CERN-based experiments and Monte-Carlo studies on focused dose delivery with very high energy electron (VHEE) beams for radiotherapy applications.

Very High Energy Electron (VHEE) beams are a promising alternative to conventional radiotherapy due to their highly penetrating nature and their applicability as a modality for FLASH (ultra-high dose-rate) radiotherapy. The dose distributions due to VHEE need to be optimised; one option is through the use of quadrupole magnets to focus the beam, reducing the dose to healthy tissue and allowing for targeted dose delivery at conventional or FLASH dose-rates. This paper presents an in depth exploration of the focusing achievable at the current CLEAR (CERN Linear Electron Accelerator for Research) facility, for beam energies >200 MeV. A shorter, more optimal quadrupole setup was also investigated using the TOPAS code in Monte Carlo simulations, with dimensions and beam parameters more appropriate to a clinical situation. This work provides insight into how a focused VHEE radiotherapy beam delivery system might be achieved.

Alanine response to low energy synchrotron x-ray radiation.

Objective. The radiation response of alanine is very well characterized in the MV photon energy range where it can be used to determine the dose delivered with an accuracy better than 1%, making it suitable as a secondary standard detector in cancer radiation therapy. This is not the case in the very low energy keV x-ray range where the alanine response is affected by large uncertainties and is strongly dependent on the x-ray beam energy. This motivated the study undertaken here.Approach. Alanine pellets with a nominal thickness of 0.5 mm and diameter of 5 mm were irradiated with monoenergetic x-rays at the Diamond Light Source synchrotron, to quantify their response in the 8-20 keV range relative to60Co radiation. The absorbed dose to graphite was measured with a small portable graphite calorimeter, and the DOSRZnrc code in the EGSnrc Monte Carlo package was used to calculate conversion factors between the measured dose to graphite and the absorbed dose to water delivered to the alanine pellets. GafChromic EBT3 films were used to measure the beam profile for modelling in the MC simulations.Main results. The relative responses measured in this energy range were found to range from 0.616 to 0.643, with a combined relative expanded uncertainty of 3.4%-3.5% (k= 2), where the majority of the uncertainty originated from the uncertainty in the alanine readout, due to the small size of the pellets used.Significance. The measured values were in good agreement with previously published data in the overlapping region of x-ray energies, while this work extended the dataset to lower energies. By measuring the response to monoenergetic x-rays, the response to a more complex broad-spectrum x-ray source can be inferred if the spectrum is known, meaning that this work supports the establishment of alanine as a secondary standard dosimeter for low-energy x-ray sources.

Safety, quality and efficiency of intra-operative imaging for treatment decisions in patients with suspected choledocholithiasis without pre-operative magnetic resonance cholangiopancreatography.

INTRODUCTION: Cholecystectomy is the accepted treatment for patients with symptomatic gallstones. In this study, we evaluate a simplified strategy for managing suspected synchronous choledocholithiasis by focussing on intra-operative imaging as the primary decision-making tool to target common bile duct (CBD) stone treatment. METHODS: All elective and emergency patients undergoing laparoscopic cholecystectomy (LC) for gallstones with any markers of synchronous choledocholithiasis were included. Patients unfit for surgery or who had pre-operative proof of choledocholithiasis were excluded. Intra-operative imaging was used for evaluation of the CBD. CBD stone treatment was with bile duct exploration (LCBDE) or endoscopic retrograde cholangiopancreatography (LC + ERCP). Outcomes were safety, effectiveness and efficiency. RESULTS: 506 patients were included. 371 (73%) had laparoscopic ultrasound (LUS), 80 (16%) had on-table cholangiography (OTC) and 55 (11%) had both. 164 (32.4%) were found to have CBD stones. There was no increase in length of surgery for LC + LUS compared with average time for LC only in our unit (p = 0.17). 332 patients (65.6%) had clear ducts. Imaging was indeterminate in 10 (2%) patients. Overall morbidity was 10.5%. There was no mortality. 142 (86.6%) patients with stones on intra-operative imaging proceeded to LCBDE. 22 (13.4%) patients had ERCP. Sensitivity and specificity of intra-operative imaging were 93.3 and 99.1%, respectively. Success rate of LCBDE was 95.8%. Effectiveness was 97.8%. CONCLUSIONS: Eliminating pre-operative bile duct imaging in favour of intra-operative imaging is safe and effective. When combined with intra-operative stone treatment, this method becomes a true 'single-stage' approach to managing suspected choledocholithiasis.

