Delivering precision antimicrobial therapy through closed-loop control systems.

Sub-optimal exposure to antimicrobial therapy is associated with poor patient outcomes and the development of antimicrobial resistance. Mechanisms for optimizing the concentration of a drug within the individual patient are under development. However, several barriers remain in realizing true individualization of therapy. These include problems with plasma drug sampling, availability of appropriate assays, and current mechanisms for dose adjustment. Biosensor technology offers a means of providing real-time monitoring of antimicrobials in a minimally invasive fashion. We report the potential for using microneedle biosensor technology as part of closed-loop control systems for the optimization of antimicrobial therapy in individual patients.

Zirconium arene triple-decker sandwich complexes: synthesis, electronic structure and bonding.

Reduction of a permethylpentalene zirconium(iv) chloride complex [η8-Pn*Zr(µ-Cl)3/2]2(µ-Cl)2Li·THFx with KC8 in benzene results in activation of the aromatic solvent to yield an "inverted sandwich" complex, [η8-Pn*Zr]2(µ-η6:η6-C6H6) (1). The reactions in toluene, cumene, o-xylene and m-xylene also yield analogous solvent activated triple-decker sandwich complexes, which have been structurally characterised by single-crystal X-ray diffraction. Edge energies in the Zr K-edge XANES spectra are not distinguishable between 1 and formally Zr(ii) and Zr(iv) reference compounds, suggesting a broad edge structure. DFT calculations best describe the bonding in 1 as highly covalent with frontier molecular orbitals showing almost equal contributions from benzene and the Zr-permethylpentalene fragments.

Developing a tissue perfusion sensor.

The development of a electrochemical tissue perfusion sensor is presented. The sensor is a platinum/platinum ring-disc microelectrode that relies on the principle of collector-generator to monitor mass transport within its vicinity. Tissue perfusion is a mass transport mechanism that describes the movement of respiratory gases, nutrients and metabolites in tissue. The sensor's capability of detecting perfusion at the cellular level in a continuous fashion is unique. This sensor will provide insight into the way nutrients and metabolites are transported in tissue especially in cases were perfusion is low such as in wounds or ischemic tissue. We present experimental work for the development and testing of the sensors in vitro. Experimental flow recordings in free steam solutions as well as the flow through tissue-like media are shown. Tests on post operative human tissue are also presented. The sensor's feature such as the continuous recoding capacities, spatial resolution and the measurement range from ml/min to microl/min are highlighted.

Situational awareness ability and cognitive skills training in a complex real-world task.

Successful performance in complex dynamic environments depends on domain-dependent factors, such as situational awareness (SA). Underlying SA in a domain are domain-independent cognitive abilities in perception, memory, attention and executive control. Individuals with lower underlying ability perform relatively poorly in complex dynamic real-world tasks. The first experiment examined whether cognitive skills training could overcome limitations in underlying SA ability that impact on complex dynamic task performance. Participants were taught a mix of cognitive management strategies (e.g. divided and focused attention and visual search) in a simulated air traffic control task. A second experiment investigated the link between underlying SA ability, TRACON and SAGAT, a widely used measure of domain-specific SA. In a third experiment, the focus was on encouraging participants to plan ahead and consider the interrelations of elements (aircraft) in the environment. Whilst both training methods ameliorated the negative impact that lower SA ability had on complex dynamic task performance, the results of the third study indicated that this may have been achieved through improved planning behaviour. Finally, participants with higher underlying SA ability performed well irrespective of training condition.

Case-control study of risk factors for fatal and non-fatal injury in crashes of rotary-wing aircraft.

INTRODUCTION: There have been few studies of the risk factors for fatal injury in air crashes of rotary-wing aircraft, and none of risk factors for all serious injury (fatal and non-fatal) in these aircraft. The aim of the study was to identify the potentially modifiable risk factors for injury in civil rotary-wing aircraft crashes in New Zealand. METHOD: We analyzed records from all reported civil rotary-wing aircraft crashes in New Zealand between 1988 and 1994. Air crash data from the official databases were merged with nationwide injury records and information obtained from Coroner's files. Crashes where the pilot-in-command was fatally injured were compared with crashes where the pilot-in-command was not fatally injured on 50 variables, covering pilot, aircraft, environmental, and operational characteristics. A second analysis compared crashes where the pilot-in-command was seriously injured (either fatally or non-fatally) with crashes where the pilot-in-command was not hospitalized with an injury. A series of multivariate logistic regression analyses were conducted to estimate the odds associated with each of the factors identified by the univariate analyses. RESULTS: The most significant risk factors for all serious injury were: (a) not obtaining a weather briefing, (b) off-airport location of the crash site, (c) flights carried out for air transport purposes, and (d) non-solo flights. Other risk factors, significant for fatal injury only, included post-crash fire and the nature of the crash terrain. Factors within the control of the pilot, environmental, and flight characteristics are the key determinants of the injury outcome of civil rotary-wing aircraft crashes.

