Use of Stokes' theorem for plasma confinement.

Stokes' theorem, in its original form and Cartan's generalization, is crucial for designing magnetic fields to confine plasma (ionized gas). The paper illustrates its use, in particular to address the question whether quasi-symmetric fields, those for which guiding-centre motion is integrable, can be made with little or no toroidal current. This article is part of the theme issue 'Stokes at 200 (Part 1)'.

Aggregation of Markov flows I: theory.

A Markov flow is a stationary measure, with the associated flows and mean first passage times, for a continuous-time regular jump homogeneous semi-Markov process on a discrete state space. Nodes in the state space can be eliminated to produce a smaller Markov flow which is a factor of the original one. Some improvements to the elimination methods of Wales are given. The main contribution of the paper is to present an alternative, namely a method to aggregate groups of nodes to produce a factor. The method can be iterated to make hierarchical aggregation schemes. The potential benefits are efficient computation, including recomputation to take into account local changes, and insights into the macroscopic behaviour.This article is part of the theme issue 'Hilbert's sixth problem'.

Spinal Cord Hamartomatous Myelodysplasia in 2 Horses With Clinical Neurologic Deficits.

Two horses euthanized for neurologic deficits were diagnosed with hamartomatous myelodysplasia of the spinal cord. One was a 5-week-old Holsteiner colt exhibiting spasms of muscle rigidity in the extensor muscles of the limbs and epaxial muscles, and the other was a 3-year-old Thoroughbred colt exhibiting progressive ataxia and hypermetria in the pelvic limbs. Each had focal disorganization of the white and gray matter of the spinal cord forming a mass interspersed with neurons, glial cells, and disoriented axon bundles. In the Holsteiner colt, the mass was at the level of C5 and included islands of meningeal tissue contiguous with the leptomeninges. The mass occluded the central canal forming hydromyelia cranial to the occlusion. In the Thoroughbred colt, the mass was at the level of L1 on the dorsal periphery of the spinal cord and did not involve the central canal.

Monitoring risk-adjusted medical outcomes allowing for changes over time.

We consider the problem of monitoring and comparing medical outcomes, such as surgical performance, over time. Performance is subject to change due to a variety of reasons including patient heterogeneity, learning, deteriorating skills due to aging, etc. For instance, we expect inexperienced surgeons to improve their skills with practice. We propose a graphical method to monitor surgical performance that incorporates risk adjustment to account for patient heterogeneity. The procedure gives more weight to recent outcomes and down-weights the influence of outcomes further in the past. The chart is clinically interpretable as it plots an estimate of the failure rate for a "standard" patient. The chart also includes a measure of uncertainty in this estimate. We can implement the method using historical data or start from scratch. As the monitoring proceeds, we can base the estimated failure rate on a known risk model or use the observed outcomes to update the risk model as time passes. We illustrate the proposed method with an example from cardiac surgery.

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.

Characterisation of the UK high energy proton research beamline for high and ultra-high dose rate (FLASH) irradiation.

Objective. This work sets out the capabilities of the high energy proton research beamline developed in the Christie proton therapy centre for Ultra-High Dose Rate (UHDR) irradiation and FLASH experiments. It also characterises the lower limits of UHDR operation for this Pencil Beam Scanning (PBS) proton hardware.Approach. Energy dependent nozzle transmission was measured using a Faraday Cup beam collector. Spot size was measured at the reference plane using a 2D scintillation detector. Integrated depth doses (IDDs) were measured. EBT3 Gafchromic film was used to compare UHDR and conventional dose rate spots. Our beam monitor calibration methodolgy for UHDR is described. A microDiamond detector was used to determine dose rates at zref. Instantaneous depth dose rates were calculated for 70-245 MeV. PBS dose rate distributions were calculated using Folkerts and Van der Water definitions.Main results. Transmission of 7.05 ± 0.1% is achieveable corresponding to a peak instantaneous dose rate of 112.7 Gy s-1. Beam parameters are comparable in conventional and UHDR mode with a spot size ofσx= 4.6 mm,σy= 6.6 mm. Dead time in the beam monitoring electonics warrants a beam current dependent MU correction in the present configuration. Fast beam scanning of 26.4 m s-1(X) and 12.1 m s-1(Y) allows PBS dose rates of the order tens of Grays per second.Significance. UHDR delivery is possible for small field sizes and high energies enabling research into the FLASH effect with PBS protons at our facility. To our knowledge this is also the first thorough characterisation of UHDR irradiation using the hardware of this clinical accelerator at energies less than 250 MeV. The data set out in this publication can be used for designing experiments at this UK research facility and inform the possible future clinical translation of UHDR PBS proton therapy.

