A single blinded, phase IV, adaptive randomised control trial to evaluate the safety of coadministration of seasonal influenza and COVID-19 vaccines (The FluVID study).

OBJECTIVES: We evaluated the frequency of moderate and severe adverse events following coadministration of seasonal influenza vaccine (SIV) versus placebo with COVID-19 vaccines among adults to support practice guidelines. METHODS: FluVID is a participant-blinded, phase IV, randomised control trial. On the same day as the participant's scheduled COVID-19 vaccine, participants were randomised to receive SIV or saline placebo; those assigned placebo at visit one then received SIV a week later, and vice versa. Self-reported adverse events were collected daily for seven days following each visit. The primary endpoint was any solicited adverse event of at least moderate severity occurring up to seven days following receipt of SIV or placebo. This was modelled using a Bayesian logistic regression model. Analyses were performed by COVID-19 vaccine type and dose number. RESULTS: Overall, 248 participants were enrolled; of these, 195 had received BNT162b2 and 53 had received mRNA1273 COVID-19 vaccines according to national guidelines. After randomisation, 119 were assigned to receive SIV and 129 were assigned to receive placebo at visit one. Adverse events were most frequently reported as mild (grade 1) in nature. Among 142 BNT162b2 booster dose one and 43 BNT162b2 booster dose two recipients, the posterior median risk difference for moderate/severe adverse events following SIV versus placebo was 13% (95% credible interval [CrI] -0.03 to 0.27) and 13% (95%CrI -0.37 to 0.12), respectively. Among 18 mRNA1273 booster dose one and 35 mRNA1273 booster dose two recipients, the posterior median risk difference of moderate/severe adverse events following influenza vaccine versus placebo was 6% (95%CrI -0.29 to 0.41) and -4% (95%CrI -0.30 to 0.23), respectively. CONCLUSION: Adverse events following SIV and COVID-19 co-administration were generally mild and occurred with similar frequency to events following COVID-19 vaccine alone. We found no evidence to justify routine separation of SIV and COVID-19 vaccine doses. CLINICAL TRIAL REGISTRATION: ACTRN12621001063808.

Core protocol for the adaptive Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO).

BACKGROUND: The need for coronavirus 2019 (COVID-19) vaccination in different age groups and populations is a subject of great uncertainty and an ongoing global debate. Critical knowledge gaps regarding COVID-19 vaccination include the duration of protection offered by different priming and booster vaccination regimens in different populations, including homologous or heterologous schedules; how vaccination impacts key elements of the immune system; how this is modified by prior or subsequent exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and future variants; and how immune responses correlate with protection against infection and disease, including antibodies and effector and T cell central memory. METHODS: The Platform Trial In COVID-19 priming and BOOsting (PICOBOO) is a multi-site, multi-arm, Bayesian, adaptive, randomised controlled platform trial. PICOBOO will expeditiously generate and translate high-quality evidence of the immunogenicity, reactogenicity and cross-protection of different COVID-19 priming and booster vaccination strategies against SARS-CoV-2 and its variants/subvariants, specific to the Australian context. While the platform is designed to be vaccine agnostic, participants will be randomised to one of three vaccines at trial commencement, including Pfizer's Comirnaty, Moderna's Spikevax or Novavax's Nuvaxovid COVID-19 vaccine. The protocol structure specifying PICOBOO is modular and hierarchical. Here, we describe the Core Protocol, which outlines the trial processes applicable to all study participants included in the platform trial. DISCUSSION: PICOBOO is the first adaptive platform trial evaluating different COVID-19 priming and booster vaccination strategies in Australia, and one of the few established internationally, that is designed to generate high-quality evidence to inform immunisation practice and policy. The modular, hierarchical protocol structure is intended to standardise outcomes, endpoints, data collection and other study processes for nested substudies included in the trial platform and to minimise duplication. It is anticipated that this flexible trial structure will enable investigators to respond with agility to new research questions as they arise, such as the utility of new vaccines (such as bivalent, or SARS-CoV-2 variant-specific vaccines) as they become available for use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12622000238774. Registered on 10 February 2022.

