Newton's Scaffolding: the instrumental roles of his optical hypotheses

This is the author accepted manuscript. The final version is available from Routledge via the link in this recordEarly modern experimental philosophers often appear to commit to, and utilise, corpuscular and mechanical hypotheses. This is somewhat mysterious: such hypotheses frequently appear to be simply assumed, odd for a research program which emphasises the careful experimental accumulation of facts. Isaac Newton was one such experimental philosopher, and his optical work is considered a clear example of the experimental method. Focusing on his optical investigations, I identify three roles for hypotheses. Firstly, Newton introduces a hypothesis to explicate his abstract theory. The purpose here is primarily to improve understanding or uptake of the theory. Secondly, he uses a hypothesis as a platform from which to generate some crucial experiments to decide between competing accounts. The purpose here is to suggest experiments in order to bring a dispute to empirical resolution. Thirdly, he uses a hypothesis to suggest an underlying physical cause, which he then operationalises and represents abstractly in his formal theory. The second and third roles are related in that they are both cases of scaffolding: hypotheses provide a temporary platform from which further experimental work and/or theorising can be carried out. In short, the entities and processes included in Newton’s optical hypothesis are not simply assumed hypothetical posits. Rather, they play instrumental roles in Newton’s experimental philosophy

Principles in Newton's Natural Philosophy

This is the author accepted manuscript. The final version is available from Routledge via the link in this recordNewton’s great work of ‘rational mechanics’ is supposedly about principles. They’re even in the title: Philosophiae naturalis principia mathematica. However, Newton’s use of the term ‘principle’ appears to be unsystematic and opaque. Was ‘principle’, then, just a ‘buzz-word’ for Newton? Or is there something important underlying his use of the term? I support the latter. While the term ‘principle’ did not play a central role in Newton’s methodology (indeed, I will suggest that hypotheses and theories are the important concepts for Newton), once we disambiguate his usage, something systematic arises. What it takes to be a principle, by Newton’s lights, is to play a certain kind of role

How Many Colours?

This is the author accepted manuscript. the final version is available from Springer via the DOI in this recordIsaac Newton’s first optical paper (published in the Philosophical Transactions in February 1672) was controversial: Newton argued for a new theory of light and colour when no one else thought the old one was inadequate, and moreover he claimed certain truth for his new theory! A debate followed, in which Newton defended his claims against the objections of optical heavy weights such as Robert Hooke and Christiaan Huygens. One major sticking point between Newton and his critics concerned the number and division of colours. Newton argued that there is an indefinite number of ‘primary’ colours, but Hooke and Huygens objected to this inflated ontology. Each critic argued, for different reasons, that there were only two original colours. I examine Newton’s responses to these objections. I argue that they are revelatory of Newton’s unique methodology: a mathematico-experimental approach that eschewed ‘hypotheses’ in favour of ‘theories’. I also show that we should read Newton’s claim that there are an ‘indefinite’ number of colours in epistemic terms. Nowadays, Newton’s first optical paper represents a landmark in the science of optics. Its exploitation of the correspondence between refraction and spectral colour, provided a new approach to the study of light. And its views on the properties and nature of light, set a new agenda for the field

Absorbate-Induced Piezochromism in a Porous Molecular Crystal

Atmospherically stable porous frameworks and materials are interesting for heterogeneous solid–gas applications. One motivation is the direct and selective uptake of pollutant/hazardous gases, where the material produces a measurable response in the presence of the analyte. In this report, we present a combined experimental and theoretical rationalization for the piezochromic response of a robust and porous molecular crystal built from an extensively fluorinated trispyrazole. The electronic response of the material is directly determined by analyte uptake, which provokes a subtle lattice contraction and an observable bathochromic shift in the optical absorption onset. Selectivity for fluorinated absorbates is demonstrated, and toluene is also found to crystallize within the pore. Furthermore, we demonstrate the application of electronic structure calculations to predict a physicochemical response, providing the foundations for the design of electronically tunable porous solids with the chemical properties required for development of novel gas-uptake media

Critical Current Longitudinal and Transverse Strain Sensitivities of High JC Nb3Sn Conductors

Characterizing critical current IC of Nb3Sn strands as function of a strain is very important for large high field superconducting magnet applications such as the superconducting outsert coil of the series-connected hybrid at the NHMFL and the ITER magnets. Apparatuses for measuring IC versus longitudinal strain and transverse stress have been developed and used at the NHMFL. We have characterized the IC strain sensitivities of a few candidate strands for the series-connected-hybrid. In addition, IC irreversibility strains are measured for the recently developed ITER high JC strands. The different strain sensitivities for different strands are discussed.Comment: 4 pages, 6 figure

Evaluating the design and reporting of pragmatic trials in osteoarthritis research

