A case study on applying formal methods to medical devices: computer-aided resuscitation algorithm

The design and functional complexity of medical devices have increased during the past 50 years, evolving from the use of a metronome circuit for the initial cardiac pacemaker to functions that include electrocardiogram analysis, laser surgery, and intravenous delivery systems that adjust dosage based on patient feedback. As device functionality becomes more intricate, concerns arise regarding efficacy, safety, and reliability. It thus becomes imperative to adopt a standard or methodology to ensure that the possibility of any defect or malfunction in these devices is minimized. It is with these facts in view that regulatory bodies are interested in investigating mechanisms to certify safety-crictical medical devices. These organizations advocate the use of formal methods techniques to evaluate safety-critical medical systems. However, the use of formal methods is keenly debated, with most manufacturers claiming that they are arduous and time consuming.In this paper we describe our experience in analyzing the requirements documents for the computer-aided resuscitation algorithm (CARA) designed by the Resuscitative Unit of the Walter Reed Army Institute of Research (WRAIR). We present our observations from two different angles – that of a nonbeliever in formal methods and that of a practitioner of formal methods. For the former we catalog the effort required by a novice user of formal methods tools to carry out an analysis of the requirements documents. For the latter we address issues related to choice of designs, errors in discovered requirements, and the tool support available for analyzing requirements .     

Reed canary grass yield and fuel quality in Estonian farmers’ fields

Reed canary grass (Phalaris arundinacea) is one of the possible raw materials for bioenergy production in northern Europe. Its cultivation is favoured because its high productivity and local origin. However, problems with the biomass quality for combustion have been reported. Usually delayed harvest in spring is suggested to improve the quality and decrease the moisture content of biomass. On the other hand, the feasibility of spring harvest depends on local climatic conditions and may cause yield losses. In current paper we studied reed canary grass fields in Estonia locating on different soil types and cultivated with various varieties. The influence of several fertilisation schemes on biomass yield was analysed. Our results indicated that production was higher on mineral soils than on the organic soil of abandoned peat extraction sites. Even different types of fertilisation did not increase the production on organic soils to the level comparable to those on mineral soils. Among studied varieties ‘Venture’ had the highest production. The highest yield per area was obtained late in the autumn (12.7 t d.w. per ha and 7.2 t d.w. per ha on mineral and organic soils, respectively). By spring the amount of biomass had decreased in all studied sites. Due to wet soil some of the fields remained unharvested, the others had high yield losses during practical harvesting. The chemical analyses did not reveal significant differences in the composition of biomass between late autumn and spring. Therefore we conclude that late autumn harvest should be preferred in local climatic conditions.     

A Novel Oxidation of Valine by N-Bromophthalimide in the Presence of Ruthenium(III) Chloride as a Homogeneous Catalyst

Kinetics of Ruthenium(III) [Ru(III)] chloride catalyzed oxidation of valine (Val) has been studied by N-bromophthalimide (NBP) in the acidic medium at 35 °C. The reaction rate follows first-order and zero-order dependence with respect to [NBP] and [Val]. First-order kinetics was observed for Ru(III) chloride at low range of concentrations and tending towards zero-order at higher concentrations. A negative effect was observed for [H⁺] and [phthalimide], while a positive effect was observed for [Cl^?] on the reaction rate. Hg(OAc)₂, ionic strength (I), and dielectric constant (D) of the medium did not change significantly the reaction rate. The rate constants as a function of temperature (298–318 K) were used to calculate activation parameters of the oxidation of Val by NBP. A plausible mechanism was proposed to explain the results of kinetic studies, reaction stoichiometry and product analysis.     

Differential scanning calorimetric investigation of polymerisation of epoxy resin based on phenolphthalein with phthalic anhydride

Polymerisation of phenolphthalein-based epoxy resin with phthalic anhydride has been investigated by differential scanning calorimetry. The overall polymerisation kinetics were found to be independent of the concentration of phthalic anhydride and scan rate. The polymerisation was found to follow a simple Arrhenius-type temperature dependence up to about 80% completion.     

Kinetics and Mechanism of Ru(III)-Catalyzed Oxidation of Paracetamol by Chloramine-T in Aqueous Acidic Medium

The present paper deals with the kinetics and mechanism of Ru(III)-catalyzed oxidation of paracetamol by chloramine-T (CAT) in aqueous perchloric acid medium at 303 K. The experimental result shows a first order dependence on paracetamol at its low concentrations, but tending towards zeroth order at its higher concentrations. The reactions follow a first order rate dependence with respect to oxidant [CAT] and [Ru(III)]. The reaction showed negative fractional-order dependence on the rate for [H⁺] and p-toluenesulphonamide. Variation in [Cl^?] and ionic strength of the medium did not bring about any significant change on the rate of reaction. The decrease in the reaction rate with decrease in the dielectric constant of the medium was observed in the oxidation of paracetamol. Kinetic and equivalence studies together with product analysis, observed effect of dielectric constant of the medium on the rate of reaction and activation parameters furnished a basis for the formation of a common reaction mechanism for the Ru(III)-catalyzed oxidation of paracetamol by CAT in the acidic medium.     

