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.

Monte Carlo Analysis and Physics Characterization of a Novel Nanoparticle Detector for Medical and Micro-dosimetry Applications

The outcomes for both (i) radiation therapy and (ii) preclinical small animal radio- biology studies are dependent on the delivery of a known quantity of radiation to a specific and intentional location. Adverse effects can result from these procedures if the dose to the target is too high or low, and can also result from an incorrect spatial distribution in which nearby normal healthy tissue can be undesirably damaged by poor radiation delivery techniques. Thus, in mice and humans alike, the spatial dose distributions from radiation sources should be well characterized in terms of the absolute dose quantity, and with pin-point accuracy. When dealing with the steep spatial dose gradients consequential to either (i) high dose rate (HDR) brachytherapy or (ii) within the small organs and tissue inhomogeneities of mice, obtaining accurate and highly precise dose results can be very challenging, considering commercially available radiation detection tools, such as ion chambers, are often too large for in-vivo use.

In this dissertation two tools are developed and applied for both clinical and preclinical radiation measurement. The first tool is a novel radiation detector for acquiring physical measurements, fabricated from an inorganic nano-crystalline scintillator that has been fixed on an optical fiber terminus. This dosimeter allows for the measurement of point doses to sub-millimeter resolution, and has the ability to be placed in-vivo in humans and small animals. Real-time data is displayed to the user to provide instant quality assurance and dose-rate information. The second tool utilizes an open source Monte Carlo particle transport code, and was applied for small animal dosimetry studies to calculate organ doses and recommend new techniques of dose prescription in mice, as well as to characterize dose to the murine bone marrow compartment with micron-scale resolution.

Hardware design changes were implemented to reduce the overall fiber diameter to <0.9 mm for the nano-crystalline scintillator based fiber optic detector (NanoFOD) system. Lower limits of device sensitivity were found to be approximately 0.05 cGy/s. Herein, this detector was demonstrated to perform quality assurance of clinical 192Ir HDR brachytherapy procedures, providing comparable dose measurements as thermo-luminescent dosimeters and accuracy within 20% of the treatment planning software (TPS) for 27 treatments conducted, with an inter-quartile range ratio to the TPS dose value of (1.02-0.94=0.08). After removing contaminant signals (Cerenkov and diode background), calibration of the detector enabled accurate dose measurements for vaginal applicator brachytherapy procedures. For 192Ir use, energy response changed by a factor of 2.25 over the SDD values of 3 to 9 cm; however a cap made of 0.2 mm thickness silver reduced energy dependence to a factor of 1.25 over the same SDD range, but had the consequence of reducing overall sensitivity by 33%.

For preclinical measurements, dose accuracy of the NanoFOD was within 1.3% of MOSFET measured dose values in a cylindrical mouse phantom at 225 kV for x-ray irradiation at angles of 0, 90, 180, and 270˝. The NanoFOD exhibited small changes in angular sensitivity, with a coefficient of variation (COV) of 3.6% at 120 kV and 1% at 225 kV. When the NanoFOD was placed alongside a MOSFET in the liver of a sacrificed mouse and treatment was delivered at 225 kV with 0.3 mm Cu filter, the dose difference was only 1.09% with use of the 4x4 cm collimator, and -0.03% with no collimation. Additionally, the NanoFOD utilized a scintillator of 11 µm thickness to measure small x-ray fields for microbeam radiation therapy (MRT) applications, and achieved 2.7% dose accuracy of the microbeam peak in comparison to radiochromic film. Modest differences between the full-width at half maximum measured lateral dimension of the MRT system were observed between the NanoFOD (420 µm) and radiochromic film (320 µm), but these differences have been explained mostly as an artifact due to the geometry used and volumetric effects in the scintillator material. Characterization of the energy dependence for the yttrium-oxide based scintillator material was performed in the range of 40-320 kV (2 mm Al filtration), and the maximum device sensitivity was achieved at 100 kV. Tissue maximum ratio data measurements were carried out on a small animal x-ray irradiator system at 320 kV and demonstrated an average difference of 0.9% as compared to a MOSFET dosimeter in the range of 2.5 to 33 cm depth in tissue equivalent plastic blocks. Irradiation of the NanoFOD fiber and scintillator material on a 137Cs gamma irradiator to 1600 Gy did not produce any measurable change in light output, suggesting that the NanoFOD system may be re-used without the need for replacement or recalibration over its lifetime.

For small animal irradiator systems, researchers can deliver a given dose to a target organ by controlling exposure time. Currently, researchers calculate this exposure time by dividing the total dose that they wish to deliver by a single provided dose rate value. This method is independent of the target organ. Studies conducted here used Monte Carlo particle transport codes to justify a new method of dose prescription in mice, that considers organ specific doses. Monte Carlo simulations were performed in the Geant4 Application for Tomographic Emission (GATE) toolkit using a MOBY mouse whole-body phantom. The non-homogeneous phantom was comprised of 256x256x800 voxels of size 0.145x0.145x0.145 mm3. Differences of up to 20-30% in dose to soft-tissue target organs was demonstrated, and methods for alleviating these errors were suggested during whole body radiation of mice by utilizing organ specific and x-ray tube filter specific dose rates for all irradiations.

