Safety assessment of oral photodynamic therapy in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Safety assessment of oral photodynamic therapy in rats

Photodynamic therapy (PDT) is based on the synergism of a photosensitive drug (a photosensitizer) and visible light to destroy target cells (e.g., malignant, premalignant, or bacterial cells). The aim of this study was to investigate the response of normal rat tongue mucosa to PDT following the topical application of hematoporphyrin derivative (Photogem®), Photodithazine®, methylene blue (MB), and poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with MB. One hundred and thirty three rats were randomly divided in various groups: the PDT groups were treated with the photosensitizers for 10 min followed by exposure to red light. Those in control groups received neither photosensitizer nor light, and they were subjected to light exposure alone or to photosensitizer alone. Fluorescent signals were obtained from tongue tissue immediately after the topical application of photosensitizers and 24 h following PDT. Histological changes were evaluated at baseline and at 1, 3, 7, and 15 days post-PDT treatment. Fluorescence was detected immediately after the application of the photosensitizers, but not 24 h following PDT. Histology revealed intact mucosa in all experimental groups at all evaluation time points. The results suggest that there is a therapeutic window where PDT with Photogem®, Photodithazine®, MB, and MB-loaded PLGA nanoparticles could safely target oral pathogenic bacteria without damaging normal oral tissue.

A Critical Response to Kevin Stenson’s Governing the Local: Sovereignty, Social Governance and Community Safety

In his compelling case study of local governance and community safety in the UK Thames Valley, Kevin Stenson makes several important contributions to the field of governmentality studies. While the paper’s merits are far-reaching, to this reader’s assessment they can be summarized in the following key areas: 1) Empirically, the article enhances our knowledge of the political economic transformation of a region otherwise overlooked in social science research ; 2) Conceptually, Stenson offers several theoretical and analytical refrains that, while becoming increasingly commonplace, are nonetheless still germane and rightly oriented to offer push back against otherwise totalizing, reified accounts of roll back/roll out neoliberalism. A welcomed new approach is offered as a corrective, The Realist Governmentality perspective, which emphasizes the interrelated and co-constitutive nature of politics, local culture, and habitus in processes related to the restructuring of social governance; 3) Methodologically, the paper makes a pitch for the ways in which finely grained, nuanced, mixed-method/ethnographic analyses have the potential to further problematize and recast a field of governmentality studies far too often dominated by discursive and textual approaches.

Trade-offs between voice and silence: a qualitative exploration of oncology staff's decisions to speak up about safety concerns

BACKGROUND Research suggests that "silence", i.e., not voicing safety concerns, is common among health care professionals (HCPs). Speaking up about patient safety is vital to avoid errors reaching the patient and thus to prevent harm and also to improve a culture of teamwork and safety. The aim of our study was to explore factors that affect oncology staff's decision to voice safety concerns or to remain silent and to describe the trade-offs they make. METHODS In a qualitative interview study with 32 doctors and nurses from 7 oncology units we investigated motivations and barriers to speaking up towards co-workers and supervisors. An inductive thematic content analysis framework was applied to the transcripts. Based on the individual experiences of participants, we conceptualize the choice to voice concerns and the trade-offs involved. RESULTS Preventing patients from serious harm constitutes a strong motivation to speaking up but competes with anticipated negative outcomes. Decisions whether and how to voice concerns involved complex considerations and trade-offs. Many respondents reflected on whether the level of risk for a patient "justifies" the costs of speaking up. Various barriers for voicing concerns were reported, e.g., damaging relationships. Contextual factors, such as the presence of patients and co-workers in the alarming situation, affect the likelihood of anticipated negative outcomes. Speaking up to well-known co-workers was described as considerably easier whereas "not knowing the actor well" increases risks and potential costs of speaking up. CONCLUSIONS While doctors and nurses felt strong obligation to prevent errors reaching individual patients, they were not engaged in voicing concerns beyond this immediacy. Our results offer in-depth insight into fears and conditions conducive of silence and voicing and can be used for educational interventions and leader reinforcement.

Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II Randomized Trial.