Objectives. Among the challenges in health research is translating interventions from controlled experimental settings to clinical and community settings where chronic disease is managed daily. Pragmatic trials offer a method for testing interventions in real-world settings but are seldom used in OA research. The aim of this study was to evaluate the literature on pragmatic trials in OA research up to August 2016 in order to identify strengths and weaknesses in the design and reporting of these trials. Methods. We used established guidelines to assess the degree to which 61 OA studies complied with pragmatic trial design and reporting. We assessed design according to the pragmatic–explanatory continuum indicator summary and reporting according to the pragmatic trials extension of the CONsolidated Standards of Reporting Trials guidelines. Results. None of the pragmatic trials met all 11 criteria evaluated and most of the trials met between 5 and 8 of the criteria. Criteria most often unmet pertained to practitioner expertise (by requiring specialists) and criteria most often met pertained to primary outcome analysis (by using intention-to-treat analysis). Conclusion. Our results suggest a lack of highly pragmatic trials in OA research. We identify this as a point of opportunity to improve research translation, since optimizing the design and reporting of pragmatic trials can facilitate implementation of evidence-based interventions for OA care

A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease.

BackgroundLate-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA.ResultsReveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (-0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks.ConclusionsAdditional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease.Trial registrationISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011

Unified force law for granular impact cratering

Experiments on the low-speed impact of solid objects into granular media have been used both to mimic geophysical events and to probe the unusual nature of the granular state of matter. Observations have been interpreted in terms of conflicting stopping forces: product of powers of projectile depth and speed; linear in speed; constant, proportional to the initial impact speed; and proportional to depth. This is reminiscent of high-speed ballistics impact in the 19th and 20th centuries, when a plethora of empirical rules were proposed. To make progress, we developed a means to measure projectile dynamics with 100 nm and 20 us precision. For a 1-inch diameter steel sphere dropped from a wide range of heights into non-cohesive glass beads, we reproduce prior observations either as reasonable approximations or as limiting behaviours. Furthermore, we demonstrate that the interaction between projectile and medium can be decomposed into the sum of velocity-dependent inertial drag plus depth-dependent friction. Thus we achieve a unified description of low-speed impact phenomena and show that the complex response of granular materials to impact, while fundamentally different from that of liquids and solids, can be simply understood

Low-pathogenicity Mycoplasma spp. alter human monocyte and macrophage function and are highly prevalent among patients with ventilator-acquired pneumonia.

BACKGROUND: Ventilator-acquired pneumonia (VAP) remains a significant problem within intensive care units (ICUs). There is a growing recognition of the impact of critical-illness-induced immunoparesis on the pathogenesis of VAP, but the mechanisms remain incompletely understood. We hypothesised that, because of limitations in their routine detection, Mycoplasmataceae are more prevalent among patients with VAP than previously recognised, and that these organisms potentially impair immune cell function. METHODS AND SETTING: 159 patients were recruited from 12 UK ICUs. All patients had suspected VAP and underwent bronchoscopy and bronchoalveolar lavage (BAL). VAP was defined as growth of organisms at >10(4) colony forming units per ml of BAL fluid on conventional culture. Samples were tested for Mycoplasmataceae (Mycoplasma and Ureaplasma spp.) by PCR, and positive samples underwent sequencing for speciation. 36 healthy donors underwent BAL for comparison. Additionally, healthy donor monocytes and macrophages were exposed to Mycoplasma salivarium and their ability to respond to lipopolysaccharide and undertake phagocytosis was assessed. RESULTS: Mycoplasmataceae were found in 49% (95% CI 33% to 65%) of patients with VAP, compared with 14% (95% CI 9% to 25%) of patients without VAP. Patients with sterile BAL fluid had a similar prevalence to healthy donor BAL fluid (10% (95% CI 4% to 20%) vs 8% (95% CI 2% to 22%)). The most common organism identified was M. salivarium. Blood monocytes from healthy volunteers incubated with M. salivarium displayed an impaired TNF-α response to lipopolysaccharide (p=0.0003), as did monocyte-derived macrophages (MDMs) (p=0.024). MDM exposed to M. salivarium demonstrated impaired phagocytosis (p=0.005). DISCUSSION AND CONCLUSIONS: This study demonstrates a high prevalence of Mycoplasmataceae among patients with VAP, with a markedly lower prevalence among patients with suspected VAP in whom subsequent cultures refuted the diagnosis. The most common organism found, M. salivarium, is able to alter the functions of key immune cells. Mycoplasmataceae may contribute to VAP pathogenesis.This study was funded by the Hospital Infection Society, Wellcome Trust/Department of Health Health Innovation Challenge Fund (HICF)(0510/078) and Sir Jules Thorn Charitable Trust (03/JTA).This is the final version of the article. It first appeared from BMJ Publishing Group via http://dx.doi.org/10.1136/thoraxjnl-2015-20805

Second trimester inflammatory and metabolic markers in women delivering preterm with and without preeclampsia.

ObjectiveInflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia.Study designA sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios.ResultsHigher 5-α-pregnan-3β,20α-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia.ConclusionsAmong women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth