Evidence of Electron Heating by Alpha Particles in JET Deuterium-Tritium Plasmas.

The fusion-born alpha particle heating in magnetically confined fusion machines is a high priority subject for studies. The self-heating of thermonuclear fusion plasma by alpha particles was observed in recent deuterium-tritium (D-T) experiments on the joint European torus. This observation was possible by conducting so-called "afterglow" experiments where transient high fusion yield was achieved with neutral beam injection as the only external heating source, and then termination of the heating at peak performance. This allowed the first direct evidence for electron heating of plasmas by fusion-born alphas to be obtained. Interpretive transport modeling of the relevant D-T and reference deuterium discharges is consistent with the alpha particle heating observation.

Fusion product measurements by nuclear diagnostics in the Joint European Torus deuterium-tritium 2 campaign (invited).

A new deuterium-tritium experimental, DTE2, campaign has been conducted at the Joint European Torus (JET) between August 2021 and late December 2021. Motivated by significant enhancements in the past decade at JET, such as the ITER-like wall and enhanced auxiliary heating power, the campaign achieved a new fusion energy world record and performed a broad range of fundamental experiments to inform ITER physics scenarios and operations. New capabilities in the area of fusion product measurements by nuclear diagnostics were available as a result of a decade long enhancement program. These have been tested for the first time in DTE2 and a concise overview is provided here. Confined alpha particle measurements by gamma-ray spectroscopy were successfully demonstrated, albeit with limitations at neutron rates higher than some 1017 n/s. High resolution neutron spectroscopy measurements with the magnetic proton recoil instrument were complemented by novel data from a set of synthetic diamond detectors, which enabled studies of the supra-thermal contributions to the neutron emission. In the area of escaping fast ion diagnostics, a lost fast ion detector and a set of Faraday cups made it possible to determine information on the velocity space and poloidal distribution of the lost alpha particles for the first time. This extensive set of data provides unique information for fundamental physics studies and validation of the numerical models, which are key to inform the physics and scenarios of ITER.

Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery.

Essentials Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. Population PK parameter values for clearance and V1 were 284 mL h-170 kg-1 and 5450 mL70 kg-1. Perioperative PK parameters differ from those during non-surgical prophylactic treatment. SUMMARY: Background Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under- and overdosing occurs frequently during surgery. Aim The objective was to quantify and explain the interpatient variability of perioperatively administered plasma-derived (pd) and recombinant (r) FIX concentrates. Methods Data were collected from 118 patients (median age, 40 years [range, 0.2-90]; weight, 79 kg [range, 5.3-132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NONMEM. Results Measured perioperative FIX level vs. time profiles were adequately described using a three-compartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h-170 kg-1 (18%); V1, 5450 mL70 kg-1 (19%); Q2, 110 mL h-170 kg-1; V2, 4800 mL70 kg-1; Q3, 1610 mL h-170 kg-1; V3, 2040 mL70 kg-1. From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. Conclusions The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery.

Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise.

INTRODUCTION: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. AIM: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed. METHODS: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL-1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines. RESULTS: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL-1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL-1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%). CONCLUSION: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment.

The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO.

Enhanced half-life factor VIII and IX products are being introduced into routine clinical practice. Published data report on clinical trials and there are limited data available on how to use these products in routine clinical practice. Many patients, for example, those with a past history of an inhibitor, have been excluded from clinical trials and there are limited data published on children. This guidance document is a consensus statement from the UK Haemophilia Centres Doctors' Organisation and aims to give pragmatic advice on the use of these products in routine practice.

Guideline on aspects of cancer-related venous thrombosis

The guideline was drafted by a writing group identified by the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). All the authors are consultants in haematology in the UK. A search was performed of PubMed and Embase using the term 'cancer' combined with 'thrombosis', 'treatment', 'prophylaxis' and 'clinical presentation'. The search covered articles published up until December 2014. Only human studies were included and articles not written in English were excluded. References in recent reviews were also examined. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH and the BCSH executive. The guideline was then reviewed by the sounding board of the British Society for Haematology (BSH). This comprises 50 or more members of the BSH who have reviewed the guidance and commented on the content and application to the UK setting. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found at: http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the prevention and management of venous thromboembolism (VTE) in patients with cancer and to advise on an approach to screening for cancer in patients with unprovoked VTE in whom cancer was not initially suspected based on clinical grounds.(AU)

Investigating fusion plasma instabilities in the Mega Amp Spherical Tokamak using mega electron volt proton emissions (invited).

