2,717 research outputs found
LEGALISING DRUGS OF ABUSE: THE LE CHATELIER THOUGHT EXPERIMENT
BackgroundThere is currently much debate on legalising some psychoactive materials such as Cannabis. This could stabilise policing costs, reduce crime, generate tax revenue and control sale by registration of outlets. Such outcomes are valuable, but legalisation may have unintended consequences that are deleterious to society or have no effects on crime or user’s health. Here, I propose that behaviour following changes to control of possession and supply may have outcomes that could be predicted by the equilibrium law proposed by Henry Le Chatelier. This law describes a system moving in such a way as to remove the constraints placed upon it. AimsThe purpose of this opinion paper is to follow Le Chatelier’s Principle (LCP) as a thought experiment to predict the outcomes (products) of drug consumption (reactants) when factors influencing this consumption (conditions) are changed. If this equilibrium law can be applied to human behaviour, it may have value to predict the outcomes of these conditions and assess whether they are positive or injurious. It must be noted that the views expressed here are solely those of the author.MethodsPubmed, ScienceDirect, SpringerLink and Google were used for literature searches and “drugs” will be used for drugs of abuse and distinct from medicinal drugs, apart from methadone and heroin (diamorphine). ResultsApplying LCP predicts that drug use may not necessarily decrease, but availability, poor health and criminal activity may increase use. The businesses behind drug treatment and illegal distribution have too much financial incentive to halt operations. ConclusionOrganisations recommending legislative changes to drug control should conduct thought experiments to horizon scan for unintended consequences, that may be costly and deleterious to society. Governments often focus too heavily on the evidence base as the sole driver for change. However, common sense drawn from opinion from these experiments may lead to wisdom. Keywords; War on drugs, legalisation, Le Chatelier’s Principle, psychoactive substance
Does hospital competition save lives? Evidence from the English NHS patient choice reforms
This paper examines whether or not hospital competition in a market with fixed reimbursement prices can prompt improvements in clinical quality. In January 2006, the British Government introduced a major extension of their market-based reforms to the English National Health Service. From January 2006 onwards, every patient in England could choose their hospital for secondary care and hospitals had to compete with each other to attract patients to secure their revenue. One of the central aims of this policy was to create financial incentives for providers to improve their clinical performance. This paper assesses whether this aim has been achieved and competition led to improvements in quality. For our estimation, we exploit the fact that choice-based reforms will create sharper financial incentives for hospitals in markets where choice is geographically feasible and that prior to 2006, in the absence of patient choice, hospitals had no direct financial incentive to improve performance in order to attract more patients. We use a modified difference-in-difference estimator to analyze whether quality improved more quickly in more competitive markets after the government introduced its new wave of market-based reforms. Using AMI mortality as a quality indicator, we find that mortality fell more quickly (i.e. quality improved) for patients living in more competitive markets after the introduction of hospital competition in January 2006. Our results suggest that hospital competition in markets with fixed prices can lead to improvements in clinical quality
Economic studies showing positive competition effects on hospital performance fully controlled for the factors cited by recent critics
Criticisms have been made of recent influential studies that show improving performance in hospitals operating in more competitive environments compared with hospitals that have a local monopoly on care. Zack Cooper, Steve Gibbons, Simon Jones and Alistair McGuire set the record straight. The claims by Pollock et al are based either on distortions of the original research, or on an apparent lack of understanding of modern economic analysi
A Proof of Uniqueness of the Taub-bolt Instanton
We show that the Riemannian Schwarzschild and the ``Taub-bolt'' instanton
solutions are the only spaces (M,g) such that
1) M is a 4-dimensional, simply connected manifold with a Riemannian,
Ricci-flat C^2-metric g which admits (at least) a 1-parameter group of
isometries H without isolated fixed points on M.
2) The quotient (M L)/H (where L is the set of fixed points of H) is an
asymptotically flat manifold, and the length of the Killing field corresponding
to H tends to a constant at infinity.Comment: 20 pages. LaTeX. Substantially extended and correcte
Studies on natural products: resistance modifying agents, antibacterials and structure elucidation
This thesis describes research starting in 1999 on three areas of natural product
science, namely bacterial resistance modifying agents, antibacterials and structure
elucidation of natural products.
Plants produce an array of structurally-complex and diverse chemical scaffolds and
whilst there is an expanding volume of published literature on structure elucidation,
there remains a need to understand why these compounds are produced and how
they function in terms of biological activity. That can only be properly realised by a
full and determined attempt at structure elucidation. This is an important concept as
molecular structure describes and precedes function. The chirality and functional
group chemistry of natural products defines the way in which a compound
specifically binds to a receptor, protein or drug target.
