Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations. METHODS: Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h) or vancomycin plus aztreonam (1 g each every 12 h) for 5-14 days. RESULTS: Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations, respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontinuations because of an adverse event, serious adverse events, and death also were similar between treatment groups. CONCLUSIONS: Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.

Spending on postapproval drug safety.

Withdrawals of high-profile pharmaceuticals have focused attention on post-approval safety surveillance. There have been no systematic assessments of spending on postapproval safety. We surveyed drug manufacturers regarding safety efforts. Mean spending on postapproval safety per company in 2003 was 56 million dollars (0.3 percent of sales). Assuming a constant safety-to-sales ratio, we estimated that total spending on postapproval safety by the top twenty drug manufacturers was 800 million dollars in 2003. We also examined, using regression analysis, the relationship between the number of safety personnel and the number of initial adverse-event reports. This study offers information for the debate on proposed changes to safety surveillance.

Herbal Dietary Supplements: Safety, Efficacy, and Use by Breast Cancer Survivors

Gemstone Team IMAC (Integrative Medicine and Cancer)

Adenosine-induced flow arrest to facilitate intracranial aneurysm clip ligation: dose-response data and safety profile.

BACKGROUND: Adenosine-induced transient flow arrest has been used to facilitate clip ligation of intracranial aneurysms. However, the starting dose that is most likely to produce an adequate duration of profound hypotension remains unclear. We reviewed our experience to determine the dose-response relationship and apparent perioperative safety profile of adenosine in intracranial aneurysm patients. METHODS: This case series describes 24 aneurysm clip ligation procedures performed under an anesthetic consisting of remifentanil, low-dose volatile anesthetic, and propofol in which adenosine was used. The report focuses on the doses administered; duration of systolic blood pressure <60 mm Hg (SBP(<60 mm Hg)); and any cardiovascular, neurologic, or pulmonary complications observed in the perioperative period. RESULTS: A median dose of 0.34 mg/kg ideal body weight (range: 0.29-0.44 mg/kg) resulted in a SBP(<60 mm Hg) for a median of 57 seconds (range: 26-105 seconds). There was a linear relationship between the log-transformed dose of adenosine and the duration of a SBP(<60 mm Hg) (R(2) = 0.38). Two patients developed transient, hemodynamically stable atrial fibrillation, 2 had postoperative troponin levels >0.03 ng/mL without any evidence of cardiac dysfunction, and 3 had postoperative neurologic changes. CONCLUSIONS: For intracranial aneurysms in which temporary occlusion is impractical or difficult, adenosine is capable of providing brief periods of profound systemic hypotension with low perioperative morbidity. On the basis of these data, a dose of 0.3 to 0.4 mg/kg ideal body weight may be the recommended starting dose to achieve approximately 45 seconds of profound systemic hypotension during a remifentanil/low-dose volatile anesthetic with propofol induced burst suppression.

Safety-critical medical device development using the UPP2SF model translation tool

Software-based control of life-critical embedded systems has become increasingly complex, and to a large extent has come to determine the safety of the human being. For example, implantable cardiac pacemakers have over 80,000 lines of code which are responsible for maintaining the heart within safe operating limits. As firmware-related recalls accounted for over 41% of the 600,000 devices recalled in the last decade, there is a need for rigorous model-driven design tools to generate verified code from verified software models. To this effect, we have developed the UPP2SF model-translation tool, which facilitates automatic conversion of verified models (in UPPAAL) to models that may be simulated and tested (in Simulink/Stateflow). We describe the translation rules that ensure correct model conversion, applicable to a large class of models. We demonstrate how UPP2SF is used in themodel-driven design of a pacemaker whosemodel is (a) designed and verified in UPPAAL (using timed automata), (b) automatically translated to Stateflow for simulation-based testing, and then (c) automatically generated into modular code for hardware-level integration testing of timing-related errors. In addition, we show how UPP2SF may be used for worst-case execution time estimation early in the design stage. Using UPP2SF, we demonstrate the value of integrated end-to-end modeling, verification, code-generation and testing process for complex software-controlled embedded systems. © 2014 ACM.

Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study.

Duchenne muscular dystrophy is caused by dystrophin deficiency and muscle deterioration and preferentially affects boys. Antisense-oligonucleotide-induced exon skipping allows synthesis of partially functional dystrophin. We investigated the efficacy and safety of drisapersen, a 2'-O-methyl-phosphorothioate antisense oligonucleotide, given for 48 weeks.

