate P/Haemate P).Thrombosis and Hemostasi

A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients >= 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients >= 5 years

Perioperative pharmacokinetic-guided factor VIII concentrate dosing in haemophilia (OPTI-CLOT trial):an open-label, multicentre, randomised, controlled trial

Background Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. Methods In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of Findings Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49.1 years (IQR 35.0 to 62.1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred. Interpretation Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care. Copyright (C) 2021 Elsevier Ltd. All rights reserved

von Willebrand Factor and Factor VIII Clearance in Perioperative Hemophilia A Patients

Background von Willebrand factor (VWF) is crucial for optimal dosing of factor VIII (FVIII) concentrate in hemophilia A patients as it protects FVIII from premature clearance. To date, it is unknown how VWF behaves and what its impact is on FVIII clearance in the perioperative setting. Aim To investigate VWF kinetics (VWF antigen [VWF:Ag]), VWF glycoprotein Ib binding (VWF:GPIbM), and VWF propeptide (VWFpp) in severe and moderate perioperative hemophilia A patients included in the randomized controlled perioperative OPTI-CLOT trial. Methods Linear mixed effects modeling was applied to analyze VWF kinetics. One-way and two-way analyses of variance were used to investigate perioperative VWFpp/VWF:Ag ratios and associations with surgical bleeding. Results Fifty-nine patients with median age of 48.8 years (interquartile range: 34.8-60.0) were included. VWF:Ag and VWF:GPIbM increased significantly postoperatively. Blood type non-O or medium risk surgery were associated with higher VWF:Ag and VWF:GPIbM levels compared with blood type O and low risk surgery. VWFpp/VWF:Ag was significantly higher immediately after surgery than 32 to 57 hours after surgery (p < 0.001). Lowest VWF:Ag quartile (0.43-0.92 IU/mL) was associated with an increase of FVIII concentrate clearance of 26 mL/h (95% confidence interval: 2-50 mL/h) compared with highest VWF antigen quartile (1.70-3.84 IU/mL). VWF levels were not associated with perioperative bleeding F (4,227) = 0.54, p = 0.710. Conclusion VWF:Ag and VWF:GPIbM levels increase postoperatively, most significantly in patients with blood type non-O or medium risk surgery. Lower VWF antigen levels did not lead to clinically relevant higher FVIII clearance. VWF:Ag or VWF:GPIbM levels were not associated with perioperative hemorrhage

The impact of para-aortic lymph node irradiation on disease-free survival in patients with cervical cancer: A systematic review and meta-analysis

Background: Patients with locally advanced cervical cancer without para-aortic lymph node metastases (PAO-LNM) at diagnosis who undergo concurrent chemoradiotherapy are at 4-11% risk of developing PAO-LNM during follow-up. Some studies suggest a beneficial influence of elective para-aortic radiotherapy (PAO-RT) on disease-free survival (DFS) in these patients. The aim of this study was to systematically review and meta-analyse literature on the impact of PAO-RT on DFS in cervical cancer patients. Methods: A systematic search of PubMed/MEDLINE and EMBASE databases was performed. The analysis included intervention studies that reported on DFS in patients with cervical cancer who received chemotherapy and pelvic radiotherapy with or without PAO-RT. From each included study, relevant study characteristics and outcome data including the hazard ratio (HR) adjusted for potential confounders were extracted. An overall pooled adjusted hazard ratio (aHR) for DFS after PAO-RT versus no PAO-RT was calculated using a random-effects model. Results: A total of 2,016 articles were evaluated. Eleven articles were included in the systematic review, of which 3 were appropriate for quantitative meta-analysis. Pooling of these 3 cohorts (including 1,113 patients) demonstrated a statistically significant association between PAO-RT and DFS (pooled aHR 0.87, 95% confidence interval: 0.79-0.97). No significant heterogeneity among reported aHRs was observed (I 2 = 0.0%). Conclusions: This meta-analysis suggests a modest but significant beneficial impact of elective para-aortic radiotherapy on DFS in patients with locally advanced cervical cancer who undergo concurrent chemoradiotherapy. This finding based on non-randomized studies provides an imperative for further investigation in prospective controlled trials

Effective industrial modeling for high-tech systems: The example of Happy Flow

Published and used by INCOSE with permission. Abstract. In the design of high-tech systems like copiers, wafer steppers and televisions, modeling plays an important role. However, not all developed models are industrially successful. It would be very beneficial if guidelines were available on how to create industrially effective models that support the system architects and speed up the multi-disciplinary design of high-tech machines. In this paper, we describe a very successful industrial model in the context of the design of copiers. The model is developed for the design of the paper transport system (the mechanical layout of the paper track, the schedule of print jobs, sensors, actuators, etc.) in a multi-functional office copier. As most other activities in the printer are synchronized to the paper transport system, this design issue is at the heart of the overall design and has a major influence on the total functioning of the machine. The so-called Happy Flow model is based on kinematic modeling and its generic elements are not restricted to copiers only. Its main ideas are applicable to a much wider range of mechatronic products. It is important to learn from such instances of successful industrial models. The aim of this paper is to identify the success factors of this particular model, which forms a first step towards a more systematic method on how to construct industrial effective models