Focused VHEE (very high energy electron) beams and dose delivery for radiotherapy applications.

This paper presents the first demonstration of deeply penetrating dose delivery using focused very high energy electron (VHEE) beams using quadrupole magnets in Monte Carlo simulations. We show that the focal point is readily modified by linearly changing the quadrupole magnet strength only. We also present a weighted sum of focused electron beams to form a spread-out electron peak (SOEP) over a target region. This has a significantly reduced entrance dose compared to a proton-based spread-out Bragg peak (SOBP). Very high energy electron (VHEE) beams are an exciting prospect in external beam radiotherapy. VHEEs are less sensitive to inhomogeneities than proton and photon beams, have a deep dose reach and could potentially be used to deliver FLASH radiotherapy. The dose distributions of unfocused VHEE produce high entrance and exit doses compared to other radiotherapy modalities unless focusing is employed, and in this case the entrance dose is considerably improved over existing radiations. We have investigated both symmetric and asymmetric focusing as well as focusing with a range of beam energies.

Evaluating very high energy electron RBE from nanodosimetric pBR322 plasmid DNA damage.

This paper presents the first plasmid DNA irradiations carried out with Very High Energy Electrons (VHEE) over 100-200 MeV at the CLEAR user facility at CERN to determine the Relative Biological Effectiveness (RBE) of VHEE. DNA damage yields were measured in dry and aqueous environments to determine that ~ 99% of total DNA breaks were caused by indirect effects, consistent with other published measurements for protons and photons. Double-Strand Break (DSB) yield was used as the biological endpoint for RBE calculation, with values found to be consistent with established radiotherapy modalities. Similarities in physical damage between VHEE and conventional modalities gives confidence that biological effects of VHEE will also be similar-key for clinical implementation. Damage yields were used as a baseline for track structure simulations of VHEE plasmid irradiation using GEANT4-DNA. Current models for DSB yield have shown reasonable agreement with experimental values. The growing interest in FLASH radiotherapy motivated a study into DSB yield variation with dose rate following VHEE irradiation. No significant variations were observed between conventional and FLASH dose rate irradiations, indicating that no FLASH effect is seen under these conditions.

Cost effectiveness of intraoperative laparoscopic ultrasound for suspected choledocholithiasis; outcomes from a specialist benign upper gastrointestinal unit.

INTRODUCTION: Common bile duct stones are present in 10% of patients with symptomatic gallstones. One-third of UK patients undergoing cholecystectomy will have preoperative ductal imaging, commonly with magnetic resonance cholangiopancreatography. Intraoperative laparoscopic ultrasound is a valid alternative but is not widely used. The primary aim of this study was to assess cost effectiveness of laparoscopic ultrasound compared with magnetic resonance cholangiopancreatography. MATERIALS AND METHODS: A prospective database of all patients undergoing laparoscopic cholecystectomy between 2015 and 2018 at a district general hospital was assessed. Inclusion criteria were all patients, emergency and elective, with symptomatic gallstones and suspicion of common bile duct stones (derangement of liver function tests with or without dilated common bile duct on preoperative ultrasound, or history of pancreatitis). Patients with known common bile duct stones (magnetic resonance cholangiopancreatography or failed endoscopic retrograde cholangiogram) were excluded. Ninety-day morbidity data were also collected. RESULTS: A total of 420 (334 elective and 86 emergency) patients were suspected to have common bile duct stones and were included in the study. The cost of a laparoscopic ultrasound was £183 per use. The cost of using the magnetic resonance cholangiopancreatography unit was £365 per use. Ten postoperative magnetic resonance cholangiopancreatographies were performed for inconclusive intraoperative imaging. The estimated cost saving was £74,650. Some 128 patients had common bile duct stones detected intraoperatively and treated. There was a false positive rate of 4.7%, and the false negative rate at 90 days was 0.7%. laparoscopic ultrasound use saved 129 bed days for emergency patients and 240 magnetic resonance cholangiopancreatography hours of magnetic resonance imaging. CONCLUSION: The use of laparoscopic ultrasound during laparoscopic cholecystectomy for the detection of common bile duct stone is safe, accurate and cost effective. Equipment and maintenance costs are quickly offset and hospital bed days can be saved with its use.