The proton detector (PD) measures 3 MeV proton yield distributions from deuterium-deuterium fusion reactions within the Mega Amp Spherical Tokamak (MAST). The PD's compact four-channel system of collimated and individually oriented silicon detectors probes different regions of the plasma, detecting protons (with gyro radii large enough to be unconfined) leaving the plasma on curved trajectories during neutral beam injection. From first PD data obtained during plasma operation in 2013, proton production rates (up to several hundred kHz and 1 ms time resolution) during sawtooth events were compared to the corresponding MAST neutron camera data. Fitted proton emission profiles in the poloidal plane demonstrate the capabilities of this new system.

Conceptual design of a neutron camera for MAST Upgrade.

This paper presents two different conceptual designs of neutron cameras for Mega Ampere Spherical Tokamak (MAST) Upgrade. The first one consists of two horizontal cameras, one equatorial and one vertically down-shifted by 65 cm. The second design, viewing the plasma in a poloidal section, also consists of two cameras, one radial and the other one with a diagonal view. Design parameters for the different cameras were selected on the basis of neutron transport calculations and on a set of target measurement requirements taking into account the predicted neutron emissivities in the different MAST Upgrade operating scenarios. Based on a comparison of the cameras' profile resolving power, the horizontal cameras are suggested as the best option.

A prospective registry of European haemophilia B patients receiving nonacog alfa, recombinant human factor IX, for usual use.

Nonacog alfa, a recombinant factor IX (FIX) used for the treatment of haemophilia B, was approved in Europe in 1998. In accordance with European Medicines Agency requirements, a registry study was conducted from 2002 to 2009. A reformulated iso-osmotic version was approved for European use in 2007. This study was conducted to evaluate the safety of nonacog alfa in a usual care setting, and provide clinical trial and postmarketing surveillance data support. This open-label, non-interventional, prospective observational cohort study (registry) comprised 52 sites in nine European countries. Patients with haemophilia B receiving nonacog alfa in either formulation for prevention or treatment were followed on a usual care schedule. A total of 218 patients were enrolled, of whom 66 (30.3%) were <18 years of age. Haemophilia severity was evenly distributed, with baseline FIX activity of <1%, 1-5% and >5% in 33.3%, 36.6% and 30.1% of patients, respectively. One hundred thirty-eight patients received the original formulation alone; 80 switched to or received only the new formulation. There was a low incidence of events of special interest (ESIs), with less-than-expected therapeutic effect in five patients (2.2%), inhibitor development in two (0.9%), thrombosis in one (0.5%) and allergic events in eight (3.7%). These accounted for the majority of the 15 serious AEs reported in six patients. Six patients discontinued because of AEs, primarily related to hypersensitivity. Nonacog alfa was shown to be safe for the treatment of haemophilia B, with a low incidence of serious AEs and ESIs.

Management of patients receiving oral anticoagulants using computer dosing software--does everyone agree? Data from a UK NEQAS (blood coagulation) exercise.

INTRODUCTION: The quality of anticoagulation management is not readily or frequently assessed, particularly between different centres. This study sought to evaluate agreement in oral anticoagulant management decisions between participating centres in UK NEQAS programmes. METHODS: Participants were asked to indicate whether they used computerized dosing support software (CDSS) and to complete a series of questions with respect to anticoagulant management provision. Four clinical scenarios were provided, together with past and current International Normalised Ratio (INR) results. Participants were asked to provide recommendations on the target INR they would assign to the patient, the dose of warfarin and a recall interval. RESULTS: Seven hundred and fifty-nine centres returned results, of which 28% were enrolled in the hospital-based EQA programme, and 72% were participants in the point-of-care testing programme. Six hundred (79%) reported use of CDSS. In one straightforward scenario, there was 99% agreement in dose recommendation. However, for three more complex scenarios, differences were apparent in target INRs employed and both dose and recall recommendations. In some cases, differences related to the software system employed. CONCLUSION: The study emphasizes large variation in the approach to managing these scenarios and warrants further investigation, together with education including promoting national guidelines for the assignment of target ranges.

Management of muscle haematomas in patients with severe haemophilia in an evidence-poor world.

Treatment studies in haemophilia focus on joint bleeds; however, some 10-25% of bleeds occur in muscles. This review addresses management of muscle haematoma in severe haemophilia, defines gaps in the published evidence, and presents a combined clinician and physiotherapist perspective of treatment modalities. The following grade 2C recommendations were synthesized: (i) Sport and activity should be based on individual factor levels, bleeding history and physical characteristics, (ii) Musculoskeletal review aids the management of children and adults, (iii) 'Time to full recovery' should be realistic and based on known timelines from the healthy population, (iv) Diagnosis should be carried out by both a clinician and physiotherapist, (v) Severe muscle bleeds should be treated similarly to surgical patients: a 50% trough for 10-14 days followed by high-level prophylaxis, (vi) Protection, rest, ice, compression and elevation should be implemented in the acute stage, and (vii) Physiotherapy and rehabilitation should be divided into: control of haemorrhage (phase 1); restoration of Range of Movement (ROM) and strength (phase 2); functional rehabilitation and return to normal living (phase 3). Recommendations specifically for inhibitor patients include: (i) Minor to moderate bleeds should be managed by home-treatment within 1 h of bleed onset using either one injection of rFVIIa 270 µg kg(-1), or two to three injections of rFVIIa 90 µg kg(-1) (2-3 h intervals), or FEIBA 50-100 U kg(-1) (repeated at 12-hourly intervals, if necessary) and (ii) Severe muscle bleeds should be supervised by the treatment centre and include bypassing agents until clinical improvement is observed.