A novel neural/symbolic hybrid approach to heuristically optimized fuel allocation and automated revision of heuristics in nuclear engineering

FUELCON is an expert system for optimized refueling design in nuclear engineering. This task is crucial for keeping down operating costs at a plant without compromising safety. FUELCON proposes sets of alternative configurations of allocation of fuel assemblies that are each positioned in the planar grid of a horizontal section of a reactor core. Results are simulated, and an expert user can also use FUELCON to revise rulesets and improve on his or her heuristics. The successful completion of FUELCON led this research team into undertaking a panoply of sequel projects, of which we provide a meta-architectural comparative formal discussion. In this paper, we demonstrate a novel adaptive technique that learns the optimal allocation heuristic for the various cores. The algorithm is a hybrid of a fine-grained neural network and symbolic computation components. This hybrid architecture is sensitive enough to learn the particular characteristics of the ‘in-core fuel management problem’ at hand, and is powerful enough to use this information fully to automatically revise heuristics, thus improving upon those provided by a human expert.

Fire safety engineering and ship design using advanced fire and evacuation simulation

When designing a new passenger ship or modifying an existing design, how do we ensure that the proposed design and crew emergency procedures are safe from an evacuation resulting from fire or other incident? In the wake of major maritime disasters such as the Scandinavian Star, Herald of Free Enterprise, Estonia and in light of the growth in the number of high density, high-speed ferries and large capacity cruise ships, issues concerning the evacuation of passengers and crew at sea are receiving renewed interest. Fire and evacuation models with features such as the ability to realistically simulate the spread of heat and smoke and the human response to fire as well as the capability to model human performance in heeled orientations linked to a virtual reality environment that produces realistic visualisations of the modelled scenarios are now available and can be used to aid the engineer in assessing ship design and procedures. This paper describes the maritimeEXODUS ship evacuation and the SMARTFIRE fire simulation model and provides an example application demonstrating the use of the models in performing fire and evacuation analysis for a large passenger ship partially based on the requirements of MSC circular 1033

The airEXODUS evacuation model and its application to aircraft safety

Computer based mathematical models describing the aircraft evacuation process have a vital role to play in the design and development of safer aircraft, the implementation of safer and more rigorous certification criteria, in cabin crew training and post-mortem accident investigation. As the risk of personal injury and the costs involved in performing full-scale certification trials are high, the development and use of these evacuation modelling tools are essential. Furthermore, evacuation models provide insight into the evacuation process that is impossible to derive from a single certification trial. The airEXODUS evacuation model has been under development since 1989 with support from the UK CAA and the aviation industry. In addition to describing the capabilities of the airEXODUS evacuation model, this paper describes the findings of a recent CAA project aimed at investigating model accuracy in predicting past certification trials. Furthermore, airEXODUS is used to examine issues related to the Blended Wing Body (BWB) and Very Large Transport Aircraft (VLTA). These radical new aircraft concepts pose considerable challenges to designers, operators and certification authorities. BWB concepts involving one or two decks with possibly four or more aisles offer even greater challenges. Can the largest exits currently available cope with passenger flow arising from four or five aisles? Do we need to consider new concepts in exit design? Should the main aisle be made wider to accommodate more passengers? In this paper we discuss various issues evacuation related issues associated VLTA and BWB aircraft and demonstrate how computer based evacuation models can be used to investigage these issues through examination of aisle/exit configurations for BWB cabin layouts.

Climate change and food safety: A review

Climate change and variability may have an impact on the occurrence of food safety hazards at various stages of the food chain, from primary production through to consumption. There are multiple pathways through which climate related factors may impact food safety including: changes in temperature and precipitation patterns, increased frequency and intensity of extreme weather events, ocean warming and acidification, and changes in contaminants’ transport pathways among others. Climate change may also affect socio-economic aspects related to food systems such as agriculture, animal production, global trade, demographics and human behaviour which all influence food safety. This paper reviews the potential impacts of predicted changes in climate on food contamination and food safety at various stages of the food chain and identifies adaptation strategies and research priorities to address food safety implications of climate change. The paper concludes that there is a need for intersectoral and international cooperation to better understand the changing food safety situation and in developing and implementing adaptation strategies to address emerging risks associated with climate change.

Treatment of effluents contaminated with prions. Chemical reactor design

The control and elimination of prionic infective agents that may be present in the effluents, turns out to be a complicated mechanism inside a High Containment bological Facility. There are two ways to carry out this neutralization: Installation of thermal systems to ensure achieve a minimum temperature of 134 ° C sterilization plateau for a residence time of 18 minutes, and the use of chemical reactors based on the addition of sodium hypochlorite so the mixture maintained 2% of free chlorine during the reaction period. This study presents the design phases, elements and benefits, of a chemical reactor that allows the treatment of prion effluents in order to serve as a model to biocontainment facilities with areas of animal experimentation, who want to develop their work with prions.