Changes in the properties of the modulatory cerebral giant cells contribute to aging in the feeding system of Lymnaea.

This study examined whether electrophysiological changes in the endogenous properties and connectivity of the modulatory serotonergic cerebral giant cells (CGCs) contributed to the age-related changes in feeding behavior of the pond snail, Lymnaea. With increasing age there was a decrease in spontaneous CGC firing rates and decreased excitability of the CGCs to both chemosensory stimulation (0.05M sucrose applied to the lips) and direct intracellular current injection. These changes could be accounted for by a decrease in the input resistance of the neuron and an increase in the amplitude and the duration of the after-hyperpolarization. Decreases were also seen in the % of CGC pairs that were electrically coupled causing asynchronous firing. Together these changes would tend to reduce the ability of the CGCs to gate and control the frequency of the feeding behavior. Part of the ability of the CGCs to gate and frequency control the feeding network is to provide a background level of excitation to the feeding motor neurons. Recordings from B1 and B4 motor neurons showed an age-related hyperpolarization of the resting membrane potential consistent with a deficit in CGC function. Increases were seen in the strength of the evoked CGC-->B1 connection, however, this increase failed to compensate for the deficits in CGC excitability. In summary, age-related changes in the properties of the CGCs were consistent with them contributing to the age-related changes in feeding behavior seen in Lymnaea.

Effects of age on feeding behavior and chemosensory processing in the pond snail, Lymnaea stagnalis.

This study used behavioral and electrophysiological techniques to examine age-related changes in the feeding behavior and chemosensory processing in the pond snail, Lymnaea stagnalis. Increasing age was associated with a 50% decrease in long-term food consumption. Analysis of short-term sucrose-evoked feeding bouts showed an age-related increase in the number of animals that failed to respond to the stimulus. Of the animals that did respond increasing age was associated with a decrease in the number of sucrose-evoked bites and a increase in the duration of the swallow phase. These changes were observed with both 0.01 and 0.05M sucrose stimuli but were not seen when 0.1M sucrose was used as the stimulus. Electrophysiological analysis of the chemosensory pathway in semi-intact lip-CNS preparations failed to demonstrate a significant change in the neuronal information entering the cerebral ganglia from the lips via the median lip nerve, but did demonstrate an age-related deficit in the neuronal output from the cerebral ganglia. This deficit was also dependent on the sucrose concentration and mirrored the concentration-dependent changes in feeding behavior. In summary, aging appeared to affect central but not peripheral processing of chemosensory information and suggests that this deficit contributes to the age-related changes in feeding behavior.

Direct and indirect cost of general aviation crashes.

BACKGROUND: There have been few well-designed studies which estimate the costs inflicted on society from injuries, fatalities, and property damage caused by aviation crashes. Furthermore, indirect cost estimates from the human capital (HC) approach tend to be substantially smaller than those obtained from the willingness-to-pay (WTP) approach. OBJECTIVES: To estimate the direct and indirect costs of general aviation crashes in New Zealand, and to contrast the HC and WTP approaches used to estimate indirect costs. METHODS: The incidence, morbidity, and mortality from aviation crashes between 1988 and 1997 were estimated from national health and aviation records. Direct costs included medical treatment, damage to aircraft and property, and the cost of crash investigation. For the HC approach, we valued losses to society as the value of lost production from both employed work and household activity. For the WTP approach, we used the Land Transport Safety Authority's estimated values of society's willingness to pay to avoid a fatality or injury. RESULTS: The annual average direct cost of aviation crashes was $9.1 m (range: $8.0 m to $11.4 m). The annual average indirect cost using the HC approach was $13.6 m ($5.6 m to $32.2 m). Using the WTP approach the annual average indirect costs was $49.3 m ($20.6 m to $106.5 m). Indirect costs from premature deaths were the key cost drivers. A sensitivity analysis showed that these values were relatively robust to changes in parameters. CONCLUSION: The annual average cost of general aviation crashes in New Zealand was between $22.6 m and $58.4 m. Indirect costs using the WTP approach were 3.5 times greater than those estimated using the HC approach.

