Judicial Review, Irrationality, and the Legitimacy of Merits-Review

The definition of the irrationality ground of judicial review recognises the constitutional principle of the separation of powers, in allowing for judicial control of the executive only very rarely. The author in a previous article in this study found that the courts, on occasions, had intervened in circumstances where administrative decisions arguably were not irrational. To this end, the purpose of this article is to assess the constitutionality of these seemingly low standards of irrationality. The author does so by reference either to the manner of review employed—the use of the proportionality principle, for example—or the context of the administrative decision under scrutiny, such as the infringement of the applicant’s fundamental rights. The author finds that the cases from the previous article where low standards of irrationality were arguably adopted were, in fact, legitimate according to these chosen methods of evaluation. However, this is an interim conclusion because, for reasons of word length, the author is unable to complete a full assessment here. It is therefore proposed that a subsequent article will continue to examine the constitutionality of these cases. Furthermore, the author will also try and establish a zone of executive decision-making, for reasons of democracy, where the courts are excluded from irrationality review. If the author is unsuccessful in this regard, the final conclusion of this study will inevitably be that low standards of judicial intervention exist without limit—a clear assault on the constitutional principle stated above

Subsurface scientific exploration of extraterrestrial environments (MINAR 5): analogue science, technology and education in the Boulby Mine, UK

The deep subsurface of other planetary bodies is of special interest for robotic and human exploration. The subsurface provides access to planetary interior processes, thus yielding insights into planetary formation and evolution. On Mars, the subsurface might harbour the most habitable conditions. In the context of human exploration, the subsurface can provide refugia for habitation from extreme surface conditions. We describe the fifth Mine Analogue Research (MINAR 5) programme at 1 km depth in the Boulby Mine, UK in collaboration with Spaceward Bound NASA and the Kalam Centre, India, to test instruments and methods for the robotic and human exploration of deep environments on the Moon and Mars. The geological context in Permian evaporites provides an analogue to evaporitic materials on other planetary bodies such as Mars. A wide range of sample acquisition instruments (NASA drills, Small Planetary Impulse Tool (SPLIT) robotic hammer, universal sampling bags), analytical instruments (Raman spectroscopy, Close-Up Imager, Minion DNA sequencing technology, methane stable isotope analysis, biomolecule and metabolic life detection instruments) and environmental monitoring equipment (passive air particle sampler, particle detectors and environmental monitoring equipment) was deployed in an integrated campaign. Investigations included studying the geochemical signatures of chloride and sulphate evaporitic minerals, testing methods for life detection and planetary protection around human-tended operations, and investigations on the radiation environment of the deep subsurface. The MINAR analogue activity occurs in an active mine, showing how the development of space exploration technology can be used to contribute to addressing immediate Earth-based challenges. During the campaign, in collaboration with European Space Agency (ESA), MINAR was used for astronaut familiarization with future exploration tools and techniques. The campaign was used to develop primary and secondary school and primary to secondary transition curriculum materials on-site during the campaign which was focused on a classroom extra vehicular activity simulation

Beam-orientation optimization of intensity-modulated radiotherapy: Clinical application to parotid gland tumours

Beam-orientation optimization of intensity-modulated radiotherapy: clinical application to parotid gland tumours. Background and purpose: An optimization algorithm has been developed to determine the best beam-arrangement for a small number of intensity-modulated radiotherapy (IMRT) fields. The algorithm is designed to avoid, if possible, beam-orientations that pass through organs-at-risk (OARs) with low radiation tolerance. Materials and methods: An independent, fast IMRT algorithm based on the Bortfeld algorithm was developed to determine the profile of the intensity-modulated beams (IMBs) for each beam-arrangement and a fast-simulated-annealing algorithm finds the 'optimal' beam-arrangement. The final beam-arrangement was transferred to the CORVUS (NOMOS Corporation) treatment planning system, and the IMBs were re-optimized for comparison with a standard nine-field, equi-spaced arrangement. The algorithm has been initially tested on a single example patient, with a parotid gland carcinoma. Results: The nine-field, IMRT plan for an example patient with a parotid gland tumour significantly reduced the dose to the cochlea compared with the conformal radiotherapy plan. In addition, the planning-target-volume (PTV) homogeneity was improved, but the plan produced a higher dose to the contralateral parotid (73% of the OAR received more than 6 Gy). The beam-orientation optimization algorithm produced a three-field plan that greatly reduced the dose to the contralateral parotid (maximum dose of 2 Gy), whilst maintaining the PTV dose homogeneity and the reduced cochlear dose of the nine-field plan. Some changes in the dose to the other OARs, namely the brain and the oral cavity, were seen, but were deemed not to be clinically significant. Conclusions: In conclusion, IMB-orientation optimization for head and neck treatment sites can produce improvements in treatment plans with only a few fields

