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Background: Previous work has suggested that the long-term regular use of inhaled beta2-agonist bronchodilators might lead to a deterioration in asthma control. The aim of TRUST (The Regular Use of Salbutamol Trial) was to study the effects of regular use of inhaled salbutamol, the most widely prescribed bronchodilator in the UK, on the control of asthma.Methods: A randomised, double-blind, placebo-controlled trial was undertaken in 983 patients with asthma being treated at least twice a week with short-acting beta2-agonist, alone or in combination with inhaled steroids (2 mg or less) daily. Patients were aged 18 years and over and were recruited from 115 general practices in the UK. 90% (881) of the patients used inhaled corticosteroid therapy, and all patients continued to use their usual inhaled beta2-agonist for symptomatic relief. Patients were randomised to receive 400 microg salbutamol or matched placebo via a Diskhaler four times per day for 12 months. The primary outcome measure was rate of exacerbations of asthma, with criteria based on data from diary cards completed daily by each patient, treatment with additional corticosteroids, or both.Findings: There were no differences in the annual rate, timing, or duration of exacerbations between the two groups. The mean morning peak expiratory flow was similar for the two groups. The mean evening peak expiratory flow (p<0.001) and the diurnal variation (p<0.001) were greater, and the use of rescue bronchodilator was less (p<0.001), in the group receiving regular salbutamol.Interpretation: There was no evidence that regular use of inhaled salbutamol 400 microg four times daily for a year increased the exacerbation rate of asthma in the population studied. [ABSTRACT FROM AUTHOR]

Spinal injury and back pain are a common problem facing patients seeking medical care including athletes, which can lead to significant disability, medical costs, and impaired performance for these patients. Rehabilitation including core muscle stabilization, Kinesio taping, and flexibility have been shown to help with treatment and prevention. Critical factors such as equipment, technique, and rule changes can also be an important part of spine injury prevention., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

An instrument and software algorithm are described for the purpose of characterization of large single crystals at the Alignment Facility of the ISIS spallation neutron source. A method for both characterizing the quality of the sample and aligning it in a particular scattering plane is introduced. A software package written for this instrument is presented, and its utility is demonstrated by way of an example of the structural characterization of large single crystals of Pb(Mg 1/3 Nb 2/3 )O 3 . Extensions and modifications of characterization instruments for future improved beamlines are suggested. It is hoped that this software will be used by the neutron community for pre-characterizing large single crystals for spectroscopy experiments and that in the future such a facility will be included as part of the spectroscopy suite at other spallation neutron sources., (© Zihao Liu et al. 2021.)

It is well established that in the low-temperature limit, the two-dimensional quantum Heisenberg antiferromagnet on a square lattice (2DQHAFSL) exhibits an anomaly in its spectrum at short-wavelengths on the zone-boundary. In the vicinity of thepoint the pole in the one-magnon response exhibits a downward dispersion, is heavily damped and attenuated, giving way to an isotropic continuum of excitations extending to high energies. The origin of the anomaly and the presence of the continuum are of current theoretical interest, with suggestions focused around the idea that the latter evidences the existence of spinons in a two-dimensional system. Here we present the results of neutron inelastic scattering experiments and Quantum Monte Carlo calculations on the metallo-organic compound Cu(DCOO)D 2 O (CFTD), an excellent physical realisation of the 2DQHAFSL, designed to investigate how the anomaly atevolves up to finite temperatures. Our data reveal that on warming the anomaly survives the loss of long-range, three-dimensional order, and that it is thus a robust feature of the two-dimensional system. With further increase of temperature the zone-boundary response gradually softens and broadens, washing out theanomaly. This is confirmed by a comparison of our data with the results of finite-temperature Quantum Monte Carlo simulations where the two are found to be in good accord. In the vicinity of the antiferromagnetic zone centre, there was no significant softening of the magnetic excitations over the range of temperatures investigated., (© 2020 IOP Publishing Ltd.)