Nonaqueous phase synthesis of copper nanoparticles

Copper nanoparticles were synthesized in a nonaqueous solution of cetyltrimethylammonium bromide with isopropanol as a solvent. Cetyltrimethylammonium bromide in isopropanol is observed to play a role as a catalyst where isopropanol is the reducing agent. The surface plasmon band characteristic for Cu nanoparticles can be observed at approximately 560 nm in the UV-visible spectra at molar ratios for Cu2+: cetyltrimethylammonium bromide of 1:15 and 1:30. On the other hand, at molar ratios of 1:0.25 and 1:1 the presence of peak at approximately 310 nm can be attributed to oligomeric clusters of Cu0. Formation of Cu0 was further confirmed from the X-ray diffraction analysis. The diffractograms exhibited peaks at 2theta = approximately 41.6 degrees, approximately 51.6 degrees, and approximately 74.3 degrees, corresponding to Cu0. At lower concentration of cetyltrimethylammonium bromide (i.e., Cu2+: cetyltrimethylammonium bromide = 1:0.25) higher degree of size dispersity (particles between approximately 5-20 nm) can be noted from transmission electron micrograph. On the other hand, at the highest concentration of cetyltrimethylammonium bromide (i.e., Cu2+: cetyltrimethylammonium bromide = 1:30), formation of finer sized particles with a lower degree of size variation, approximately 2-10 nm, can be observed.     

Methotrexate-loaded biodegradable nanoparticles: preparation,characterization and evaluation of its cytotoxic potential against U-343 MGa human neuronal glioblastoma cells

Nanoparticles represent one of the attractive alternatives in the effective treatment of cancer chemotherapy. In the present work, formulation and development of a novel methotrexate (MTX)-loaded biodegradable nanoparticles using poly(D,L-lactide-co-glycolide) (PLGA) was carried out. The prepared nanoparticles were evaluated for physicochemical properties such as particle size, zeta potential, release studies, etc and also evaluated for its in vitro cytotoxic potential against U-343 MGa human neuronal glioblastoma cells. Particle size of optimized formulation was < 200 nm. There was a considerable decrease in cell viability and enhancement in cytotoxic activity of MTX-loaded nanoparticles compared to MTX alone when tested against U-343 MGa human neuronal glioblastoma cells.     

Kinetics of glycine oxidation by N-bromophthalimide in the presence of sodium dodecyl sulfate

The kinetics of oxidation of glycine by N-bromophthalimide (NBP) were studied in the presence of an anionic surfactant, sodium dodecyl sulfate, in acidic medium at 308 K. The rate of reaction was found to have first-order dependence on [NBP] and fractional-order dependence on [glycine] and [H⁺]. The addition of reduced product of the oxidant had no significant effect on the rate of reaction. Increasing [Hg(OAc)₂] and [Br⁻] increased the rate of reaction, whereas a change in ionic strength (μ) of the medium had no effect on oxidation velocity. The rate of reaction decreased with a decrease in dielectric constant of the medium. HCN was identified as the main oxidation product of the reactions. The various activation parameters have been computed. A suitable mechanism consistent with the experimental findings has been proposed. The index of cooperativity and the micelle binding constant have been calculated.     

An Unsteady Subsurface Drainage Equation Incorporating Variability of Soil Drainage Properties

Almost all unsteady subsurface drainage equations developed so far use constant value of drainable porosity and hydraulic conductivity which may not be representative of entire drainage flow region. A drainage equation was, thus, developed incorporating depth-wise variability of drainable porosity (f) and hydraulic conductivity (K) of saline soils of Haryana state in India. The drain spacing with measured hydraulic heads at different periods of drainage were estimated by the developed equation and compared with the corresponding drain spacing estimated by commonly used unsteady drainage equations. The study revealed that the developed equation estimated the drain spacing that was nearest to the actual drain spacing of the existing subsurface drainage system, when a generally used design criterion of 30 cm water table drop in 2 days is considered. For a criterion of desired water table drop in 3 days and beyond, Glover equation was found to be the most superior. Hence, both the developed equation and Glover equation can be readily used with the associated design criteria for designing unsteady subsurface drainage systems in saline soils of the state of Haryana, India.