My independent research career started with studies on the ability of plant extracts
and phytochemicals to modulate the activity of antibiotics that are substrates for
bacterial multidrug efflux. These investigations are described in the first section,
“Natural Product Resistance Modifying Agents”. Studies were, in the first instance,
simple assays to look at potentiation and synergy of extracts and pure
phytochemicals to potentiate the activity of antibiotics against resistant bacteria. This
research evolved to study efflux inhibition, where we learnt much from the
collaborations with Professors Piddock (Birmingham), Kaatz (Wayne State) and
Bhakta (Birkbeck). Latterly, we were inspired by the highly imaginative and creative
work of Dr Paul Stapleton (UCL), to study the plasmid transfer inhibitory effects of
natural products; the rationale being that plasmids carry antibiotic-resistance genes
and virulence factors. Inhibition of transfer could result in a reduction in the spread of
antibiotic resistance and a reduction in pathogenicity.
The second section of this thesis describes antibacterial natural products that were
evaluated against clinically-relevant species of bacteria, in the main Gram-positive
organisms such as Staphylococcus aureus and its methicillin- (MRSA) and
multidrug-resistant variants and Mycobacterium tuberculosis, the causative agent of
tuberculosis, which still continues to affect millions of people globally and for which
antibiotic resistance is considerable.
The papers described in this section detail the extraction of the plant and the
bioassay-guided isolation of the active compounds, which were then subjected to
structure elucidation, using in the majority of cases, Nuclear Magnetic Resonance
(NMR) spectroscopy, High-Resolution Mass Spectrometry, and Infrared and
Ultraviolet-Visible Spectroscopy. Natural products from the acylphloroglucinol,
terpenoid, polyacetylene, alkaloid and sulphide classes are well represented in these
publications with some of these antibacterial natural products displaying minimum
inhibitory concentrations (MIC) values of less than 1 mg/L against MRSA and
Mycobacterium tuberculosis strains. These activity levels approach those of existing
clinically used antibiotics and this highlights the value of plant natural products as a
resource for antibacterial templates.
Mechanistic studies have also been conducted on selected compounds, for example
the natural products from Hypericum acmosepalum were found to inhibit ATP-
dependent MurE ligase, a key enzyme involved in bacterial cell wall biosynthesis.
Other examples included the main component of cinnamon (Cinnamomum
zeylanicum), an ancient medicinal material cited in the Bible in Exodus, which has
been used in antiquity as an anti-infective substance. The main compound from this
medicinal material is trans-cinnamaldehyde, a simple phenylpropanoid which has
been shown to inhibit Acetyl-CoA Carboxylase, a pivotal enzyme that catalyses the
first committed step in fatty acid biosynthesis in all animals, plants and bacteria. In
collaboration with the marine natural product chemist Professor Vassilios Roussis,
we have also been able to characterise the antibacterial activities of marine plants,
particularly compounds of the diterpene class that display promising levels of
antibacterial activity against MRSA and S. aureus strains. Work on the antibacterial
properties of Cannabis sativa showed that some of the main cannabinoids display
excellent potency towards drug-resistant variants of S. aureus and support the
ancient medicinal usage of Cannabis as an anti-infective and wound healing
preparation. The acylphloroglucinol class of plant natural products are also
noteworthy, particularly from Hypericum and Mediterranean medicinal plant species
such as Myrtle (Myrtus communis), again with MIC values reaching 1 mg/L against
pathogenic bacteria. We synthesised some of these acylphloroglucinols and made
analogues and not surprisingly, were unable to improve the activity as nature really
is the best chemist of all.
The final section describes early and continuing research into the isolation and
structure elucidation of natural products from plants and microbes. The rationale for
this research is manifold: training for isolation to understand the medicinal use of a
plant or microbe, chemotaxonomic investigations, the ecological relevance of
phytochemicals in plants that are halophytic and xerophytic and in some cases just
plain academic curiosity. These studies use classical phytochemical techniques to
isolate and determine the structures of the species of investigation and where
possible, absolute stereochemistry is undertaken. It should be noted however that
isolation can be exceptionally challenging and frustrating. This can be due to the
paucity of biomass, low concentrations of compounds, complexity of the resulting
natural product mixtures and finally a lack of chemical stability of the products. All of
these issues need to be faced before structure determination can even be
attempted. A word of caution is therefore needed to the young natural product
chemist embarking on their first isolation project. However, words of encouragement
are also needed: the isolation of new, chemically complex and exquisitely biologically
active molecules is a beautiful endeavour and exceptionally rewarding on many
levels.This thesis describes research starting in 1999 on three areas of natural product
science, namely bacterial resistance modifying agents, antibacterials and structure
elucidation of natural products.