BACKGROUND Drug eluting stents with durable polymers may be associated with hypersensitivity, delayed healing, and incomplete endothelialization, which may contribute to late/very late stent thrombosis and the need for prolonged dual antiplatelet therapy. Bioabsorbable polymers may facilitate stent healing, thus enhancing clinical safety. The SYNERGY stent is a thin-strut, platinum chromium metal alloy platform with an ultrathin bioabsorbable Poly(D,L-lactide-co-glycolide) abluminal everolimus-eluting polymer. We performed a multicenter, randomized controlled trial for regulatory approval to determine noninferiority of the SYNERGY stent to the durable polymer PROMUS Element Plus everolimus-eluting stent. METHODS AND RESULTS Patients (n=1684) scheduled to undergo percutaneous coronary intervention for non-ST-segment-elevation acute coronary syndrome or stable coronary artery disease were randomized to receive either the SYNERGY stent or the PROMUS Element Plus stent. The primary end point of 12-month target lesion failure was observed in 6.7% of SYNERGY and 6.5% PROMUS Element Plus treated subjects by intention-to-treat (P=0.83 for difference; P=0.0005 for noninferiority), and 6.4% in both the groups by per-protocol analysis (P=0.0003 for noninferiority). Clinically indicated revascularization of the target lesion or definite/probable stent thrombosis were observed in 2.6% versus 1.7% (P=0.21) and 0.4% versus 0.6% (P=0.50) of SYNERGY versus PROMUS Element Plus-treated subjects, respectively. CONCLUSIONS In this randomized trial, the SYNERGY bioabsorbable polymer everolimus-eluting stent was noninferior to the PROMUS Element Plus everolimus-eluting stent with respect to 1-year target lesion failure. These data support the relative safety and efficacy of SYNERGY in a broad range of patients undergoing percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01665053.

Bursting Boilers and the Federal Power Redux: The Evolution of Safety on the Western Rivers

Using newly constructed data series on explosions, deaths, and steamboat traffic, we examine econometrically the causes of increased safety in steamboat boilers in the nineteenth century. Although the law of 1852 (but not that of 1838) did have a dramatic initial effect in reducing explosions, that reduction came against the background not of a system out of control but of a system that from the beginning was steadily increasing boiler safety per person- mile. The role of the federal government in conducting and disseminating basic research on boiler technology may have been more significant for increased safety than its explicit regulatory efforts.

Accident Management Actions In An Upper-Head Small-Break Loss-Of-Coolant Accident With High-Pressure Safety Injection Failed

Since the Three Mile Island accident, an important focus of pressurized water reactor (PWR) transient analyses has been a small-break loss-of-coolant accident (SBLOCA). In 2002, the discovery of thinning of the vessel head wall at the Davis Besse nuclear power plant reactor indicated the possibility of an SBLOCA in the upper head of the reactor vessel as a result of circumferential cracking of a control rod drive mechanism penetration nozzle - which has cast even greater importance on the study of SBLOCAs. Several experimental tests have been performed at the Large Scale Test Facility to simulate the behavior of a PWR during an upper-head SBLOCA. The last of these tests, Organisation for Economic Co-operation and Development Nuclear Energy Agency Rig of Safety Assessment (OECD/NEA ROSA) Test 6.1, was performed in 2005. This test was simulated with the TRACE 5.0 code, and good agreement with the experimental results was obtained. Additionally, a broad analysis of an upper-head SBLOCA with high-pressure safety injection failed in a Westinghouse PWR was performed taking into account different accident management actions and conditions in order to check their suitability. This issue has been analyzed also in the framework of the OECD/NEA ROSA project and the Code Applications and Maintenance Program (CAMP). The main conclusion is that the current emergency operating procedures for Westinghouse reactor design are adequate for these kinds of sequences, and they do not need to be modified.

Co-simulation Methodologies for Hybrid and Electric Vehicle Dynamics

In recent decades, full electric and hybrid electric vehicles have emerged as an alternative to conventional cars due to a range of factors, including environmental and economic aspects. These vehicles are the result of considerable efforts to seek ways of reducing the use of fossil fuel for vehicle propulsion. Sophisticated technologies such as hybrid and electric powertrains require careful study and optimization. Mathematical models play a key role at this point. Currently, many advanced mathematical analysis tools, as well as computer applications have been built for vehicle simulation purposes. Given the great interest of hybrid and electric powertrains, along with the increasing importance of reliable computer-based models, the author decided to integrate both aspects in the research purpose of this work. Furthermore, this is one of the first final degree projects held at the ETSII (Higher Technical School of Industrial Engineers) that covers the study of hybrid and electric propulsion systems. The present project is based on MBS3D 2.0, a specialized software for the dynamic simulation of multibody systems developed at the UPM Institute of Automobile Research (INSIA). Automobiles are a clear example of complex multibody systems, which are present in nearly every field of engineering. The work presented here benefits from the availability of MBS3D software. This program has proven to be a very efficient tool, with a highly developed underlying mathematical formulation. On this basis, the focus of this project is the extension of MBS3D features in order to be able to perform dynamic simulations of hybrid and electric vehicle models. This requires the joint simulation of the mechanical model of the vehicle, together with the model of the hybrid or electric powertrain. These sub-models belong to completely different physical domains. In fact the powertrain consists of energy storage systems, electrical machines and power electronics, connected to purely mechanical components (wheels, suspension, transmission, clutch…). The challenge today is to create a global vehicle model that is valid for computer simulation. Therefore, the main goal of this project is to apply co-simulation methodologies to a comprehensive model of an electric vehicle, where sub-models from different areas of engineering are coupled. The created electric vehicle (EV) model consists of a separately excited DC electric motor, a Li-ion battery pack, a DC/DC chopper converter and a multibody vehicle model. Co-simulation techniques allow car designers to simulate complex vehicle architectures and behaviors, which are usually difficult to implement in a real environment due to safety and/or economic reasons. In addition, multi-domain computational models help to detect the effects of different driving patterns and parameters and improve the models in a fast and effective way. Automotive designers can greatly benefit from a multidisciplinary approach of new hybrid and electric vehicles. In this case, the global electric vehicle model includes an electrical subsystem and a mechanical subsystem. The electrical subsystem consists of three basic components: electric motor, battery pack and power converter. A modular representation is used for building the dynamic model of the vehicle drivetrain. This means that every component of the drivetrain (submodule) is modeled separately and has its own general dynamic model, with clearly defined inputs and outputs. Then, all the particular submodules are assembled according to the drivetrain configuration and, in this way, the power flow across the components is completely determined. Dynamic models of electrical components are often based on equivalent circuits, where Kirchhoff’s voltage and current laws are applied to draw the algebraic and differential equations. Here, Randles circuit is used for dynamic modeling of the battery and the electric motor is modeled through the analysis of the equivalent circuit of a separately excited DC motor, where the power converter is included. The mechanical subsystem is defined by MBS3D equations. These equations consider the position, velocity and acceleration of all the bodies comprising the vehicle multibody system. MBS3D 2.0 is entirely written in MATLAB and the structure of the program has been thoroughly studied and understood by the author. MBS3D software is adapted according to the requirements of the applied co-simulation method. Some of the core functions are modified, such as integrator and graphics, and several auxiliary functions are added in order to compute the mathematical model of the electrical components. By coupling and co-simulating both subsystems, it is possible to evaluate the dynamic interaction among all the components of the drivetrain. ‘Tight-coupling’ method is used to cosimulate the sub-models. This approach integrates all subsystems simultaneously and the results of the integration are exchanged by function-call. This means that the integration is done jointly for the mechanical and the electrical subsystem, under a single integrator and then, the speed of integration is determined by the slower subsystem. Simulations are then used to show the performance of the developed EV model. However, this project focuses more on the validation of the computational and mathematical tool for electric and hybrid vehicle simulation. For this purpose, a detailed study and comparison of different integrators within the MATLAB environment is done. Consequently, the main efforts are directed towards the implementation of co-simulation techniques in MBS3D software. In this regard, it is not intended to create an extremely precise EV model in terms of real vehicle performance, although an acceptable level of accuracy is achieved. The gap between the EV model and the real system is filled, in a way, by introducing the gas and brake pedals input, which reflects