Barriers and facilitators to conducting radiotherapy clinical trials: Findings from a UK survey.

INTRODUCTION: As an essential component of service delivery, radiotherapy clinical trials were championed within the NHS England service specifications. A call for a 15% increase in research and clinical trial activity, alongside a demand for equity of access for patients with cancer subsequently ensued. National understanding of current radiotherapy clinical trials operational practices is absent, but essential to help establish the current provision required to support the development of a strategic plan for implementation of NHS England's specifications. METHODS: A cross-sectional survey was developed by a multi-disciplinary team and distributed to therapeutic radiography clinical trial leads across the UK to ascertain the current provision of radiotherapy clinical trials only, including workforce resources and the trials management processes to establish a benchmark and identify potential barriers, enablers, and opportunities to increase access to clinical trials. RESULTS: Thirty-two complete responses were obtained equating to 49% of the total UK NHS departments and 74% of those departments invited. Four key findings were identified: 1) research strategy and systems, 2) participation and activity in radiotherapy clinical trials, 3) access to clinical trials at alternative departments and 4) facilitators & barriers. Overarchingly a lack of radiotherapy clinical trials strategy or supported processes were apparent across the UK, aggravating existing barriers to trial activity. CONCLUSION: It is essential for radiotherapy clinical trials to be embedded in to departmental and Trust strategy, this will help to ensure the processes and resources required for trial delivery are not only in place, but also recognised as imperative and important for patients with cancer as radiotherapy treatment delivery. IMPLICATIONS FOR PRACTICE: Failure to address the barriers or build upon the facilitators may result in UK radiotherapy departments facing challenges in achieving the 15% increase in radiotherapy clinical trial activity.

Monitoring radiation use in cardiac fluoroscopy imaging procedures.

PURPOSE: Timely identification of systematic changes in radiation delivery of an imaging system can lead to a reduction in risk for the patients involved. However, existing quality assurance programs involving the routine testing of equipment performance using phantoms are limited in their ability to effectively carry out this task. To address this issue, the authors propose the implementation of an ongoing monitoring process that utilizes procedural data to identify unexpected large or small radiation exposures for individual patients, as well as to detect persistent changes in the radiation output of imaging platforms. METHODS: Data used in this study were obtained from records routinely collected during procedures performed in the cardiac catheterization imaging facility at St. Andrew's War Memorial Hospital, Brisbane, Australia, over the period January 2008-March 2010. A two stage monitoring process employing individual and exponentially weighted moving average (EWMA) control charts was developed and used to identify unexpectedly high or low radiation exposure levels for individual patients, as well as detect persistent changes in the radiation output delivered by the imaging systems. To increase sensitivity of the charts, we account for variation in dose area product (DAP) values due to other measured factors (patient weight, fluoroscopy time, and digital acquisition frame count) using multiple linear regression. Control charts are then constructed using the residual values from this linear regression. The proposed monitoring process was evaluated using simulation to model the performance of the process under known conditions. RESULTS: Retrospective application of this technique to actual clinical data identified a number of cases in which the DAP result could be considered unexpected. Most of these, upon review, were attributed to data entry errors. The charts monitoring the overall system radiation output trends demonstrated changes in equipment performance associated with relocation of the equipment to a new department. When tested under simulated conditions, the EWMA chart was capable of detecting a sustained 15% increase in average radiation output within 60 cases (<1 month of operation), while a 33% increase would be signaled within 20 cases. CONCLUSIONS: This technique offers a valuable enhancement to existing quality assurance programs in radiology that rely upon the testing of equipment radiation output at discrete time frames to ensure performance security.