Prediction of pork quality with near infrared spectroscopy (NIRS) 2. Feasibility and robustness of NIRS measurements under production plant conditions.

Longissimus dorsi samples (685) collected at four processing plants were used to develop prediction equations for meat quality with near infrared spectroscopy. Equations with R(2)>0.70 and residual prediction deviation (RPD)≥2.0 were considered as applicable for screening. One production plant showed R(2) 0.76 and RPD 2.05, other plants showed R(2)<0.70 and RPD<2.0 for drip loss %. RPD values were ≤2.05 for drip loss%, for colour L*≤1.82 and pH ultimate (pHu)≤1.57. Samples were grouped for drip loss%; superior (<2.0%), moderate (2-4%), inferior (>4.0%). 64% from the superior group and 56% from the inferior group were predicted correctly. One equation could be used for screening drip loss %. Best prediction equation for L* did not meet the requirements (R(2) 0.70 and RPD 1.82). pHu equation could not be used. Results suggest that prediction equations can be used for screening drip loss %.

The cost effectiveness of in vivo dosimetry is not proven.

In vivo dosimetry is a check of the radiotherapy treatment process. Recently, it has been argued that in vivo dosimetry at the start of every patient's radiotherapy is cost effective. We have examined and extended the cost effectiveness argument and show that the model does not deliver the stated benefits.

Shading correction algorithm for improvement of cone-beam CT images in radiotherapy.

Cone-beam CT (CBCT) images have recently become an established modality for treatment verification in radiotherapy. However, identification of soft-tissue structures and the calculation of dose distributions based on CBCT images is often obstructed by image artefacts and poor consistency of density calibration. A robust method for voxel-by-voxel enhancement of CBCT images using a priori knowledge from the planning CT scan has been developed and implemented. CBCT scans were enhanced using a low spatial frequency grey scale shading function generated with the aid of a planning CT scan from the same patient. This circumvents the need for exact correspondence between CBCT and CT and the process is robust to the appearance of unshared features such as gas pockets. Enhancement was validated using patient CBCT images. CT numbers in regions of fat and muscle tissue in the processed CBCT were both within 1% of the values in the planning CT, as opposed to 10-20% different for the original CBCT. Visual assessment of processed CBCT images showed improvement in soft-tissue visibility, although some cases of artefact introduction were observed.

Real-time noninvasive assessment of pancreatic ATP levels during cold preservation.

31P-NMR spectroscopy was utilized to investigate rat and porcine pancreatic ATP:P(i) ratios to assess the efficacy of existing protocols for cold preservation (CP) in maintaining organ quality. Following sacrifice, rat pancreata were immediately excised or left enclosed in the body for 15 minutes of warm ischemia (WI). After excision, rat pancreata were stored at 6 degrees C to 8 degrees C using histidine-tryptophan-ketoglutarate solution (HTK) presaturated with air (S1), HTK presaturated with O2 (S2), or the HTK/perfluorodecalin two-layer method (TLM) with both liquids presaturated with O2 (S3). 31P-NMR spectra were sequentially collected at 3, 6, 9, 12, and 24 hours of CP from pancreata stored with each of the three protocols examined. The ATP:Pi ratio for rat pancreata exposed to 15 minutes of WI and stored with S3 increased during the first 9 hours of CP, approaching values observed for organs procured with no WI. A marked reduction in the ATP:Pi ratio was observed beyond 12 hours of CP with S3. After 6 hours of CP, the ATP:Pi ratio was highest for S3, substantially decreased for S2, and below detection for S1. In sharp contrast to the rat model, ATP was barely detectable in porcine pancreata exposed to minimal warm ischemia (<15 minutes) stored with the TLM regardless of CP time. We conclude that 31P-NMR spectroscopy is a powerful tool that can be used to (1) noninvasively evaluate pancreata prior to islet isolation, (2) assess the efficacy of different preservation protocols, (3) precisely define the timing of reversible versus irreversible damage, and (4) assess whether intervention will extend this timing.

Developments in and experience of kilovoltage X-ray cone beam image-guided radiotherapy.