Background: c-Fos is a cellular proto-oncogene which dimerizes with c-Jun proto-oncogene to form AP-1 transcription factor, which upregulates transcription of genes involved in proliferation and cancer formation. Four cardiac hormones, that is, long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide (KP) and atrial natriuretic peptide (ANP) with anticancer effects in vivo are potent inhibitors of the Ras-MEK 1/2-ERK 1/2 kinase cascade and signal transducer and activator of transcription-3 (STAT-3) that activate c-Fos and c-Jun. These four cardiac hormones were investigated for their effects on proto-oncogenes c-Fos and c-Jun within the nucleus of cancer cells., Materials and Methods: Four cardiac hormones were evaluated for their ability to decrease proto-oncogenes c-Fos and c-Jun, measured by ELISA in extracted nuclei of three human cancer cell lines., Results: Vessel dilator, LANP, KP and ANP over a concentration range of 100 pM-10 μM, maximally decreased c-Fos by 61%, 60%, 61% and 59% in human hepatocellular cancer cells, by 82%, 74%, 78% and 74% in small-cell lung cancer cells, and by 82%, 73%, 78% and 74% in human renal adenocarcinoma cells. c-Jun was maximally reduced by vessel dilator, LANP, KP and ANP by 43%, 31%, 61% and 35% in hepatocellular cancer cells, by 65%, 49%, 59% and 40% in small-cell lung cancer cells, and by 47%, 43%, 57% and 49% in renal cancer cells., Conclusion: Four cardiac hormones are potent inhibitors of c-Fos and c-Jun proto-oncogenes within the nucleus of cancer cells., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The space-and time-dependent response of many-body quantum systems is the most informative aspect of their emergent behavior. The dynamical structure factor, experimentally measurable using neutron scattering, can map this response in wave vector and energy with great detail, allowing theories to be quantitatively tested to high accuracy. Here, we present a comparison between neutron scattering measurements on the one-dimensional spin-1/2 Heisenberg antiferromagnet KCuF3, and recent state-of-the-art theoretical methods based on integrability and density matrix renormalization group simulations. The unprecedented quantitative agreement shows that precise descriptions of strongly correlated states at all distance, time, and temperature scales are now possible, and highlights the need to apply these novel techniques to other problems in low-dimensional magnetism.

The magnetic symmetry and structure of the non-Fermi liquid heavy fermion compound CeNiGa2 has been determined by neutron powder diffraction. The orthorhombic CeNiGa2 compound orders antiferromagnetically below 4.4(2) K at ambient pressure with a magnetic moment magnitude of μCe = 0.80(4) μB for moments aligned along the c-axis. The magnetic (Shubnikov) space group is C2cm'm'm. The nature of the magnetic order of CeNiGa2 is further elucidated by neutron diffraction at elevated pressures up to 4.5 kbar, allowing for the confirmation of a critical pressure PC of about 4.2(2) kbar above which the magnetic moment ordering is suppressed.

Signal transducers and activators of transcription (STATs) are the final "switches" that activate gene expression patterns that lead to human malignancy. Extracellular signal-regulated kinases (ERK 1/2) activate STAT 3; four cardiovascular hormones inhibit ERK 1/2 kinases, leading to the hypothesis that they may also inhibit STATs. These four cardiac hormones, i.e., vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP), eliminate human cancers growing in mice. These four cardiac hormones' effects on STATs 1 and 3 were examined in human small-cell lung cancer and human pancreatic adenocarcinoma cells. Vessel dilator, LANP, kaliuretic peptide, and ANP maximally decreased STAT 3 by 88, 54, 55, and 65 %, respectively, at their 1 μM concentrations in human small-cell lung cancer cells and STAT 3 by 66, 57, 70, and 77 % in human pancreatic adenocarcinoma cells, respectively. The cardiac hormones (except LANP) also significantly decreased STAT 3 measured by Western blots. These cardiac hormones did not decrease STAT 1 in either human small-cell lung cancer or pancreatic adenocarcinoma cells. We conclude that these four cardiac hormones are significant inhibitors of STAT 3, but not STAT 1, in human small-cell lung cancer and pancreatic adenocarcinoma cells, which suggests a specificity for these hormones' anticancer mechanism(s) of action enzymology in human cancer cells.

