English engineer John Smeaton's experimental method(s): Optimisation, hypothesis testing and exploratory experimentation.

In this paper I provide a detailed account of eighteenth-century engineer John Smeaton's experimental methods, with the aim of bringing our understanding of his work into line with recent research in the history and philosophy of science. Starting from his use of the technique of parameter variation, I identify three distinct methodological aims in the research he carried out on waterwheels, windmills and hydraulic mortars. These aims are: optimisation, hypothesis testing and maxim generation. The main claim of this paper is that Smeaton did more than merely improve engineering methods by systematising earlier artisanal approaches, which is the classic view of Smeaton's method developed by historians of technology in the 1990s. I argue instead that his approach bridged the divide between science and technology, by integrating both hypothesis testing and exploratory experimentation. This is borne out, in particular, by the way that Smeaton emphasised the exploratory side of the work he published in the Philosophical Transactions, in contrast to his account of the construction of the Eddystone lighthouse, which was aimed at a broader, non-specialist public. I contribute to recent research on exploratory experimentation by showing - in line with other work on this topic - that exploratory experimentation is not incompatible with hypothesis testing. This new perspective on Smeaton's method will hopefully lead to further research and new insights into the relation between science and technology at the start of the Industrial Revolution.

Evaluating John Theophilus Desaguliers' Newtonianism: the case of waterwheel knowledge in A course of experimental philosophy.

John Theophilus Desaguliers (1683-1744) was a French-born English Huguenot who made his name as a public lecturer in London and a demonstrator at the Royal Society, writing a very popular introduction to Isaac Newton's natural philosophy, the two-volume A course of experimental philosophy (1734-1744). This paper looks at the influence of three French natural philosophers, Edme Mariotte (1620-1684), Antoine Parent (1666-1716) and Bernard Forest de Bélidor (1698-1761), on the account of waterwheel functioning in the second volume of that work. The aim of the paper is to show that, although Desaguliers demonstrated a commitment to Newton's work, his own natural philosophical objectives also led him to borrow ideas from natural philosophers outside Newton's direct sphere of influence. To do this I shall give an account of what Desaguliers appropriated from Newton's Principia, how it fitted in with his own project and how he also made use of other natural philosophers' theories in his discussion of fluid mechanics. This will hopefully result in a more nuanced conception of Desaguliers' 'Newtonianism' that takes into account the diverse sources and influences in his work.

John Smeaton and the vis viva controversy: Measuring waterwheel efficiency and the influence of industry on practical mechanics in Britain 1759-1808.

In this paper, I will examine John Smeaton's contribution to the vis viva controversy in Britain, focusing on how the hybridization of science, technology, and industry helped to establish vis viva, or mechanic power, as a measure of motive force. Smeaton, embodying the 'hybrid expert' who combined theoretical knowledge and practical knowhow, demonstrated that the notion of vis viva possessed a greater explanatory power than momentum, because it could be used to explain the difference in efficiency between overshot and undershot waterwheels. Smeaton's conclusions were correct since waterwheel efficiency was already measured in terms that were proportional to vis viva, not momentum, as a result of the industrial applications of waterwheel technology, which favored measuring efficiency by the product of mass and vertical displacement. Toward the end of the eighteenth century, the loss of motive force in the inelastic collision driving the undershot wheel began to be seen as equivalent to the expenditure of labor in the manufacture of commodities, further underlining how strictly scientific conclusions about motive force could have their origin in industrial practices.

Exploration of the impact of stereochemistry on the identification of the novel translocator protein PET imaging agent [(18)F]GE-180.