This paper offers a realistic review of kilovoltage X-ray cone beam tomography integrated with the treatment machine for image-guided radiotherapy in the light of experience taking a commercial system from prototype development into clinical use. It shows that key practicalities cannot be ignored, in particular the regular characterization of mechanical flex during gantry rotation, the mapping of defects in flat panel image transducers and their response to X-ray exposure. The number of X-ray projections and the doses required for clinically useful cone beam reconstruction at different therapy sites are considered in the context of imaging that is fit for purpose. Three roles for cone beam tomography in radiotherapy are identified: patient setup in three dimensions (3D), where even low dose cone beam tissue detail is superior to megavoltage imaging; disease targeting where, despite wide field scatter and slow scanning, it is possible to generate images that are suitable for tumour delineation even at challenging sites; adaptive treatment planning, where calibrated cone beam images have been shown to provide sufficient target detail to support "plan of the day" selection and have the potential for planning with bulk corrections. With frequent use in mind, the need to limit patient dose during setup, yet maximize much needed image quality in the target zone, is considered. Finally, it is noted that the development of cone beam tomography for radiotherapy is far from complete, with X-ray source, image transducer, reconstruction algorithms and techniques for image profile collection still being researched.

IMRT: delivery techniques and quality assurance.

Intensity modulated radiotherapy (IMRT) is a major development in the delivery of radiation therapy that has the potential to improve patient outcome by reducing morbidity or increasing local tumour control. Delivery techniques include those based on purpose built devices and treatment machines together with those utilizing the capabilities of computer controlled multileaf collimators which are more widely available. The complexity of IMRT techniques demands a high level of quality control both in the operation of the equipment and in the delivery of treatment to individual patients. The purpose of this paper is therefore to review the techniques available, concentrating on the use of multileaf collimators, and to consider the necessary quality control requirements for clinical application. It demonstrates that the technology is mature and sufficiently well understood so that IMRT can be safely implemented in the general clinical environment rather than being limited to application in the research environment.

Indexing artefacts using a tertiary collimator and a method to avoid them.

A tertiary, slotted grid collimator has been proposed as a method by which the spatial resolution of radiation fields shaped using a multileaf collimator (MLC) may be improved. The prototype device previously reported in the literature allowed each slot in the grid to be aligned with each pair of opposing leaves in the MLC. Irradiation through the collimator resulted in a regular pattern of high dose strips, with the width of each strip defined by the width of the slot and the length by the relative separation of the MLC leaf pair. To complete the field, the patient must be indexed relative to the collimator, with the number of sub-fields required determined by the width of the slots and the spacing between them. This indexing is achieved by rotation of the collimator along a radius centred on the radiation source, thus avoiding the effects of beam divergence on the uniformity of delivered composite beams. However, rotation of the tertiary collimator has been shown to result in artefacts in field definition. The source of such artefacts is the proximity of the long edge of a slot to the junction between two MLC leaves, if one leaf is withdrawn with respect to the next. A simple cause for such artefacts was identified as a small misalignment between the slot edge and the leaf junction. Another source of such effects is the finite size of the radiation source, which allows for partial shielding effects beyond the leaf edge. Finally, the effect of the leaf edge penumbra was identified as the cause of potential areas of underdose within the field boundary. Measurements were performed using a mini-diode of the potential magnitude of the last two effects for slot widths of 2.5 and 5.0 mm beneath a single open MLC leaf. For both slot widths, the unwanted overdose due to partial shielding by neighbouring leaves did not exceed 8% of the dose with the slot at the centre of the single open leaf. The potential for underdose within the field was a much more significant effect, especially for the narrower slot, with the peak intensity through the 2.5 mm slot positioned just inside the open leaf only reaching 41% of that measured with it positioned centrally. Such an arrangement of slots and leaves is unavoidable if the separation between neighbouring slots is identical to that of the MLC leaves (1 cm at isocentre). An alternative arrangement is proposed, and has been demonstrated to avoid the generation of the artefacts detailed above.

The required number of treatment imaging days for an effective off-line correction of systematic errors in conformal radiotherapy of prostate cancer--a radiobiological analysis.