Real time observation of the hydrothermal crystallization of barium titanate using in situ neutron powder diffraction.

The hydrothermal crystallization of barium titanate, BaTiO3, has been studied in situ by time-resolved powder neutron diffraction methods using the recently developed Oxford/ISIS hydrothermal cell. This technique has allowed the formation of the ferroelectric ceramic to be followed in a noninvasive manner in real time and under genuine reaction conditions. In a first set of experiments, Ba(OD)2-8D2O was reacted with two different titanium sources, either crystalline TiO2 (anatase) or amorphous TiO2-H2O in D2O, at 100-140 degrees C and the reaction studied using the POLARIS time-of-flight neutron powder diffractometer, at the ISIS Facility. In a second series of experiments, the reaction between barium chloride and crystalline TiO2 (anatase) in NaOD/D2O was studied at temperatures between 100 and 200 degrees C and at different deuterioxide concentrations using the constant-wavelength D20 neutron powder diffractometer at the Institut Laue Langevin. Quantitative growth and decay curves were determined from analysis of the integrated intensities of Bragg reflections of starting materials and product phases. In both sets of experiments the rapid dissolution of the barium source was observed, followed by dissolution of the titanium source before the onset of crystallization of barium titanate. Using a nucleation-growth model we are able to simulate the growth curve of barium titanate at three temperatures. Our results indicate the predominance of a homogeneous dissolution-precipitation mechanism for the hydrothermal formation of barium titanate, rather than other possible mechanisms that have been discussed in the literature. Analysis of the line widths of the Bragg reflections in the neutron diffraction data indicates that the particle size of the BaTiO3 product phase prepared from the amorphous TiO2-H2O is smaller than that prepared from crystalline TiO2 (anatase).

Variable coordination modes of hydrotris(3-isopropyl-4-bromopyrazolyl)borate (Tp') in Fe(II), Mn(II), Cr(II), and Cr(III) Complexes: formation of MTp'Cl (M = Fe and Mn), structural isomerism in CrTp'(2), and the observation of Tp' (-) as an uncoordinated anion.

The syntheses of the 4-coordinate Tp'MCl complexes (where M = Fe (1), Mn (2); and Tp' = hydrotris(3-isopropyl-4-bromopyrazolyl)borate) are described. The single-crystal X-ray structures show that the metal centers have distorted tetrahedral coordination. Analogous reaction of CrCl(2)(MeCN)(2) with TlTp' gave Cr(kappa(3)-Tp')(kappa(2)-Tp') (3) as the initial product. The 5-coordinate structure was assigned by single-crystal X-ray crystallography, and it was found that the kappa(3) ligand had isomerized to hydro(3-isopropyl-4-bromopyrazolyl)(2)(5-isopropyl-4-bromopyrazolyl)borate). 3 is labile in solution: in pentane it slowly converts to the 6-coordinate isomer Cr(kappa(3)-Tp')(2) (4), whose structure was determined by X-ray crystallography. In 4 both ligands are isomerized. Both 3 and 4 display Jahn-Teller distorted structures expected for high-spin d(4) configurations. Variable temperature magnetic susceptibility measurements confirm that 1, 2, and 3 all have high-spin electronic configurations in the range 5-300 K. In benzene solution 3 decomposes; one product [Cr(kappa(3)-Tp')(2)](+)[Tp'](-) (5), was identified by X-ray crystallography. 5 contains a pseudooctahedral Cr(III) cation with both ligands in the isomerized form and an uncoordinated Tp' ligand as counterion. Mechanistic studies reveal that this reaction is light rather than heat induced. IR spectroscopy is utilized to confirm the ligand hapticity in all complexes from the value of nu(B)(-)(H), and comparison is made with similar compounds.

Arterial blood sampling practices in intensive care units in England and Wales.

A postal survey of arterial blood sampling practices in 280 intensive care units throughout England and Wales found that very few measures are taken to reduce diagnostic blood loss in adult intensive care patients from arterial sampling. The average volume of blood withdrawn to clear the arterial line before sampling is 3.2 ml; subsequently returned to the patient in only 18.4% of intensive care units. Specific measures to reduce the blood sample size by the routine use of paediatric sample tubes in adult patients occurs in only 9.3% of intensive care units. In paediatric units, the average volume withdrawn was 1.9 ml and this was routinely returned in 67% of units. Some aspects of arterial blood sampling practices identified in this survey may contribute to iatrogenic anaemia in intensive care patients.