Beam phase retrieval based on higher order modes in cylindrical superconducting radio frequency cavities.

The control of beam phase relative to the accelerating RF field within a superconducting cavity is important in many accelerator applications and is of particular importance for a free electron laser facility. As standard practice, the phase is usually inferred from the beam-induced transient field with respect to a timing reference. We report here on an alternative and novel means of beam phase determination based on beam-excited higher order electromagnetic modes and the accelerating electromagnetic mode, which are conveniently available from the same coupler. The monopole modes are immune to the electron beam offset and therefore are best suited for the task. A coupled circuit model is used to assist the development and to rapidly assess the facility of the method. Simulations based on the circuit model indicate that the resolution of this system depends critically on the signal to noise ratio. Beam-based measurements with a test setup were carried out at the European X-ray Free Electron Laser (XFEL), Germany. Based on this new method, we have routinely obtained a resolution of 0.1°. The best resolution observed with the current setup was 0.03°. These results agree very well with the predictions from those predicted by a circuit model. The system investigated here can be used to provide diagnostic information for the current low level RF system employed in the European XFEL. To this end, the associated electronics are under development. This monitor is the first of its kind that can deliver direct and online measurements of the beam phase with respect to the RF field.

Oral 2-oleyl glyceryl ether improves glucose tolerance in mice through the GPR119 receptor.

The intestinal G protein-coupled receptor GPR119 is a novel metabolic target involving glucagon-like peptide-1 (GLP-1)-derived insulin-regulated glucose homeostasis. Endogenous and diet-derived lipids, including N-acylethanolamines and 2-monoacylglycerols (2-MAG) activate GPR119. The purpose of this work is to evaluate whether 2-oleoyl glycerol (2-OG) improves glucose tolerance through GPR119, using wild type (WT) and GPR 119 knock out (KO) mice. We here show that GPR119 is essential for 2-OG-mediated release of GLP-1 and CCK from GLUTag cells, since a GPR119 specific antagonist completely abolished the hormone release. Similarly, in isolated primary colonic crypt cultures from WT mice, GPR119 was required for 2-OG-stimulated GLP-1 release while there was no response in crypts from KO mice. In vivo, gavage with 2-oleyl glyceryl ether ((2-OG ether), a stable 2-OG analog with a potency of 5.3 µM for GPR119 with respect to cAMP formation as compared to 2.3 µM for 2-OG), significantly (P < 0.05) improved glucose clearance in WT littermates, but not in GPR119 KO mice. Finally, deletion of GPR119 in mice resulted in lower glucagon levels, whereas the levels of insulin and GIP were unchanged. In the present study we show that 2-OG stimulates GLP-1 secretion through GPR119 activation in vitro, and that fat-derived 2-MAGs are potent candidates for mediating fat-induced GLP-1 release through GPR119 in vivo. © 2016 BioFactors, 42(6):665-673, 2016.

Transmission blocking potency and immunogenicity of a plant-produced Pvs25-based subunit vaccine against Plasmodium vivax.

Malaria transmission blocking (TB) vaccines (TBVs) directed against proteins expressed on the sexual stages of Plasmodium parasites are a potentially effective means to reduce transmission. Antibodies induced by TBVs block parasite development in the mosquito, and thus inhibit transmission to further human hosts. The ookinete surface protein P25 is a primary target for TBV development. Recently, transient expression in plants using hybrid viral vectors has demonstrated potential as a strategy for cost-effective and scalable production of recombinant vaccines. Using a plant virus-based expression system, we produced recombinant P25 protein of Plasmodium vivax (Pvs25) in Nicotiana benthamiana fused to a modified lichenase carrier protein. This candidate vaccine, Pvs25-FhCMB, was purified, characterized and evaluated for immunogenicity and efficacy using multiple adjuvants in a transgenic rodent model. An in vivo TB effect of up to a 65% reduction in intensity and 54% reduction in prevalence was observed using Abisco-100 adjuvant. The ability of this immunogen to induce a TB response was additionally combined with heterologous prime-boost vaccination with viral vectors expressing Pvs25. Significant blockade was observed when combining both platforms, achieving a 74% and 68% reduction in intensity and prevalence, respectively. This observation was confirmed by direct membrane feeding on field P. vivax samples, resulting in reductions in intensity/prevalence of 85.3% and 25.5%. These data demonstrate the potential of this vaccine candidate and support the feasibility of expressing Plasmodium antigens in a plant-based system for the production of TBVs, while demonstrating the potential advantages of combining multiple vaccine delivery systems to maximize efficacy.

Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid-lowering therapies.

Homozygous familial hypercholesterolaemia (FH) causes severe premature coronary artery disease because of very high levels of low density lipoprotein (LDL)-cholesterol. Standard lipid-lowering drugs and LDL-apheresis may not be sufficiently effective. Liver transplantation replaces defective LDL receptors and vastly improves the lipid profile, and we present the first report of an Australian adult to receive this treatment. Emerging drug treatments for FH may be alternatives to LDL-apheresis and transplantation, but long-term safety and efficacy data are lacking for all of these options.

Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress.

It has become increasingly clear that oncogenes not only provide aberrant growth signals to cells but also cause DNA damage at replication forks (replication stress), which activate the ataxia telangiectasia mutated (ATM)/p53-dependent tumor barrier. Here we studied underlying mechanisms of oncogene-induced replication stress in cells overexpressing the oncogene Cyclin E. Cyclin E overexpression is associated with increased firing of replication origins, impaired replication fork progression and DNA damage that activates RAD51-mediated recombination. By inhibiting replication initiation factors, we show that Cyclin E-induced replication slowing and DNA damage is a consequence of excessive origin firing. A significant amount of Cyclin E-induced replication slowing is due to interference between replication and transcription, which also underlies the activation of homologous recombination. Our data suggest that Cyclin E-induced replication stress is caused by deregulation of replication initiation and increased interference between replication and transcription, which results in impaired replication fork progression and DNA damage triggering the tumor barrier or cancer-promoting mutations.

Genetic parameters for haemoglobin levels in pigs and iron content in pork.

Genetic parameters were obtained for iron content in m. longissimus dorsi (2255 records) and haemoglobin levels recorded at 5 (4974 records) and 21 (2405 records) weeks of age in two sire lines from September 2009 until January 2011. The measure of iron in pork was the mean of two replicates. Genetic associations of haematological traits with meat quality traits (2255 records), as well as growth rate and backfat (close to 60 000 records), were estimated. Analyses were based on an animal model using residual maximum likelihood procedures. Iron content in pork was moderately heritable (0.34 ± 0.07) and genetic correlations with haemoglobin measures ranged from 0.39 ± 0.24 to 0.58 ± 0.13, indicating their potential use as selection criteria for increasing iron levels in pork. However, heritabilities for haemoglobin levels were low, ranging from 0.04 ± 0.2 to 0.18 ± 0.04. Procedures to measure haemoglobin on farm may require refinement. Redness of pork, quantified by a* value, had high genetic correlations with iron content (0.90 ± 0.04 to 0.94 ± 0.03) and moderate genetic correlations with haemoglobin levels (0.31 ± 0.22 to 0.55 ± 0.15). Iron content had significant genetic associations with L* measures (-0.61 ± 0.14 to -0.54 ± 0.23), b* value (0.60 ± 0.14 for dorsal b* measure, 0.50 ± 0.15 for average of dorsal and ventral b* measures) and pH at 45 min post mortem (-0.42 ± 0.14). These high genetic correlations between colour measurements and iron content in pork provide further avenues for selection strategies to improve iron content in pork. Current selection practices are not expected to affect iron content in pork, as no significant genetic correlations between performance and haematological traits were found.

Co-existence of organising pneumonia in a patient with Mycobacterium avium intracellulare pulmonary infection.

Non-tuberculous mycobacterias (NTMs) have many clinical manifestations in humans, depending on the underlying immunological status. We present a patient with Mycobacterium avium intracellulare pulmonary infection and co-existing, biopsy proven non-granulomatous organising pneumonia in distinct regions within the lungs. Treatment consisting of anti-mycobacterial therapy and corticosteroids led to clinico-radiological resolution. This case represents a potential broader clinico-pathological manifestation of Mycobacterium avium intracellulare.