Monte Carlo analysis was used on 1 µm resolution CT images of a mouse femur and a mouse vertebra to calculate the dose gradients within the bone marrow (BM) compartment of mice based on different radiation beam qualities relevant to x-ray and isotope type irradiators. Results and findings indicated that soft x-ray beams (160 kV at 0.62 mm Cu HVL and 320 kV at 1 mm Cu HVL) lead to substantially higher dose to BM within close proximity to mineral bone (within about 60 µm) as compared to hard x-ray beams (320 kV at 4 mm Cu HVL) and isotope based gamma irradiators (137Cs). The average dose increases to the BM in the vertebra for these four aforementioned radiation beam qualities were found to be 31%, 17%, 8%, and 1%, respectively. Both in-vitro and in-vivo experimental studies confirmed these simulation results, demonstrating that the 320 kV, 1 mm Cu HVL beam caused statistically significant increased killing to the BM cells at 6 Gy dose levels in comparison to both the 320 kV, 4 mm Cu HVL and the 662 keV, 137Cs beams.

Merely Birds of Passage: Lady Hariot Dufferin's Travel Writings and Medical Work in India, 1884-88

This article examines the travel writings and medical work in India of Lady Hariot Dufferin, Vicereine of India between 1884 and 1888. Lady Dufferin accompanied her husband, the Viceroy Lord Dufferin, through various social and political engagements in India, and carved her own niche in colonial and postcolonial history as a pioneer in the medical training of women in India. The article examines her travel writings on India and explores the nature of her complicity in the Raj, as well as the gendered nature of the separate public role she created for herself in relation to her 'zenana work' in providing medical care for the women of India. The author suggests that, through her work, Lady Dufferin challenges and extends the theoretical paradigms of postcolonialist and feminist critiques of empire.

Why people experiencing acute myocardial infarction delay seeking medical assistance

Background: Delay time from onset of symptoms of myocardial infarction to seeking medical assistance can have life- 31 threatening consequences. A number of factors have been associated with delay, but there is little evidence regarding the predictive 32 value of these indices. Aim: To explore potential predictors of patient delay from onset of symptoms to time medical assistance 33 was sought in a consecutive sample of patients admitted to CCU with acute myocardial infarction. Methods: The Cardiac Denial 34 of Impact Scale, Health Locus of Control Scale, Health Value Scale and Pennebaker Inventory of Limbic Languidness were 35 administered to 62 patients between 3 and 6 days after admission. Results: Attribution of symptoms to heart disease and health 36 locus of control had a significant predictive effect on patients seeking help within 60 min, while previous experience of heart 37 disease did not. Conclusion: Assisting individuals to recognise the potential for symptoms to have a cardiac origin is an important 38 objective. Interventions should take into account the variety of cognitive and behavioural factors involved in decision making.

Belief, Knowledge and Expertise. The emergence of the lay expert in medical sociology

The paper has three main aims. First, to trace – through the pages of the Journal – the changing ways in which lay understandings of health and illness have been represented during the 1979-2002 period. Second, to say something about the limits of lay knowledge (and particularly lay expertise) in matters of health and medicine. Third, to call for a re-assessment of what lay people can offer to a democratised and customer sensitive system of health care and to attempt to draw a boundary around the domain of expertise. In following through on those aims, the author calls upon data derived from three current projects. These latter concern the diagnosis of Alzheimer’s disease in people with Down’s syndrome; the development of an outcome measure for people who have suffered a traumatic brain injury; and a study of why older people might reject annual influenza vaccinations. Key words: Lay health beliefs, lay expertise, Alzheimer’s, Traumatic Brain Injury, Vaccinations

The impact of curricular change on medical students' knowledge of anatomy

Background: In recent years, following the publication of Tomorrow's Doctors, the undergraduate medical curriculum in most UK medical schools has undergone major revision. This has resulted in a significant reduction in the time allocated to the teaching of the basic medical sciences, including anatomy. However, it is not clear what impact these changes have had on medical students' knowledge of surface anatomy. Aim: This study aimed to assess the impact of these curricular changes on medical students' knowledge of surface anatomy. Setting: Medical student intakes for 1995-98 at the Queen's University of Belfast, UK. Methods: The students were invited to complete a simple examination paper testing their knowledge of surface anatomy. Results from the student intake of 1995, which undertook a traditional, 'old' curriculum, were compared with those from the student intakes of 1996-98, which undertook a new, 'systems-based' curriculum. To enhance linear response and enable the use of linear models for analysis, all data were adjusted using probit transformations of the proportion (percentage) of correct answers for each item and each year group. Results: The student intake of 1995 (old curriculum) were more likely to score higher than the students who undertook the new, systems-based curriculum. Conclusion: The introduction of the new, systems-based course has had a negative impact on medical students' knowledge of surface anatomy.