the actual driver behavior. This input is included directly in the differential equations of the model, and determines the amount of current provided to the electric motor. For a separately excited DC motor, the rotor current is proportional to the traction torque delivered to the car wheels. Therefore, as it occurs in the case of real vehicle models, the propulsion torque in the mathematical model is controlled through acceleration and brake pedal commands. The designed transmission system also includes a reduction gear that adapts the torque coming for the motor drive and transfers it. The main contribution of this project is, therefore, the implementation of a new calculation path for the wheel torques, based on performance characteristics and outputs of the electric powertrain model. Originally, the wheel traction and braking torques were input to MBS3D through a vector directly computed by the user in a MATLAB script. Now, they are calculated as a function of the motor current which, in turn, depends on the current provided by the battery pack across the DC/DC chopper converter. The motor and battery currents and voltages are the solutions of the electrical ODE (Ordinary Differential Equation) system coupled to the multibody system. Simultaneously, the outputs of MBS3D model are the position, velocity and acceleration of the vehicle at all times. The motor shaft speed is computed from the output vehicle speed considering the wheel radius, the gear reduction ratio and the transmission efficiency. This motor shaft speed, somehow available from MBS3D model, is then introduced in the differential equations corresponding to the electrical subsystem. In this way, MBS3D and the electrical powertrain model are interconnected and both subsystems exchange values resulting as expected with tight-coupling approach.When programming mathematical models of complex systems, code optimization is a key step in the process. A way to improve the overall performance of the integration, making use of C/C++ as an alternative programming language, is described and implemented. Although this entails a higher computational burden, it leads to important advantages regarding cosimulation speed and stability. In order to do this, it is necessary to integrate MATLAB with another integrated development environment (IDE), where C/C++ code can be generated and executed. In this project, C/C++ files are programmed in Microsoft Visual Studio and the interface between both IDEs is created by building C/C++ MEX file functions. These programs contain functions or subroutines that can be dynamically linked and executed from MATLAB. This process achieves reductions in simulation time up to two orders of magnitude. The tests performed with different integrators, also reveal the stiff character of the differential equations corresponding to the electrical subsystem, and allow the improvement of the cosimulation process. When varying the parameters of the integration and/or the initial conditions of the problem, the solutions of the system of equations show better dynamic response and stability, depending on the integrator used. Several integrators, with variable and non-variable step-size, and for stiff and non-stiff problems are applied to the coupled ODE system. Then, the results are analyzed, compared and discussed. From all the above, the project can be divided into four main parts: 1. Creation of the equation-based electric vehicle model; 2. Programming, simulation and adjustment of the electric vehicle model; 3. Application of co-simulation methodologies to MBS3D and the electric powertrain subsystem; and 4. Code optimization and study of different integrators. Additionally, in order to deeply understand the context of the project, the first chapters include an introduction to basic vehicle dynamics, current classification of hybrid and electric vehicles and an explanation of the involved technologies such as brake energy regeneration, electric and non-electric propulsion systems for EVs and HEVs (hybrid electric vehicles) and their control strategies. Later, the problem of dynamic modeling of hybrid and electric vehicles is discussed. The integrated development environment and the simulation tool are also briefly described. The core chapters include an explanation of the major co-simulation methodologies and how they have been programmed and applied to the electric powertrain model together with the multibody system dynamic model. Finally, the last chapters summarize the main results and conclusions of the project and propose further research topics. In conclusion, co-simulation methodologies are applicable within the integrated development environments MATLAB and Visual Studio, and the simulation tool MBS3D 2.0, where equation-based models of multidisciplinary subsystems, consisting of mechanical and electrical components, are coupled and integrated in a very efficient way.

CO in vehicle inspection stations : feasibility of achieving the NIOSH recommended carbon monoxide standards in New Jersey motor vehicle inspection stations /

Mode of access: Internet.

Experimental safety car study. Phase I. Final report.

National Highway Safety Bureau, Washington, D.C.

A treatise on soap-making : containing an account of the alkaline materials, test for discovering the presence of an alkali, &c. : with full directions for manufacturing yellow, pure, white, and perfumed hard soap : also, complete instructions for the making of green or soft soap, with other requisites necessary to finish the soap-boiler : to which is added, abstracts of the excise laws relative to hard and soft soap-makers /

Mode of access: Internet.

Report of Minnesota Commission of Public Safety.

"The period generally covered is from April 23, 1917, to December 31, 1918." - p. 7.

Railroad accident report : Southern Pacific Transportation Co. freight train 2nd BSM 22 munitions explosion, Benson, Arizona, May 24, 1973 /

Mode of access: Internet.