Optimization of dose and route of administration of the P‐glycoprotein inhibitor, valspodar (PSC‐833) and the P‐glycoprotein and breast cancer resistance protein dual‐inhibitor, elacridar (GF120918) as dual infusion in rats

Abstract Transporters can play a key role in the absorption, distribution, metabolism, and excretion of drugs. Understanding these contributions early in drug discovery allows for more accurate projection of the clinical pharmacokinetics. One method to assess the impact of transporters in vivo involves co‐dosing specific inhibitors. The objective of the present study was to optimize the dose and route of administration of a P‐glycoprotein (P‐gp) inhibitor, valspodar (PSC833), and a dual P‐gp/breast cancer resistance protein (BCRP) inhibitor, elacridar (GF120918), by assessing the transporters’ impact on brain penetration and absorption. A dual‐infusion strategy was implemented to allow for flexibility with dose formulation. The chemical inhibitor was dosed intravenously via the femoral artery, and a cassette of known substrates was infused via the jugular vein. Valspodar or elacridar was administered as 4.5‐hour constant infusions over a range of doses. To assess the degree of inhibition, the resulting ratios of brain and plasma concentrations, Kp's, of the known substrates were compared to the vehicle control. These data demonstrated that doses greater than 0.9 mg/hr/kg valspodar and 8.9 mg/hr/kg elacridar were sufficient to inhibit P‐gp‐ and BCRP‐mediated efflux at the blood‐brain barrier in rats without any tolerability issues. Confirmation of BBB restriction by efflux transporters in preclinical species allows for subsequent prediction in humans based upon the proteomic expression at rodent and human BBB. Overall, the approach can also be applied to inhibition of efflux at other tissues (gut absorption, liver clearance) or can be extended to other transporters of interest using alternate inhibitors

Improvements in target coverage and reduced spinal cord irradiation using intensity-modulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland

Improvements in target coverage and reduced spinal cord irradiation using intensity-modulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland. Background and purpose: External beam radiotherapy for thyroid carcinoma poses a significant technical challenge as the target volume lies close to or surrounds the spinal cord. The potential of intensity-modulated radiotherapy (IMRT) to improve the dose distributions was investigated. Materials and methods: A planning study was performed on patients with thyroid carcinoma. Plans were generated to irradiate the thyroid bed alone or to treat the thyroid bed and the loco-regional lymph nodes in two phases. Conventional plans with minimal beam shaping were compared to three-dimensional conformal radiotherapy (3DCRT) and inverse-planned IMRT plans to assess target coverage and normal tissue sparing. IMRT techniques were optimized to find the minimum number of equispaced beams required to achieve the clinical benefit and a concomitant boost technique was explored. Results: For the thyroid bed alone and the thyroid bed plus loco-regional lymph nodes, conventional and conformal techniques produced low minimum doses to the planning target volume (PTV) if spinal cord tolerance was respected. 3DCRT reduced the irradiated volume of normal tissue (P=0.01). IMRT plans achieved the goal dose to the PTV (P<0.01) and also reduced the spinal cord maximum dose (P<0.01). IMRT, using a concomitant boost technique, produced better target coverage than a two-phase technique. For both the two-phase and concomitant boost techniques, IMRT plans with seven and five equispaced fields produced similar dose distributions to nine fields, but three fields were significantly worse. Conclusions: 3DCRT reduced normal tissue irradiation compared to conventional techniques, but did not improve PTV or spinal cord doses. IMRT improved the PTV coverage and reduced the spinal cord dose. A simultaneous integrated boost technique with five equispaced fields produced the best dose distribution. IMRT should reduce the risk of myelopathy or may allow dose escalation in patients with thyroid cancer