BACKGROUND AND PURPOSE: To use radiobiological modelling to estimate the number of initial days of treatment imaging required to gain most of the benefit from off-line correction of systematic errors in the conformal radiation therapy of prostate cancer. MATERIALS AND METHODS: Treatment plans based on the anatomical information of a representative patient were generated assuming that the patient is treated with a multi leaf collimator (MLC) four-field technique and a total isocentre dose of 72 Gy delivered in 36 daily fractions. Target position variations between fractions were simulated from standard deviations of measured data found in the literature. Off-line correction of systematic errors was assumed to be performed only once based on the measured errors during the initial days of treatment. The tumour control probability (TCP) was calculated using the Webb and Nahum model. RESULTS: Simulation of daily variations in the target position predicted a marked reduction in TCP if the planning target volume (PTV) margin was smaller than 4 mm (TCP decreased by 3.4% for 2 mm margin). The systematic components of target position variations had greater effect on the TCP than the random components. Off-line correction of estimated systematic errors reduced the decrease in TCP due to target daily displacements, nevertheless, the resulting TCP levels for small margins were still less than the TCP level obtained with the use of an adequate PTV margin of approximately 10 mm. The magnitude of gain in TCP expected from the correction depended on the number of treatment imaging days used for the correction and the PTV margin applied. Gains of 2.5% in TCP were estimated from correction of systematic errors performed after 6 initial days of treatment imaging for a 2 mm PTV margin. The effect of various possible magnitudes of systematic and random components on the gain in TCP expected from correction and on the number of imaging days required was also investigated. CONCLUSIONS: Daily variations of target position markedly reduced the TCP if small margins were used. Off-line correction of systematic errors can only partly compensate for these TCP reductions. The adequate number of treatment imaging days required for systematic error correction depends on the magnitude of the random component compared with the systematic component, and on the size of PTV margin used. For random components equal to or smaller than the systematic component, 3 consecutive treatment imaging days are estimated to be sufficient to gain most of the benefit from correction for current clinically used margins (6-10 mm); otherwise more days are required.

Vanquishing virtue: the impact of medical education.

North American physicians emerge from their medical training with a wide array of professional beliefs and values. Many are thoughtful and introspective. Many are devoted to patients' welfare. Some bring to their work a broad view of social responsibility. Nonetheless, the authors contend that North American medical education favors an explicit commitment to traditional values of doctoring-empathy, compassion, and altruism among them-and a tacit commitment to behaviors grounded in an ethic of detachment, self-interest, and objectivity. They further note that medical students and young physicians respond to this conflict in various ways. Some re-conceptualize themselves primarily as technicians and narrow their professional identities to an ethic of competence, thus adopting the tacit values and discarding the explicit professionalism. Others develop non-reflective professionalism, an implicit avowal that they best care for their patients by treating them as objects of technical services (medical care). Another group appears to be "immunized" against the tacit values, and thus they internalize and develop professional virtue. Certain personal characteristics of the student, such as gender, belief system, and non-medical commitments, probably play roles in "immunization," as do medical school features such as family medicine, communication skills courses, medical ethics, humanities, and social issues in medicine. To be effective, though, these features must be prominent and tightly integrated into the medical school curriculum. The locus of change in the culture of medicine has now shifted to ambulatory settings and the marketplace. It remains to be seen whether this move will lessen the disjunction between the explicit curriculum and the manifestly contradictory values of detachment and entitlement, and the belief that the patient's interest always coincides with the physician's interest.

Optimizing the indexing of a resolution-enhancing tertiary collimator for radiotherapy.