INTRODUCTION: The tricyclic indole compound, [(18)F]GE-180 has been previously identified as a promising positron emission tomography (PET) imaging agent of the translocator protein (TSPO) with the potential to aid in the diagnosis, prognosis and therapy monitoring of degenerative neuroinflammatory conditions such as multiple sclerosis. [(18)F]GE-180 was first identified and evaluated as a racemate, but subsequent evaluations of the resolved enantiomers have shown that the S-enantiomer has a higher affinity for TSPO and an improved in vivo biodistribution performance, in terms of higher uptake in specific brain regions and good clearance (as described previously). Here we describe the additional biological evaluations carried out to confirm the improved performance of the S-enantiomer and including experiments which have demonstrated the stability of the chiral centre to chemical and biological factors. MATERIALS AND METHODS: GE-180 and the corresponding radiolabelling precursor were separated into single enantiomers using semi-preparative chiral supercritical fluid chromatography (SFC). A detailed comparison of the individual enantiomers and the racemate was carried out in a number of biological studies. TSPO binding affinity was assessed using a radioligand binding assay. Incubation with rat hepatic S9 fractions was used to monitor metabolic stability. In vivo biodistribution studies up to 60 min post injection (PI) in naïve rats were carried out to monitor uptake and clearance. Achiral and chiral in vivo metabolite detection methods were developed to assess the presence of metabolite/s in plasma and brain samples, with the chiral method also determining potential racemisation at the chiral centre. RESULTS: Evaluation of the chiral stability of the two enantiomers to metabolism by rat S9 fractions, showed no racemisation of enantiomers. There were notable differences in the biodistribution between the racemate and the R- and S-enantiomers. All compounds had similar initial brain uptake between 0.99 and 1.01% injected dose (id) at 2 min PI, with S-[(18)F]GE-180 showing significantly greater retention than the R-enantiomer at 10 and 30 min PI (P<0.05). S-[(18)F]GE-180 uptake to the TSPO-expressing olfactory bulbs was 0.45% id (SD ± 0.17) at 30 min PI in comparison to RS-[(18)F]GE-180 or R-[(18)F]GE-180 levels of 0.41% id ± 0.09 and 0.23% id ± 0.02 respectively, at the same timepoint (P > 0.05). The signal-to-noise ratio (ratio olfactory bulb to striata binding) were similar for both RS-[(18)F]GE-180 and S-[(18)F]GE-180 (3.2 and 3.4 respectively). Initial uptake to the lungs (an organ with high TSPO expression) was more than 3-fold greater with S-[(18)F]GE-180 than R-[(18)F]GE-180, and significantly higher at 10 and 30 min PI (P < 0.05). Furthermore lung uptake of S-[(18)F]GE-180 at 2 and 10 min PI was also significant when compared to the racemate (P < 0.05). The majority of the radioactivity in the rat brain following administration of RS-[(18)F]GE-180 or S-[(18)F]GE-180 was due to the presence of the parent compound (91% ± 1.5 and 94% ± 2.0 of total radioactivity at 60 min PI respectively). In contrast at 60 min PI for the plasma samples, the parent compounds accounted for only 28% ± 1.2 and 21% ± 4.6 of total radioactivity for RS-[(18)F]GE-180 and S-[(18)F]GE-180 respectively. Chiral assessment confirmed that the S-enantiomer was chirally stable in vivo, with no stereochemical conversion in brain and plasma samples up to 60 min PI. CONCLUSIONS: Developing racemic radiotracers, as for racemic therapeutics, is a considerable challenge due to differences of the enantiomers in pharmacokinetics, efficacy and potential toxicity. We have shown that the enantiomers of the promising racemic PET ligand [(18)F]GE-180 do not share identical performance, with S-[(18)F]GE-180 demonstrating higher TSPO affinity, higher brain uptake and better retention to the high TSPO-expressing lungs. Furthermore, S-[(18)F]GE-180 has also been shown to be enantiomerically stable in vivo, with no observed conversation of the eutomer to the distomer. As a single enantiomer, S-[(18)F]GE-180 retains the beneficial characteristics of the racemate and is a promising imaging agent for imaging neuroinflammation in vivo.

Model-based assessment of dosing strategies in children for monoclonal antibodies exhibiting target-mediated drug disposition.

Body weight/body surface area-based and/or tiered fixed dosing strategies are widely utilized for monoclonal antibodies with linear clearance to scale adult clinical doses to children. However, there is limited knowledge on whether or not body weight-based dosing strategies also yield comparable dose-concentration-response relationships in adults and children for monoclonal antibodies that exhibit target-mediated drug disposition. Our findings indicate that it is important to interpret pharmacokinetics information in a pharmacokinetics/pharmacodynamics context as similar systemic drug exposure in adults and children may not be reflective of the corresponding target occupancy. They further indicate that BW-based dosing is superior to fixed dosing for the same target concentration, whereas the opposite holds true for the same target amount in adults and children. Michaelis-Menten approximations yielded similar profiles compared to the full target-mediated drug disposition model for all simulation scenarios and may be used to guide the selection of appropriate dosing regimens in children.

Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies.

Amoxicillin is recommended for anthrax prevention in pregnancy. The objective of this study was to evaluate the pharmacokinetics of amoxicillin during pregnancy and postpartum (PP). Sixteen women received amoxicillin during gestation (18-22 weeks (T2) and 30-34 weeks (T3)) as well as 3 months postpartum (PP) to evaluate single-dose pharmacokinetics. Amoxicillin compartmental pharmacokinetic parameters were used to simulate amoxicillin concentration-time profiles following different dosage strategies. Amoxicillin CL(renal) (T2: 24.8+/-6.7 l/h, P<0.001; T3: 24.0+/-3.9 l/h, P<0.001; and PP: 15.3+/-2.6 l/h) and renal CL(secretion) (T2: 280+/-105 ml/min, P<0.002; T3: 259+/-54 ml/min, P<0.001; and PP: 167+/-47 ml/min) were higher during pregnancy than postpartum. Simulations suggest that amoxicillin concentrations adequate to prevent anthrax may be difficult to achieve during pregnancy and postpartum. Increases in amoxicillin CL(renal) and renal CL(secretion) reflect increases in filtration and secretory transport or diminished reabsorption in the kidneys. Amoxicillin may not be an appropriate antibiotic for post-anthrax exposure prophylaxis.

The occupational therapist's role in the management of diabetes.

This paper will describe the Diabetic Day Centre program at the Lions Gate Hospital, and the occupational therapist's unique role in that program. Diabetic processes or characteristics which influence assessment and intervention by rehabilitation personnel will be discussed, as well as lifestyle management techniques which promote the patient's physical and psychological well-being. Adaptive equipment available for managing medications will be reviewed.