Meta-analysis of benzene exposure and non-Hodgkin lymphoma: biases could mask an important association.

OBJECTIVES: Benzene is a widely recognised cause of leukaemia but its association with non-Hodgkin's lymphoma (NHL) is less well established. The goal of this project is to review the current published literature on this association. METHODS: We performed a meta-analysis of cohort and case-control studies of benzene exposure and NHL and a meta-analysis of NHL and refinery work, a potential source of benzene exposure. RESULTS: In 22 studies of benzene exposure, the summary relative risk for NHL was 1.22 (95% CI 1.02 to 1.47; one-sided p value = 0.01). When studies that likely included unexposed subjects in the "exposed" group were excluded, the summary relative risk increased to 1.49 (95% CI 1.12 to 1.97, n = 13), and when studies based solely on self-reported work history were excluded, the relative risk rose to 2.12 (95% CI 1.11 to 4.02, n = 6). In refinery workers, the summary relative risk for NHL in all 21 studies was 1.21 (95% CI 1.00 to 1.46; p = 0.02). When adjusted for the healthy worker effect, this relative risk estimate increased to 1.42 (95% CI 1.19 to 1.69). CONCLUSIONS: The finding of elevated relative risks in studies of both benzene exposure and refinery work provides further evidence that benzene exposure causes NHL. In addition, the finding of increased relative risks after removing studies that included unexposed or lesser exposed workers in "exposed" cohorts, and increased relative risk estimates after adjusting for the healthy worker effect, suggest that effects of benzene on NHL might be missed in occupational studies if these biases are not accounted for.

The validity of a computer-assisted simulation system for orthognathic surgery (CASSOS) for planning the surgical correction of class III skeletal deformities: single-jaw versus bimaxillary surgery.

The aim of this study was to assess the accuracy of the two-dimensional profile prediction produced by the computer-assisted simulation system for orthognathic surgery (CASSOS), for the correction of class III facial deformities. Correction was by maxillary advancement (n=17) or bimaxillary surgery (n=16). The mean age was 24 years (range 18-42). The surgical and dental movements obtained from the postoperative cephalogram were used to produce a CASSOS profile prediction, which was compared with the soft-tissue profile. The prediction was superimposed onto the postoperative radiograph, and a coordinate system was used to measure linear differences. For the maxillary advancement group there were statistical differences for three horizontal landmarks: superior labial sulcus (p=0.017), labrale superious (p=0.038) and labiomental fold (p=0.014). In the bimaxillary group only the landmark vertical labrale superious (p=0.002) showed a statistical difference. Generally, CASSOS produced useful profile predictions for maxillary advancement surgery or bimaxillary surgery for Class III patients, although there was considerable individual variation. The main areas of inaccuracy were the lips. The major difference between the two types of surgery was that most of the errors in the maxillary surgery group were in the horizontal direction, whilst for the bimaxillary surgery the errors were mainly in the vertical direction.

The orientationally controlled assembly of genetically modified enzymes in an amperometric biosensor.

A novel, nitroreductase (NTR) containing a sequence of six cysteine amino acids, enabling strong thiolate bonds to form on a gold electrode surface without the loss of enzyme activity, was genetically engineered. The enzyme was directly immobilised at a gold electrode without the need for pre-treatment of the surface with a self-assembled monolayer or a conducting polymer. The ensemble was used to develop an amperometric biosensor for the detection of explosives containing nitroaromatic compounds. Preliminary results demonstrate detection levels down to 100 parts per trillion, signifying tremendous promise towards an in situ sensor for the detection of explosives.

Detection of epidural catheters with ultrasound in children.