Treatment related factors and inhibitor development in children with severe haemophilia A.

With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.

Faster evolution of highly conserved DNA in tropical plants.

A faster rate of nuclear DNA evolution has recently been found for plants occupying warmer low latitudes relative to those in cooler high latitudes. That earlier study by our research group compared substitution rates within the variable internal transcribed spacer (ITS) region of the ribosomal gene complex amongst 45 congeneric species pairs, each member of which differed in their latitudinal distributions. To determine whether this rate differential might also occur within highly conserved DNA, we sequenced the 18S ribosomal gene in the same 45 pairs of plants. We found that the rate of evolution in 18S was 51% faster in the tropical plant species relative to their temperate sisters and that the substitution rate in 18S correlated positively with that in the more variable ITS. This result, with a gene coding for ribosomal structure, suggests that climatic influences on evolution extend to functionally important regions of the genome.

Comparison of a point of care device against current laboratory methodology using citrated and EDTA samples for the determination of D-dimers in the exclusion of proximal deep vein thrombosis.

UNLABELLED: D-dimer estimation is a routine part of diagnostic algorithms for the exclusion of venous thromboembolism (VTE). We evaluated a point of care device, Biosite Triage (Inverness Medical UK, Cheshire, UK) for the estimation of D-dimers in both samples taken into citrate and EDTA against our routine laboratory D-dimer (Liatest D-dimer, Diagnostica Stago, Reading, UK) performed on the STA-R Evolution. With informed consent, 102 consecutive patients presenting with possible deep vein thrombosis (DVT) were enrolled and D-dimers along with Wells scores and compression ultrasonography (CUS) were recorded. Using the manufacturers' recommended cut offs of 500 microg/l fibrinogen equivalent units and 400 microg/l for the Stago and Triage, respectively, sensitivity, specificity, positive and negative predictive values were calculated. These were 1.00, 0.42, 0.17, and 1.00 for the Triage machine using citrate samples, 1.00, 0.32, 0.14, and 1.00 using EDTA samples and 1.00, 0.29, 0.16, and 1.00 for the Stago Liatest assay, respectively. Three patients had significantly higher results for the Stago Liatest D-dimer assay compared with the Biosite Triage device although ultrasound scans were negative. CONCLUSION: The Biosite Triage D-dimer assay performed on either citrate or EDTA samples is comparable with the Stago Liatest laboratory D-dimer assay when used in conjunction with clinical pretest probability scoring and CUS for the exclusion of DVT.

Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia.

SUMMARY: All UK patients with bleeding disorders treated with any UK-sourced pooled factor concentrates between 1980 and 2001 have been informed that they may be at an increased risk of infection with variant Creutzfeldt-Jakob disease (vCJD). We describe a study to detect disease-associated, protease-resistant prion protein (PrP(res)) in 17 neurologically aymptomatic patients with haemophilia considered to be at increased risk of vCJD. Materials from 11 autopsy and seven biopsy cases were analysed for PrP(res). The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrP(res) by Western blot analysis. This tissue came from a 73-year-old male patient with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene. He had received over 9000 units of factor VIII concentrate prepared from plasma pools known to include donations from a vCJD-infected donor, and some 400,000 units not known to include donations from vCJD-infected donors. He had also received 14 units of red blood cells and had undergone several surgical and invasive endoscopic procedures. Estimates of the relative risks of exposure through diet, surgery, endoscopy, blood transfusion and receipt of UK-sourced plasma products suggest that by far the most likely route of infection in this patient was receipt of UK plasma products.

Changing patterns of bleeding in patients with severe haemophilia A.

Previous studies on the pattern of joint bleeding in patients with haemophilia have reported that the knee joint is most frequently affected. Home treatment data reporting bleeding frequency and location collected from 100 patients registered at six haemophilia centres in the UK have been analysed to determine current patterns of bleeding. Bleeding frequency has markedly decreased although bleeding into joints remains the main characteristic of haemophilia. However, the ankle joint has replaced the knee joint as the most common joint affected. Furthermore, it seems that the frequency of knee joint bleeding is also less than the elbow joint suggesting that the traditional pattern of joint bleeding in haemophilia has now changed significantly.