‘Great ease and simplicity of action’: Dr Nelson’s Inhaler and the origins of modern inhalation therapy

This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Unveiled at the conclusion of a meeting of the Royal Medical and Chirurgical Society in 1861,[1] ‘Dr Nelson’s Improved Inhaler’ was one of the most important milestones in the genesis of reliable treatment of respiratory ailments in the modern era. Affordable and suitable for self-medication, the Dr Nelson’s Inhaler offered simple and reliable relief for patients with respiratory and pulmonary ailments. Conspicuous for its modesty and simplicity, it was one of the most widely produced, reproduced, and used inhalation devices in the final third of the nineteenth century. By reconstructing the ‘biography’ of the Nelson Inhaler, this article will attempt to sketch a network of medical and commercial interests and expertise in London which aligned in the 1860s to help establish inhalation as a popular, inexpensive, and trusted form of medical therapy for pulmonary ailments. This article will look at what connects physicians, apothecaries, and patients in the era: the medicines and technologies that were prescribed, made, bought, and which caused wellness, side-effects, and even death. This approach allows us to develop a narrative of respiratory illness as it was experienced by practitioners and patients alike.Peer reviewe

Findings of the 2019 National Food Hub Survey

This report was nearing completion in March 2020 and therefore does not address the impacts of the COVID-19 crisis in detail. Please see the epilogue, on page 44, for the authors' reflections on the role food hubs have played in supporting and enhancing the resiliency of local and regional food systems throughout the pandemic. We encourage readers to consider this context as they read the report, which offers a unique snapshot of pre-COVID food hub operations.

Environmental drivers of Culicoides phenology: how important is species-specific variation when determining disease policy?

Since 2006, arboviruses transmitted by Culicoides biting midges (Diptera: Ceratopogonidae) have caused significant disruption to ruminant production in northern Europe. The most serious incursions involved strains of bluetongue virus (BTV), which cause bluetongue (BT) disease. To control spread of BTV, movement of susceptible livestock is restricted with economic and animal welfare impacts. The timing of BTV transmission in temperate regions is partly determined by the seasonal presence of adult Culicoides females. Legislative measures therefore allow for the relaxation of ruminant movement restrictions during winter, when nightly light-suction trap catches of Culicoides fall below a threshold (the ‘seasonally vector free period’: SVFP). We analysed five years of time-series surveillance data from light-suction trapping in the UK to investigate whether significant inter-specific and yearly variation in adult phenology exists, and whether the SVFP is predictable from environmental factors. Because female vector Culicoides are not easily morphologically separated, inter-specific comparisons in phenology were drawn from male populations. We demonstrate significant inter-specific differences in Culicoides adult phenology with the season of Culicoides scoticus approximately eight weeks shorter than Culicoides obsoletus. Species-specific differences in the length of the SVFP were related to host density and local variation in landscape habitat. When the Avaritia Culicoides females were modelled as a group (as utilised in the SFVP), we were unable to detect links between environmental drivers and phenological metrics. We conclude that the current treatment of Avaritia Culicoides as a single group inhibits understanding of environmentally-driven spatial variation in species phenology and hinders the development of models for predicting the SVFP from environmental factors. Culicoides surveillance methods should be adapted to focus on concentrated assessments of species-specific abundance during the start and end of seasonal activity in temperate regions to facilitate refinement of ruminant movement restrictions thereby reducing the impact of Culicoides-borne arboviruses

Multiorder coherent Raman scattering of a quantum probe field

We study the multiorder coherent Raman scattering of a quantum probe field in a far-off-resonance medium with a prepared coherence. Under the conditions of negligible dispersion and limited bandwidth, we derive a Bessel-function solution for the sideband field operators. We analytically and numerically calculate various quantum statistical characteristics of the sideband fields. We show that the multiorder coherent Raman process can replicate the statistical properties of a single-mode quantum probe field into a broad comb of generated Raman sidebands. We also study the mixing and modulation of photon statistical properties in the case of two-mode input. We show that the prepared Raman coherence and the medium length can be used as control parameters to switch a sideband field from one type of photon statistics to another type, or from a non-squeezed state to a squeezed state and vice versa.Comment: 12 pages, 7 figures, to be published in Phys. Rev.

Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial

The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research arms and 1 control arm. The trial has a pilot stage assessing safety and feasibility, 3 intermediate “activity” stages (I-III) where the outcome measure is failure-free survival (FFS) and one final “efficacy” stage (IV) with overall survival as primary outcome measure. At the end of each stage, each research arm is formally compared pairwise to the control arm. Accrual of further patients is discontinued early for any research arm either not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to arms showing activity with acceptable safety. The stopping guideline compares the treatment effect against a pre-defined cut-off value using the hazard ratio when the hazards are proportional and restricted-mean survival time otherwise. This interim hurdle becomes increasingly stringent stage-by-stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is independent of any of the original research arms stopping accrual early subject to adequate recruitment to support the overall trial aims

Contradiction of Quantum Mechanics with Local Hidden Variables for Continuous Variable Quadrature Phase Amplitude Measurements

We demonstrate a contradiction of quantum mechanics with local hidden variable theories for continuous variable quadrature phase amplitude (``position'' and ``momentum'') measurements, by way of a violation of a Bell inequality. For any quantum state, this contradiction is lost for situations where the quadrature phase amplitude results are always macroscopically distinct. We show that for optical realisations of this experiment, where one uses homodyne detection techniques to perform the quadrature phase amplitude measurement, one has an amplification prior to detection, so that macroscopic fields are incident on photodiode detectors. The high efficiencies of such detectors may open a way for a loophole-free test of local hidden variable theories.Comment: 9 pages,4 figures, previously publishe

Dispersing the Mists: An Experimental History of Medicine Study into the Quality of Volatile Inhalations

This document is the Accepted Manuscript version. The final publication is available from Mary Ann Liebert, Inc. Publishers at https://doi.org/10.1089/jamp.2016.1357.Background: Dr. Nelson's Improved Inhaler was first marketed with an advertisement in The Lancet in 1865. Revolutionary at the time for its ease of use and patient-friendliness, the inhaler is still in use for self-treatment by many all over the world. On the occasion of its 150th anniversary, this study reports an experimental historical medicine approach to identify evidence for the quality of vapor inhalers. Methods: Through accessing reviews of the device's use by the contemporary medical establishment, it was established that Dr. Nelson's Inhaler enjoyed a reputation of quality and efficacy among reputable physicians generating empirical evidence of clinical performance. There was a general absence of product performance tests during this period. Therefore, modern inhalation performance testing was applied to test the aerosol delivery performance for Friars' Balsam, and its key chemical constituent, benzoic acid (BA). Results: A respirable dose of 59.9 ± 9.0 μg of BA was aerosolized in a 10 minutes period from a dose of 3.3 mL Friars' Balsam (equivalent to 35.1 ± 0.2 mg of BA) in 375 mL of steaming water using the glass twin stage impinger at a flow rate of 60 L·min−1. The respirable dose from a standardized aqueous BA inhalation formulation increased from 115.9 ± 10.6 to 200.2 ± 19.9 μg by increasing the simulated inhalation period from 5 to 10 minutes. When tested with a simulated inhalation maneuver (500 mL tidal volume, 13 minutes−1 respiration rate, 1:2 inspiratory:expiratory ratio) a respirable dose of 112.8 ± 40.3 μg was produced. Conclusions: This work has highlighted the potential for aerosol drug delivery using steam inhalers that are popular with patients. Physicians should therefore be aware of the potential for lung dosing with irritants when patients self-medicate using the Nelson Inhaler with vaporizing formulations such as Friars' Balsam.Peer reviewedFinal Accepted Versio

Violations of Bell Inequalities for Measurements with Macroscopic Uncertainties: What does it Mean to Violate Macroscopic Local Realism?

We suggest to test the premise of ``macroscopic local realism'' which is sufficient to derive Bell inequalities when measurements of photon number are only accurate to an uncertainty of order $n$ photons, where $n$ is macroscopic. Macroscopic local realism is only sufficient to imply, in the context of the original Einstein-Podolsky-Rosen argument, fuzzy ``elements of reality'' which have a macroscopic indeterminacy. We show therefore how the violation of local realism in the presence of macroscopic uncertainties implies the failure of ``macroscopic local realism''. Quantum states violating this macroscopic local realism are presented.Comment: 28 pages, 5 figures- new version is unchanged but tightened-20 pages, 5 figure

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

Searching for gravitational waves from known pulsars

We present upper limits on the amplitude of gravitational waves from 28 isolated pulsars using data from the second science run of LIGO. The results are also expressed as a constraint on the pulsars' equatorial ellipticities. We discuss a new way of presenting such ellipticity upper limits that takes account of the uncertainties of the pulsar moment of inertia. We also extend our previous method to search for known pulsars in binary systems, of which there are about 80 in the sensitive frequency range of LIGO and GEO 600.Comment: Accepted by CQG for the proceeding of GWDAW9, 7 pages, 2 figure