BACKGROUND: The aim of this study was to assess whether a noninvasive imaging technique such as ultrasound could visualize an epidural catheter in the epidural space in children. METHODS: Following local ethics committee approval and informed parental consent a pilot study of 12 cases was performed. Children undergoing major surgery requiring epidural analgesia were recruited. All catheters were introduced via the lumbar region. All children were scanned within 24 h of epidural insertion by consultant paediatric radiologists. If the catheter was identified in the epidural space then an attempt was made to visualize the entire length of the catheter. RESULTS: The epidural catheter was detected in nine of 12 patients. All of these were less than 6 months old. The entire length of the catheter was visualized in five of the nine patients. It was possible to estimate the most cephalad level of the catheter in seven of the nine patients. This was in the thoracic region in all cases and an appropriate level for the intended surgical procedure. It was not possible to precisely identify the tip of the catheter as a distinct entity using ultrasound. CONCLUSION: This study shows that it is possible to visualize an epidural catheter in the epidural space in children under 6 months of age using ultrasound.

Analysis of facial growth in subjects with syndromic ectodermal dysplasia: a longitudinal analysis.

OBJECTIVE: To examine the craniofacial growth pattern of patients diagnosed with syndromic ectodermal dysplasia. DESIGN: Mixed longitudinal analysis of lateral cephalograms. SETTING: The data were analysed using a multilevel modelling technique with the MLwiN application software and the results presented numerically and graphically. SAMPLE POPULATION: All 61 subjects had severe hypodontia with the number of absent teeth (excluding third molars) ranging from 6 to 28 (mean = 15.4). At presentation the subjects had a mean age of 133 months and were followed longitudinally for between one and five subsequent occasions (mean 2.66 occasions; mean age at completion of observation 207 months). OUTCOME MEASURES: Lateral cephalograms taken at each visit. EXPERIMENTAL VARIABLES: Analysis of four angular measurements and four linear measurements, together with one calculated ratio. RESULTS: Growth curves are presented showing the trends of craniofacial growth. CONCLUSIONS: The most significant findings were for a universal tendency for the individuals to undergo a change in sagittal relationship of the jaws, becoming markedly more Class III with time. We have also demonstrated a significant difference in growth between the anterior and posterior face heights indicating that the subjects have a tendency to an anterior growth rotation.

Randomized clinical trial comparing totally extraperitoneal inguinal hernia repair with the Shouldice technique.

BACKGROUND: The optimal technique for inguinal hernia repair remains contentious. This study compared the Shouldice repair with the totally extraperitoneal endoscopic (TEP) method in a randomized clinical trial, with quality of life (QoL) and cost analysis. METHODS: Two hundred patients were randomized to Shouldice or TEP repair. Patients were assessed after operation by questionnaire to determine operative outcomes, complications, QoL, and return to work and normal lifestyle. RESULTS: There were 117 TEP and 115 Shouldice repairs. Median operating time was longer for TEP repair (70 versus 56 min; P = 0.0001), but patients were discharged earlier (68 versus 48 per cent within 1 day; P = 0.0065), and had a quicker return to work (14 versus 30 days; P = 0.0001) and normal lifestyle (21 versus 35 days; P = 0.0001). Open repair was nearly 40 per cent cheaper. Late follow-up in 171 patients (86 per cent) at a median of 1.3 years found that TEP repair led to fewer complications at 1 year (9 versus 21 per cent; P = 0.05) and was associated with significant improvement for the QoL components of work performance and satisfaction, physical symptoms and sense of well-being. CONCLUSION: TEP repair results in fewer complications and an earlier return to work and normal lifestyle, but is more expensive and takes longer to perform.

The hepatic artery: a reminder of surgical anatomy.

This study was carried out to document the anatomy of the hepatic artery with the purpose of reminding surgeons of the need for this essential knowledge in order to practice safe hepatobiliary surgery. Repeated surgical mistakes on patients referred to our unit prompted the study. One hundred and eighty consecutive livers procured for transplantation was studied, and the anatomy drawn immediately after dissection. The left hepatic artery arose from the left gastric artery in 15%, and either the splenic, gastroduodenal artery or the aorta in 4% of cases. The right hepatic artery arose from the superior mesenteric artery in 15%, the gastroduodenal, right gastric artery or aorta in 10% of cases. There was a major variation of the coeliac axis in 9% of cases studied. Overall, there was an abnormality in 43% of dissections: 48% were multiple and 27% had more than two vascular variations. A constant pattern of abnormalities occurred in the anatomy of the hepatic artery. Realisation of this vascular pattern should make identification of the anatomy easier. When there is one vascular variation, there is a high chance of there being multiple variations.