A method for improving the resolution of multileaf collimator (MLC) defined radiotherapy fields using a tertiary, slotted grid collimator has been investigated and developed further. The original concept was for each slot to be aligned with each leaf pair of opposing MLC leaves. The total treated area is composed of a series of sub-fields, a pattern of irradiated strips, with the width of each strip defined by the width of the slot and the length by the relative separation of the MLC leaf pair. To complete the field, the patient must be indexed relative to the collimator, with the number of sub-fields required determined by the width of the slots and the spacing between them. Two methods were considered by which this indexing could be achieved: movement of the patient while holding the tertiary collimator fixed, or rotating the grid with the point of rotation defined as the radiation source. Consideration of the movement resolution and precision required for the patient support system for non-cardinal gantry, collimator and table angles cast doubt on the practicality of the use of such a strategy. To assess the effect of divergence on the abutting sub-fields, measurements were also performed to assess the uniformity of single fields generated by the tertiary collimator in planes above and below the isocentre using both methods of indexing. As expected, rotation of the collimator resulted in a similar degree of non-uniformity for any plane chosen, whereas significant dose heterogeneities were introduced to treatment planes within 5 cm above and below the isocentre if the patient support system was used. Therefore, the rotation strategy will be implemented with all future versions of the device.

High-resolution field shaping utilizing a masked multileaf collimator.

Multileaf collimators (MLCs) have become an important tool in the modern radiotherapy department. However, the current limit of resolution (1 cm at isocentre) can be too coarse for acceptable shielding of all fields. A number of mini- and micro-MLCs have been developed, with thinner leaves to achieve approved resolution. Currently however, such devices are limited to modest field sizes and stereotactic applications. This paper proposes a new method of high-resolution beam collimation by use of a tertiary grid collimator situated below the conventional MLC. The width of each slit in the grid is a submultiple of the MLC width. A composite shaped field is thus built up from a series of subfields, with the main MLC defining the length of each strip within each subfield. Presented here are initial findings using a prototype device. The beam uniformity achievable with such a device was examined by measuring transmission profiles through the grid using a diode. Profiles thus measured were then copied and superposed to generate composite beams, from which the uniformity achievable could be assessed. With the average dose across the profile normalized to 100%, hot spots up to 5.0% and troughs of 3% were identified for a composite beam of 2 x 5.0 mm grids, as measured at Dmax for a 6 MV beam. For a beam composed from 4 x 2.5 mm grids, the maximum across the profile was 3.0% above the average, and the minimum 2.5% below. Actual composite profiles were also formed using the integrating properties of film, with the subfield indexing performed using an engineering positioning stage. The beam uniformity for these fields compared well with that achieved in theory using the diode measurements. Finally sine wave patterns were generated to demonstrate the potential improvements in field shaping and conformity using this device as opposed to the conventional MLC alone. The scalloping effect on the field edge commonly seen on MLC fields was appreciably reduced by use of 2 x 5.0 mm grids, and still further by the use of 4 x 2.5 mm grids, as would be expected. This was also achieved with a small or negligible broadening of the beam penumbra as measured at Dmax.

Requirements for leaf position accuracy for dynamic multileaf collimation.

Intensity modulated radiation therapy can be achieved by driving the leaves of a multileaf collimator (MLC) across an x-ray therapy beam. Algorithms to generate the required leaf trajectories assume that the leaf positions are exactly known to the MLC controller. In practice, leaf positions depend upon calibration accuracy and stability and may vary within set tolerances. The purpose of this study was to determine the effects of potential leaf position inaccuracies on intensity modulated beams. Equations are derived which quantify the absolute error in delivered monitor units given a known error in leaf position. The equations have been verified by ionization chamber measurements in dynamically delivered flat fields, comparing deliveries in which known displacements have been applied to the defined leaf positions with deliveries without displacements applied. The equations are then applied to two clinical intensity modulations: an inverse planned prostate field and a breast compensating field. It is shown that leaf position accuracy is more critical for a highly modulated low-dose intensity profile than a moderately modulated high-dose intensity profile. Suggestions are given regarding the implications for quality control of dynamic MLC treatments.

Verification of dynamic multileaf collimation using an electronic portal imaging device.