Plants produce an array of structurally-complex and diverse chemical scaffolds and
whilst there is an expanding volume of published literature on structure elucidation,
there remains a need to understand why these compounds are produced and how
they function in terms of biological activity. That can only be properly realised by a
full and determined attempt at structure elucidation. This is an important concept as
molecular structure describes and precedes function. The chirality and functional
group chemistry of natural products defines the way in which a compound
specifically binds to a receptor, protein or drug target.
My independent research career started with studies on the ability of plant extracts
and phytochemicals to modulate the activity of antibiotics that are substrates for
bacterial multidrug efflux. These investigations are described in the first section,
“Natural Product Resistance Modifying Agents”. Studies were, in the first instance,
simple assays to look at potentiation and synergy of extracts and pure
phytochemicals to potentiate the activity of antibiotics against resistant bacteria. This
research evolved to study efflux inhibition, where we learnt much from the
collaborations with Professors Piddock (Birmingham), Kaatz (Wayne State) and
Bhakta (Birkbeck). Latterly, we were inspired by the highly imaginative and creative
work of Dr Paul Stapleton (UCL), to study the plasmid transfer inhibitory effects of
natural products; the rationale being that plasmids carry antibiotic-resistance genes
and virulence factors. Inhibition of transfer could result in a reduction in the spread of
antibiotic resistance and a reduction in pathogenicity.
The second section of this thesis describes antibacterial natural products that were
evaluated against clinically-relevant species of bacteria, in the main Gram-positive
organisms such as Staphylococcus aureus and its methicillin- (MRSA) and
multidrug-resistant variants and Mycobacterium tuberculosis, the causative agent of
tuberculosis, which still continues to affect millions of people globally and for which
antibiotic resistance is considerable.
The papers described in this section detail the extraction of the plant and the
bioassay-guided isolation of the active compounds, which were then subjected to
structure elucidation, using in the majority of cases, Nuclear Magnetic Resonance
(NMR) spectroscopy, High-Resolution Mass Spectrometry, and Infrared and
Ultraviolet-Visible Spectroscopy. Natural products from the acylphloroglucinol,
terpenoid, polyacetylene, alkaloid and sulphide classes are well represented in these
publications with some of these antibacterial natural products displaying minimum
inhibitory concentrations (MIC) values of less than 1 mg/L against MRSA and
Mycobacterium tuberculosis strains. These activity levels approach those of existing
clinically used antibiotics and this highlights the value of plant natural products as a
resource for antibacterial templates.
Mechanistic studies have also been conducted on selected compounds, for example
the natural products from Hypericum acmosepalum were found to inhibit ATP-
dependent MurE ligase, a key enzyme involved in bacterial cell wall biosynthesis.
Other examples included the main component of cinnamon (Cinnamomum
zeylanicum), an ancient medicinal material cited in the Bible in Exodus, which has
been used in antiquity as an anti-infective substance. The main compound from this
medicinal material is trans-cinnamaldehyde, a simple phenylpropanoid which has
been shown to inhibit Acetyl-CoA Carboxylase, a pivotal enzyme that catalyses the
first committed step in fatty acid biosynthesis in all animals, plants and bacteria. In
collaboration with the marine natural product chemist Professor Vassilios Roussis,
we have also been able to characterise the antibacterial activities of marine plants,
particularly compounds of the diterpene class that display promising levels of
antibacterial activity against MRSA and S. aureus strains. Work on the antibacterial
properties of Cannabis sativa showed that some of the main cannabinoids display
excellent potency towards drug-resistant variants of S. aureus and support the
ancient medicinal usage of Cannabis as an anti-infective and wound healing
preparation. The acylphloroglucinol class of plant natural products are also
noteworthy, particularly from Hypericum and Mediterranean medicinal plant species
such as Myrtle (Myrtus communis), again with MIC values reaching 1 mg/L against
pathogenic bacteria. We synthesised some of these acylphloroglucinols and made
analogues and not surprisingly, were unable to improve the activity as nature really
is the best chemist of all.