Inference of dominant modes for linear stochastic processes.

For dynamical systems that can be modelled as asymptotically stable linear systems forced by Gaussian noise, this paper develops methods to infer (estimate) their dominant modes from observations in real time. The modes can be real or complex. For a real mode (monotone decay), the goal is to infer its damping rate and mode shape. For a complex mode (oscillatory decay), the goal is to infer its frequency, damping rate and (complex) mode shape. Their amplitudes and correlations are encoded in a mode covariance matrix that is also to be inferred. The work is motivated and illustrated by the problem of detection of oscillations in power flow in AC electrical networks. Suggestions of some other applications are given.

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.

Determining the parameter space for effective oxygen depletion for FLASH radiation therapy.

There has been a recent revival of interest in the FLASH effect, after experiments have shown normal tissue sparing capabilities of ultra-high-dose-rate radiation with no compromise on tumour growth restraint. A model has been developed to investigate the relative importance of a number of fundamental parameters considered to be involved in the oxygen depletion paradigm of induced radioresistance. An example eight-dimensional parameter space demonstrates the conditions under which radiation may induce sufficient depletion of oxygen for a diffusion-limited hypoxic cellular response. Initial results support experimental evidence that FLASH sparing is only achieved for dose rates on the order of tens of Gy s-1or higher, for a sufficiently high dose, and only for tissue that is slightly hypoxic at the time of radiation. We show that the FLASH effect is the result of a number of biological, radiochemical and delivery parameters. Also, the threshold dose for a FLASH effect occurring would be more prominent when the parameterisation was optimised to produce the maximum effect. The model provides a framework for further FLASH-related investigation and experimental design. An understanding of the mechanistic interactions producing an optimised FLASH effect is essential for its translation into clinical practice.

Inter- and intra-fractional stability of rectal gas in pelvic cancer patients during MRIgRT.

PURPOSE: Due to the electron return effect (ERE) during magnetic resonance imaging guided radiotherapy (MRIgRT), rectal gas during pelvic treatments can result in hot spots of over-dosage in the rectal wall. Determining the clinical impact of this effect on rectal toxicity requires estimation of the amount and mobility (and stability) of rectal gas during treatment. We therefore investigated the amount of rectal gas and local inter- and intra-fractional changes of rectal gas in pelvic cancer patients. METHODS: To estimate the volume of gas present at treatment planning, the rectal gas contents in the planning computed tomography (CT) scans of 124 bladder, 70 cervical and 2180 prostate cancer patients were calculated. To estimate inter- and intra-fractional variations in rectal gas, 174 and 131 T2-w MRIs for six cervical and eleven bladder cancer patients were used. These scans were acquired during four scan-sessions (~20-25 min each) at various time-points. Additionally, 258 T2-w MRIs of the first five prostate cancer patients treated using MRIgRT at our center, acquired during each fraction, were analyzed. Rectums were delineated on all scans. The area of gas within the rectum delineations was identified on each MRI slice using thresholding techniques. The area of gas on each slice of the rectum was used to calculate the inter- and intra-fractional group mean, systematic and random variations along the length of the rectum. The cumulative dose perturbation as a result of the gas was estimated. Two approaches were explored: accounting or not accounting for the gas at the start of the scan-session. RESULTS: Intra-fractional variations in rectal gas are small compared to the absolute volume of rectal gas detected for all patient groups. That is, rectal gas is likely to remain stable for periods of 20-25 min. Larger volumes of gas and larger variations in gas volume were observed in bladder cancer patients compared with cervical and prostate cancer patients. For all patients, local cumulative dose perturbations per beam over an entire treatment in the order of 60 % were estimated when gas had not been accounted for in the daily adaption. The calculated dose perturbation over the whole treatment was dramatically reduced in all patients when accounting for the gas in the daily set-up image. CONCLUSION: Rectal gas in pelvic cancer patients is likely to remain stable over the course of an MRIgRT fraction, and also likely to reappear in the same location in multiple fractions, and can therefore result in clinically relevant over-dosage in the rectal wall. The over-dosage is reduced when accounting for gas in the daily adaption.