High standards of treatment verification are necessary where complex new delivery techniques, such as intensity modulated radiation therapy using dynamic multileaf collimation, are being developed. This paper describes the use of a fluoroscopic electronic portal imaging device (EPID) to provide real-time qualitative verification of leaf position during delivery of a dynamic MLC prescription in addition to off-line quantitative verification. A custom-built circuit triggers the EPID to capture a series of snap-shot images at equally spaced dose points during a dynamic MLC prescription. Real-time verification is achieved by overlaying a template of expected leaf positions onto the images as they are acquired. Quantitative off-line verification is achieved using a maximum gradient edge detection algorithm to measure individual leaf positions for comparison with required leaf positions. Investigations have been undertaken to optimize image acquisition and assess the edge detection algorithm for variations in machine dose rate, leaf velocity and beam attenuation. On-line verification enables the operator to monitor the progress of a dynamic delivery and has been used for independent confirmation of accurate dynamic delivery during intensity modulated treatments. Off-line verification allows measurement of leaf position with a precision of 1 mm although image acquisition times must be less than or equal to 140 ms to ensure coincidence of the maximum gradient in the image with the 50% dose level.

Customised compensation using intensity modulated beams delivered by dynamic multileaf collimation.

BACKGROUND AND PURPOSE: This paper describes the development of customised compensation by intensity modulated radiation therapy (IMRT), delivered by dynamic application of a multileaf collimator (MLC), in order to improve dose homogeneity in treatments of the pelvic region. The introduction of this simple IMRT procedure will help facilitate the clinical implementation of more complex 3D conformal therapy techniques. MATERIALS AND METHOD: Computer software is used to generate profiles of the intensity modulated beams which are required to deliver a uniform dose in a plane, passing through the isocentre and normal to the beam axis, under an irregular surface contour. These profiles are then operated on by interpreter software which determines the leaf trajectories that are necessary to deliver these beam profiles using a single, unidirectional sweep of the MLC leaves. A full dose calculation based on the calculated leaf positions is subsequently performed, allowing further fine adjustments to the modulation where required. RESULTS AND CONCLUSION: The compensation procedure has been successfully tested using films placed under a test phantom. The effect of the compensation procedure on dose distributions in the transverse plane has been investigated using an anthropomorphic phantom. Overall dose homogeneity has been improved through the use of customised compensation delivered by dynamic multileaf collimation.

The performance of a fluoroscopic electronic portal imaging device modified for portability.

Advances in external beam therapy technology have made routine, efficient conformal therapy a reality. With it comes the increasing need for online treatment verification, which is only achievable at present through the use of electronic portal imaging devices (EPIDs). For a large radiotherapy centre, the provision of one EPID per treatment machine proves extremely expensive. This paper details modifications to the design of a commercial fluoroscopic EPID (the SRI-100) to produce a portable system, capable of providing quick, high quality imaging on more than one treatment machine. We describe the necessary hardware and software changes made to the system, as well as the variety of mechanical and quality control checks performed for testing the stability and quality of the imaging. The modified system has been found to be both electronically and mechanically robust, with associated image quality, scaling, distortion and movement similar to other EPIDs in the department. Although the modification was designed specifically to allow for the acquisition of images from multiple treatment machines, it may also enable the operation of the EPID for other uses such as total body irradiation (TBI) treatment verification and a further range of quality control procedures on the linear accelerator itself.

An experimental investigation of the tongue and groove effect for the Philips multileaf collimator.

The tongue and groove effect is an underdosing effect which can occur in certain applications of multileaf collimators. It results from the need to overlap adjacent leaves of a multileaf collimator in order to limit leakage between leaves. The applications in which the effect can occur are the abutment of fields where the beam edges are defined by the leaf edge and the production of intensity-modulated fields by dynamic collimation. The effect has been measured for the 'worst case' when just two MLC fields are matched along leaf edges which have overlapping steps. Measurements of the dose have been made at d(max) and also at a more clinically relevant depth of 87 mm in Perspex for beam energies of 6 MV, 8 MV and 20 MV on two Philips SL series accelerators. Dose distributions were recorded on radiographic film which was subsequently digitized for analysis. The dose reduction of the tongue and groove effect was found to be 15-28% and spread over a width of 3.8 to 4.2 mm. This is somewhat shallower and wider than would be expected from a simple, idealized model of the effect which would predict a dose reduction of 80% over a width of 1 mm.