The final section describes early and continuing research into the isolation and
structure elucidation of natural products from plants and microbes. The rationale for
this research is manifold: training for isolation to understand the medicinal use of a
plant or microbe, chemotaxonomic investigations, the ecological relevance of
phytochemicals in plants that are halophytic and xerophytic and in some cases just
plain academic curiosity. These studies use classical phytochemical techniques to
isolate and determine the structures of the species of investigation and where
possible, absolute stereochemistry is undertaken. It should be noted however that
isolation can be exceptionally challenging and frustrating. This can be due to the
paucity of biomass, low concentrations of compounds, complexity of the resulting
natural product mixtures and finally a lack of chemical stability of the products. All of
these issues need to be faced before structure determination can even be
attempted. A word of caution is therefore needed to the young natural product
chemist embarking on their first isolation project. However, words of encouragement
are also needed: the isolation of new, chemically complex and exquisitely biologically
active molecules is a beautiful endeavour and exceptionally rewarding on many
levels
Does Hospital Competition Improve Efficiency? An Analysis of the Recent Market-Based Reforms to the English NHS
This paper uses a difference-in-difference estimator to test whether the introduction of patient choice and hospital competition in the English NHS in January 2006 has prompted hospitals to become more efficient. Efficiency was measured using hospitals' average length of stay (LOS) for patients undergoing elective hip replacement. LOS was broken down into its two key components: the time from a patient's admission until their surgery and the time from their surgery until their discharge. Our results illustrate that hospitals exposed to competition after a wave of market-based reforms took steps to shorten the time patients were in the hospital prior to their surgery, which resulted in a decrease in overall LOS. We find that hospitals shortened patients' LOS without compromising patient outcomes or by operating on healthier, wealthier or younger patients. Our results suggest that hospital competition within markets with fixed prices can increase hospital efficiency.Hospital Competition, Market Structure, Prospective Payment, Incentive Structure
Does Competition Improve Public Hospitals' Efficiency? Evidence from a Quasi-Experiment in the English National Health Service
This paper uses a difference-in-difference style estimation strategy to test separately the impact of competition from public sector and private sector hospitals on the efficiency of public hospitals. Our identification strategy takes advantage of the phased introduction of a recent set of substantive reforms introduced in the English NHS from 2006 onwards. These reforms forced public sector health care providers to compete with other public hospitals and eventually to face competition from existing private sector providers for care delivered to publicly funded patients. In this study, we measure efficiency using hospitals' average length of stay (LOS) for patients undergoing elective surgery. For a more nuanced assessment of efficiency, we break LOS down into its two key components: the time from patients' admission to the hospital until their surgery and the time from their surgery until their discharge. Here, pre-surgery LOS serves as a proxy for hospitals' lean efficiency. Our results suggest that competition between public providers prompted public hospitals to improve their productivity by decreasing their pre-surgery, overall and post-surgery length of stay. In contrast, competition from private hospitals did not spur public providers to improve their performance and instead left incumbent public providers with a more costly case mix of patients and led to increases in post-surgical LOS.Hospital competition, market structure, prospective payment, incentivestructure
A new AF gravitational instanton
It has long been conjectured that the Euclidean Schwarzschild and Euclidean
Kerr instantons are the only non-trivial asymptotically flat (AF) gravitational
instantons. In this letter, we show that this conjecture is false by explicitly
constructing a new two-parameter AF gravitational instanton with a U(1)xU(1)
isometry group, using the inverse-scattering method. It has Euler number \chi=3
and Hirzebruch signature \tau=1, and its global topology is CP^2 with a circle
S^1 removed appropriately. Various other properties of this gravitational
instanton are also discussed.Comment: 10 pages, 2 figures, LaTe
Antibacterial constituents of Neohyptis paniculata
A new -pyrone, 6R-[5R,6S-diacetyloxy-1Z,3E-heptadienyl]-5,6-dihydro-2H-pyran-2one (1), along with six known compounds including an α-pyrone, flavones and terpenes was isolated from the aerial parts of Neohyptis paniculata. The structure of 1 was established unambiguously by MS and a series of 1D and 2D-NMR spectroscopic analyses. The antibacterial activity of the compounds (1-7) was investigated against five strains of multi-drug resistant (MDR) and methicillin-resistant Staphylococcus aureus and minimum inhibitory concentrations (MICs) of these compounds were found to be in the range of 64-256 g/mL
Toric anti-self-dual 4-manifolds via complex geometry
Using the twistor correspondence, this article gives a one-to-one
correspondence between germs of toric anti-self-dual conformal classes and
certain holomorphic data determined by the induced action on twistor space.
Recovering the metric from the holomorphic data leads to the classical problem
of prescribing the Cech coboundary of 0-cochains on an elliptic curve covered
by two annuli. The classes admitting Kahler representatives are described; each
such class contains a circle of Kahler metrics. This gives new local examples
of scalar-flat Kahler surfaces and generalises work of Joyce who considered the
case where the distribution orthogonal to the torus action is integrable.Comment: 25 pages, 2 figures, v2 corrected some misprints, v3 corrected more
misprints, published version (minus one typo
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