Optimal two-stage reliability studies.

The intraclass correlation is often used to assess the reliability of a measurement system. There is a considerable literature devoted to optimizing the standard assessment plan in which a number of subjects are measured repeatedly. We propose a two-stage investigation, here called a leveraged plan (LP), where in Stage I, we measure a number of subjects once. Then in Stage II, we select a subset of subjects with extreme initial measurements for repeated measurement. For a fixed total number of measurements, we show that the optimal LP provides a more precise estimate of the intraclass correlation coefficient than does the optimal standard plan (SP). We provide a table for finding the optimal LP given the true intraclass correlation and a specified precision for the estimate. For a fixed total number of measurements N, a nearly optimal LP makes roughly N/2 measurements in Stage I and then selects roughly N/6 extreme subjects to re-measure thrice each in Stage II. We also compare optimal leveraged with optimal SPs when there is a limit on the number of times each subject can be re-measured.

How directed is a directed network?

The trophic levels of nodes in directed networks can reveal their functional properties. Moreover, the trophic coherence of a network, defined in terms of trophic levels, is related to properties such as cycle structure, stability and percolation. The standard definition of trophic levels, however, borrowed from ecology, suffers from drawbacks such as requiring basal nodes, which limit its applicability. Here we propose simple improved definitions of trophic levels and coherence that can be computed on any directed network. We demonstrate how the method can identify node function in examples including ecosystems, supply chain networks, gene expression and global language networks. We also explore how trophic levels and coherence relate to other topological properties, such as non-normality and cycle structure, and show that our method reveals the extent to which the edges in a directed network are aligned in a global direction.

Experimental verification the electron return effect around spherical air cavities for the MR-Linac using Monte Carlo calculation.

PURPOSE: Dose deposition around unplanned air cavities during magnetic resonance-guided radiotherapy (MRgRT) is influenced by the electron return effect (ERE). This is clinically relevant for gas forming close to or inside organs at risk (OARs) that lie in the path of a single beam, for example, intestinal track during pelvic treatment. This work aims to verify Monte Carlo calculations that predict the dosimetric effects of ERE around air cavities. For this, we use GafChromic EBT3 film inside poly-methyl methacrylate (PMMA) -air phantoms. METHOD: Four PMMA phantoms were produced. Three of the phantoms contained centrally located spherical air cavities (0.5, 3.5, 7.5 cm diameter), and one phantom contained no air. The phantoms were split to sandwich GafChromic EBT3 film in the center. The phantoms were irradiated on an Elekta Unity system using a single 10 × 10 cm2 7-MV photon beam under the influence of a 1.5-T transverse magnetic field. The measurements were replicated using the Elekta Monaco treatment planning system (TPS). Gamma analysis with pass criteria 3%/3 mm was used to compare the measured and calculated dose distributions. We also consider 3%/2 mm, 2%/3 mm, and 2%/2 mm pass criteria for interest. RESULTS: The gamma analysis showed that >95% of the points agreed between the TPS-calculated and measured dose distributions, using 3%/3 mm criteria. The phantom containing the largest air cavity had the lowest agreement, with most of the disagreeing points lying inside the air cavity (dose to air region). CONCLUSIONS: The dose effects due to ERE around spherical air cavities are being calculated in the TPS with sufficient accuracy for clinical use.

Dolphin vocalization mechanisms.

Although humans have difficulty whistling when in a habitat that is more than 20 meters underwater, dolphins can make certain sounds at great depths through a related mechanism. Other dolphin sounds, such as clicks and complex buzzes, are produced by vibrations of the tissue of the nasal plugs, apparently without the use of the larynx; in these instances, the air sacs act as reservoirs. This was determined from studies of Tursiops truncatus and Delphinus delphis with harmless ultrasonic beams projected noninvasively to determine movements of the air sacs.

Ethnic differences in time trends in asthma prevalence in New Zealand: ISAAC Phases I and III.