The use of botulinum toxin in otorhinolaryngology.

In recent years, the use of botulinum toxin has become more popular for the treatment of a wide variety of diseases in the head and neck. It offers the possibility of non-invasive treatment of conditions whose aetiology lies in neuromuscular dyskinesis.

High resolution imaging of the distribution and permeability of methyl viologen dication in bovine articular cartilage using scanning electrochemical microscopy.

Scanning electrochemical microscopy (SECM) has been used in the induced transfer (SECMIT) mode to image the permeability of a probe cation, methyl viologen (MV(2+)), in samples of articular cartilage. An ultramicroelectrode (UME), scanned just above the surface of a sample, is used to amperometrically detect the probe solute. The resulting depletion of MV(2+) in solution induces the transfer of this cation from the sample into the solution for detection at the UME. The current provides quantitative information on local permeability, provided that the sample-UME distance is known. It is shown that the necessary topographical information can be obtained using the amperometric response for the oxidation of Ru(CN)(4-)(6), which does not permeate into the cartilage matrix. This procedure was validated by marking samples in situ, after electrochemical imaging, with subsequent examination by ex situ interferometry and optical microscopy. Wide variations in the permeability of MV(2+) have been detected by SECMIT. These observations represent the first demonstration of the inhomogeneous permeability of a cation in cartilage on a micrometre scale. The permeability maps show similar features to the proteoglycan distribution, identified by toluidine blue staining, and it is likely that proteoglycans are the main determinant of MV(2+) permeability in articular cartilage.

Intercalation and controlled release of pharmaceutically active compounds from a layered double hydroxide.

A series of pharmaceutically active compounds including diclofenac, gemfibrozil, ibuprofen, naproxen, 2-propylpentanoic acid, 4-biphenylacetic acid and tolfenamic acid can be reversibly intercalated into a layered double hydroxide, initial studies suggest that these materials may have application as the basis of a novel tuneable drug delivery system.

(eta 5-Cyclopentadienyl)(kappa 3-hydrotris(pyrazolyl)borate)cobalt(II)--the first high-spin cobalt organometallic complex.

(eta 5-Cyclopentadienyl)(kappa 3-hydrotris(pyrazolyl)borate)-cobalt(II) has been synthesised; magnetic and crystallographic data indicate this to be the first example of a high-spin cobalt organometallic complex whilst its pentamethylcyclopentadienyl analogue is found to have a low-spin electronic configuration.

Synthesis and characterisation of (C4N2H12)(UO2)2(PO3H)2(PO2(OH)H)2: a three dimensionally connected actinide framework.

The material (C4N2H12)(UO2)2(PO3H)2(PO2(OH)H)2 (MUPH-1) has been prepared hydrothermally; it is a three dimensional structure consisting of four intersecting elliptical shaped one-dimensional channels, the largest channel has dimensions of 13.1 x 7.2 A.

Direct in situ observation of increasing structural dimensionality during the hydrothermal formation of open-framework zinc phosphates.

The first time-resolved in situ X-ray diffraction studies of the hydrothermal crystallisation of open-framework zinc phosphates reveal a pathway of sequential crystallisation involving formation of a metastable low dimensional chain phase before the growth of three-dimensional zeolitic architectures.

Oxygenation and perfusion of rabbit tibialis anterior muscle subjected to different patterns of electrical stimulation.

Dual amperometric microelectrodes were used to measure local pO2 and perfusion at multiple sites in the fast-twitch tibialis anterior muscles of anaesthetized rabbits. Six muscles were stimulated continuously at 10, 5, or 2.5 Hz. For all three frequencies, perfusion declined to about 50% of resting levels and recovered after stimulation. These changes corresponded to a rise followed by a fall in extracellular pO2. The highest levels of pO2 were reached during stimulation at 10 Hz. Eight muscles were stimulated tetanically at 100 Hz for 200 ms with duty cycles that were varied between 1.3 and 20.0%. Perfusion rose to 8.7 +/- 2.0 ml s(-1) 100 g(-1) at a duty cycle of 5% and declined with further increases in duty cycle. pO2 was depressed for duty cycles less than 10% but rose above resting levels at higher duty cycles. It is suggested that the paradoxical combination of elevated pO2 and depressed perfusion is attributable to stimulation conditions that exceed the oxygen transport capacity of a fast muscle.