Is protocolised weaning that includes early extubation onto non-invasive ventilation more cost effective than protocolised weaning without non-invasive ventilation? Findings from the Breathe Study

Background Optimising techniques to wean patients from invasive mechanical ventilation (IMV) remains a key goal of intensive care practice. The use of non-invasive ventilation (NIV) as a weaning strategy (transitioning patients who are difficult to wean to early NIV) may reduce mortality, ventilator-associated pneumonia and intensive care unit (ICU) length of stay. Objectives Our objectives were to determine the cost effectiveness of protocolised weaning, including early extubation onto NIV, compared with weaning without NIV in a UK National Health Service setting. Methods We conducted an economic evaluation alongside a multicentre randomised controlled trial. Patients were randomised to either protocol-directed weaning from mechanical ventilation or ongoing IMV with daily spontaneous breathing trials. The primary efficacy outcome was time to liberation from ventilation. Bivariate regression of costs and quality-adjusted life-years (QALYs) provided estimates of the incremental cost per QALY and incremental net monetary benefit (INMB) overall and for subgroups [presence/absence of chronic obstructive pulmonary disease (COPD) and operative status]. Long-term cost effectiveness was determined through extrapolation of survival curves using flexible parametric modelling. Results NIV was associated with a mean INMB of £620 ($US885) (cost-effectiveness threshold of £20,000 per QALY) with a corresponding probability of 58$US6594 per QALY gained). Conclusions The probability of NIV being cost effective relative to weaning without NIV ranged between 57 and 59% overall and between 82 and 87% for the COPD subgroup

On the Inconsistency of Fayet-Iliopoulos Terms in Supergravity Theories

Motivated by recent discussions, we revisit the issue of whether globally supersymmetric theories with non-zero Fayet-Iliopoulos terms may be consistently coupled to supergravity. In particular, we examine claims that a fundamental inconsistency arises due to the conflicting requirements which are imposed on the $R$-symmetry properties of the theory by the supergravity framework. We also prove that certain kinds of Fayet-Iliopoulos contributions to the supercurrent supermultiplets of theories with non-zero Fayet-Iliopoulos terms fail to exist. A key feature of our discussion is an explicit comparison between results from the chiral (or ``old minimal'') and linear (or ``new minimal'') formulations of supergravity, and the effects within each of these formalisms that are induced by the presence of non-zero Fayet-Iliopoulos terms.Comment: Comments: 69 pages, LaTeX, 2 figures, 7 tables. Significant new material on conformal-compensator formalisms added, previous results clarified and extended, references adde

Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Simple SummaryPatients with medulloblastoma receive treatment according to a risk stratification, which is a combination of clinical and biological factors. To date there have been a limited number of trials for high-risk disease in children older than 3 years, with a wide range of treatment philosophies that usually involve higher doses of radiotherapy delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, to date, trials in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international, biomarker-driven, randomised clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens.AbstractMedulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort

Containment and Analysis Capability Insights Gained from Drop Testing Representative Spent Nuclear Fuel Containers

The National Spent Nuclear Fuel Program (NSNFP), operating from the Idaho National Engineering and Environmental Laboratory (INEEL), developed the standardized Department of Energy (DOE) spent nuclear fuel (SNF) canister. This canister is designed to be loaded with DOE SNF (including other radioactive materials) and then be used during interim storage, during transportation to the nation’s repository, and for final disposal at the repository without having to be reopened. The canister has been fully designed and has completed significant testing that clearly demonstrates that it can safely achieve its intended design goals. During 1999, nine 457-mm diameter test canisters were fabricated at the INEEL to represent the standardized DOE SNF canister design. Various "worst case" internals were incorporated. Seven of the test canisters were 4.57 m long and weighed approximately 2721 kg, while two were 3.00 m long and weighed approximately 1360 kg and 1725 kg. Seven of the test canisters were dropped from 9 m onto an essentially unyielding flat surface and one of the test canisters was dropped from 1 m onto a 15-cm diameter puncture post. The final test canister was dropped from 61 cm onto a 50.8 mm thick vertically oriented steel plate, and then fell over to impact another 50.8 mm thick vertically oriented steel plate. This last test represented a canister dropping onto another larger container such as a repository disposal container or waste package. The 1999 drop testing was performed at Sandia National Laboratories (SNL). The nine test canisters experienced varying degrees of damage to their skirts, lifting rings, and pressure boundary components (heads and main body). However, all of the canisters were shown to have maintained their pressure boundary (through pressure testing). Four heavily damaged canisters were also shown to be leaktight via helium leak testing. Pre- and post-drop finite element (FE) analyses were also performed. The results clearly indicated that accurate predictions of canister responses to the drop tests were achieved. The results achieved for the standardized canister can also be applicable to other well-constructed containers (canisters, casks, cans, vessels, etc.) subjected to similar loads. Properly designed containers can maintain a containment system after being subjected to dynamically induced high strains and FE computer analyses can accurately predict the resulting responses

Preliminary Drop Testing Results to Validate an Analysis Methodology for Accidental Drop Events of Containers for Radioactive Materials

The National Spent Nuclear Fuel Program, operating from the Idaho National Engineering and Environmental Laboratory (INEEL), developed the standardized Department of Energy (DOE) spent nuclear fuel (SNF) canister. During the development of this canister, more than twenty drop tests were completed, evaluating high strain behavior, puncture resistance, maintenance of containment, and other canister responses. Computer analyses of these drop-test specimens/canisters employed the ABAQUS/Explicit software. A pre-drop analysis was performed for each test specimen to predict the deformed shape and resulting material straining. Typically, a postdrop analysis was also performed to better match actual test specifics (actual impact angle, test specimen material properties, etc.). The purpose for this analysis effort was to determine the capability of current analysis techniques to accurately predict the deformed shape of a standardized DOE SNF canister subjected to a defined drop event, without actually having to perform a drop test for every drop event of interest. Those analytical efforts yielded very accurate predictions for nearly all of the drop tests. However, it was noted, during one small-scale test, that the calculated deformed shape of the test specimen depended on the modeled frictional behavior as it impacted the essentially unyielding flat surface. In order to calculate the correct deformed shape, the modeled frictional behavior had to be changed to an unanticipated value. This paper will report the results of a preliminary investigation that determined the appropriate frictional modeling for a variety of impact angles. That investigation included drop testing performed at the INEEL from September 2000 to January 2001