SETTING: The International Study of Asthma and Allergies in Childhood (ISAAC) Phase III survey, New Zealand. OBJECTIVE: To assess the prevalence of asthma symptoms and time trends by ethnicity between ISAAC Phase I (1992-1993) and Phase III (2001-2003). DESIGN: Information on asthma symptoms and environmental exposures was collected in children aged 6-7 years (n = 10,873) and adolescents aged 13-14 years (n = 13,317). RESULTS: In children, the prevalence of current wheeze was 28.5% in Maori (prevalence odds ratio [POR] = 1.49, 95%CI 1.32-1.68), and 25.2% in Pacific Islanders (POR 1.28, 95%CI 1.07-1.54) compared with 20.7% in Europeans/Pakeha. In adolescents, 29.9% of Maori (POR = 1.13, 95%CI 1.03-1.23) and 20.8% of Pacific Islanders (POR 0.74, 95%CI 0.62-0.87) experienced current wheeze compared to 28.6% of Europeans/Pakeha. Between Phases I and III, the prevalence of current wheeze increased significantly by 0.49%/year in Pacific Islanders, increased non-significantly by 0.12%/year in Maori, and decreased significantly by 0.25%/year in Europeans/Pakeha children. In adolescents, the prevalence of current wheeze increased by 0.05%/year in Pacific Islanders and decreased by 0.33%/year in Europeans/Pakeha and by 0.07%/year in Maori. CONCLUSION: Ethnic differences in asthma symptom prevalence in New Zealand have increased. The reasons for this are unclear, but may reflect inequalities in access to health services.

Using telematics data to find risky driver behaviour.

Usage-based insurance schemes provide new opportunities for insurers to accurately price and manage risk. These schemes have the potential to better identify risky drivers which not only allows insurance companies to better price their products but it allows drivers to modify their behaviour to make roads safer and driving more efficient. However, for Usage-based insurance products, we need to better understand how driver behaviours influence the risk of a crash or an insurance claim. In this article, we present our analysis of automotive telematics data from over 28 million trips. We use a case control methodology to study the relationship between crash drivers and crash-free drivers and introduce an innovative method for determining control (crash-free) drivers. We fit a logistic regression model to our data and found that speeding was the most important driver behaviour linking driver behaviour to crash risk.

Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway.

Following radiation induced DNA damage, several repair pathways are activated to help preserve genome integrity. Double Strand Breaks (DSBs), which are highly toxic, have specified repair pathways to address them. The main repair pathways used to resolve DSBs are Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Cell cycle phase determines the availability of HR, but the repair choice between pathways in the G2 phases where both HR and NHEJ can operate is not clearly understood. This study compares several in silico models of repair choice to experimental data published in the literature, each model representing a different possible scenario describing how repair choice takes place. Competitive only scenarios, where initial protein recruitment determines repair choice, are unable to fit the literature data. In contrast, the scenario which uses a more entwined relationship between NHEJ and HR, incorporating protein co-localisation and RNF138-dependent removal of the Ku/DNA-PK complex, is better able to predict levels of repair similar to the experimental data. Furthermore, this study concludes that co-localisation of the Mre11-Rad50-Nbs1 (MRN) complexes, with initial NHEJ proteins must be modeled to accurately depict repair choice.

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons.

Relative Biological Effectiveness (RBE), the ratio of doses between radiation modalities to produce the same biological endpoint, is a controversial and important topic in proton therapy. A number of phenomenological models incorporate variable RBE as a function of Linear Energy Transfer (LET), though a lack of mechanistic description limits their applicability. In this work we take a different approach, using a track structure model employing fundamental physics and chemistry to make predictions of proton and photon induced DNA damage, the first step in the mechanism of radiation-induced cell death. We apply this model to a proton therapy clinical case showing, for the first time, predictions of DNA damage on a patient treatment plan. Our model predictions are for an idealised cell and are applied to an ependymoma case, at this stage without any cell specific parameters. By comparing to similar predictions for photons, we present a voxel-wise RBE of DNA damage complexity. This RBE of damage complexity shows similar trends to the expected RBE for cell kill, implying that damage complexity is an important factor in DNA repair and therefore biological effect.