Emicizumab Dosing in Children and Adults with Hemophilia A: Simulating a User-Friendly and Cost-Efficient Regimen

BACKGROUND: When emicizumab is dosed according to label, clinicians are obligated to discard or overdose medication due to discrepancies between calculated dose and vial content. The aim of this study was to compose a cost-efficient emicizumab maintenance dosing regimen using Monte Carlo simulation based on vial size, patient-friendly intervals, and patient characteristics, while striving for similar plasma concentrations as observed in clinical trials. METHODS: Monte Carlo simulations were used to investigate alternative dosing regimens in patients weighing 3 to 150 kg. Simulated regimens were targeted to achieve median emicizumab plasma concentrations at a steady state (C av,ss) of 40 to 60 (90% range: 25-95) µg/mL. The cost-efficiency of the alternative dosing regimen was calculated in mg and costs saved per patient per year. RESULTS: The developed alternative dosing regimen achieved similar emicizumab C av,ss levels compared with the registered dosing regimen with a median deviation of less than 2 µg/mL in 78% of the body-weight categories. A dose of 60 mg every 3 weeks was advised for children weighing 12 to 16 kg, while adults weighing 76 to 85 kg can receive 120 mg emicizumab every week. Compared with the registered weekly dosing of 1.5 mg/kg, alternative dosing saved €35,434 per year in children weighing between 12 and 16 kg. For patients weighing 76 to 85 kg, the median saving was €29,529 (range: €0-€59,057). CONCLUSION: This alternative maintenance dosing scheme-applicable in patients with hemophilia A receiving emicizumab prophylaxis-reduces financial costs, avoids medication spillage, and is patient-friendly without loss of efficacy

Emicizumab Dosing in Children and Adults with Hemophilia A: Simulating a User-Friendly and Cost-Efficient Regimen

BACKGROUND: When emicizumab is dosed according to label, clinicians are obligated to discard or overdose medication due to discrepancies between calculated dose and vial content. The aim of this study was to compose a cost-efficient emicizumab maintenance dosing regimen using Monte Carlo simulation based on vial size, patient-friendly intervals, and patient characteristics, while striving for similar plasma concentrations as observed in clinical trials. METHODS: Monte Carlo simulations were used to investigate alternative dosing regimens in patients weighing 3 to 150 kg. Simulated regimens were targeted to achieve median emicizumab plasma concentrations at a steady state (C av,ss) of 40 to 60 (90% range: 25-95) µg/mL. The cost-efficiency of the alternative dosing regimen was calculated in mg and costs saved per patient per year. RESULTS: The developed alternative dosing regimen achieved similar emicizumab C av,ss levels compared with the registered dosing regimen with a median deviation of less than 2 µg/mL in 78% of the body-weight categories. A dose of 60 mg every 3 weeks was advised for children weighing 12 to 16 kg, while adults weighing 76 to 85 kg can receive 120 mg emicizumab every week. Compared with the registered weekly dosing of 1.5 mg/kg, alternative dosing saved €35,434 per year in children weighing between 12 and 16 kg. For patients weighing 76 to 85 kg, the median saving was €29,529 (range: €0-€59,057). CONCLUSION: This alternative maintenance dosing scheme-applicable in patients with hemophilia A receiving emicizumab prophylaxis-reduces financial costs, avoids medication spillage, and is patient-friendly without loss of efficacy

Emicizumab Dosing in Children and Adults with Hemophilia A: Simulating a User-Friendly and Cost-Efficient Regimen

Background When emicizumab is dosed according to label, clinicians are obligated to discard or overdose medication due to discrepancies between calculated dose and vial content. The aim of this study was to compose a cost-efficient emicizumab maintenance dosing regimen using Monte Carlo simulation based on vial size, patient-friendly intervals, and patient characteristics, while striving for similar plasma concentrations as observed in clinical trials.Methods Monte Carlo simulations were used to investigate alternative dosing regimens in patients weighing 3 to 150kg. Simulated regimens were targeted to achieve median emicizumab plasma concentrations at a steady state ( C-av,C-ss ) of 40 to 60 (90% range: 25-95) mu g/mL. The cost-efficiency of the alternative dosing regimen was calculated in mg and costs saved per patient per year.Results The developed alternative dosing regimen achieved similar emicizumab C-av,C-ss levels compared with the registered dosing regimen with a median deviation of less than 2 mu g/mL in 78% of the body-weight categories. A dose of 60mg every 3 weeks was advised for children weighing 12 to 16kg, while adults weighing 76 to 85kg can receive 120mg emicizumab every week. Compared with the registered weekly dosing of 1.5mg/kg, alternative dosing saved Euro35,434 per year in children weighing between 12 and 16kg. For patients weighing 76 to 85kg, the median saving was Euro29,529 (range: Euro0-Euro59,057).Conclusion This alternative maintenance dosing scheme-applicable in patients with hemophilia A receiving emicizumab prophylaxis-reduces financial costs, avoids medication spillage, and is patient-friendly without loss of efficacy