The methane reforming reaction with carbon dioxide as the oxidant over alumina-supported nickel and gold-doped nickel catalysts is studied using a variety of techniques such as reaction testing, vibrational spectroscopy (inelastic neutron scattering (INS), Raman scattering and infrared absorption), temperature-programmed oxidation (TPO), transmission electron microscopy and X-ray powder diffraction. The quantities of retained carbon and hydrogen are determined by TPO and INS, respectively. Minimal hydrogen retention indicates these catalysts to be very efficient at cycling hydrogen. The relative partitioning of hydrogen within the reaction media is used to formulate a qualitative description of the reaction kinetics. The presence of the gold modifier does not appear to provide any improvement in catalyst performance under the specified reaction conditions.

Rocky Mountain spotted fever is caused by Rickettsia rickettsii infection. R. rickettsii can be transmitted to mammals, including humans, through the bite of an infected hard-bodied tick of the family Ixodidae. Since the R. rickettsii genome contains only one cold-shock-like protein and given the essential nature of cold-shock proteins in other bacteria, the structure of the cold-shock-like protein from R. rickettsii was investigated. With the exception of a short α-helix found between β-strands 3 and 4, the solution structure of the R. rickettsii cold-shock-like protein has the typical Greek-key five-stranded β-barrel structure found in most cold-shock domains. Additionally, the R. rickettsii cold-shock-like protein, with a ΔG of unfolding of 18.4 kJ mol(-1), has a similar stability when compared with other bacterial cold-shock proteins.

Background: Vascular endothelial growth factor (VEGF) helps control tumour growth via causing new capillaries growth in tumours. Four cardiac hormones [i.e. vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide (KP) and atrial natriuretic peptide (ANP)] that eliminate up to up to 86% of human small-cell lung cancers growing in mice were investigated for their effects on VEGF and the VEGFR2/KDR/Flk-1 receptor. The VEGFR2 receptor is the main receptor mediating VEGF's cancer-enhancing effects., Materials and Methods: Four cardiac hormones were evaluated for their ability to decrease VEGF/VEGFR2 measured by ELISAs in three human cancer cell lines., Results: Vessel dilator, LANP, KP and ANP, over a concentration range of 100 pM to 10 μM, maximally decreased the VEGFR2 receptor in human pancreatic adenocarcinoma cells by 48%, 49%, 74% and 83%. Vessel dilator, LANP, KP and ANP decreased the VEGFR2 receptor by 77%, 89%, 88% and 67% in human small-cell lung cancer cells and by 48%, 92%, 64% and 71% in human prostate cancer cells. These results were confirmed with the cardiac hormones also decreasing the VEGFR2 receptor measured by Western blots. VEGF itself in pancreatic carcinoma cells was decreased by 42%, 58%, 36% and 40% by vessel dilator, LANP, KP and ANP. VEGF levels were decreased 25%, 23%, 17% and 23% in small-cell lung cancer cells and decreased by 24%, 20%, 23% and 24% in prostate cancer cells by vessel dilator, LANP, KP and ANP., Conclusion: Four cardiac hormones are the first dual inhibitors of VEGF and the VEGFR2/KDR/Flk-1 receptor., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Four cardiac peptide hormones, namely vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP) have anticancer effects., Materials and Methods: The effects of these four cardiac hormones on human c-Jun-N-terminal kinase 2 (JNK2) were examined in human small cell lung cancer and human prostate cancer cells., Results: Vessel dilator, LANP, kaliuretic peptide and ANP maximally reduced expression of JNK2 by 89%, 56%, 45%, and 28%, respectively (each at p<0.0001) in human small cell lung cancer cells. In human prostate adenocarcinoma cells, JNK2 was maximally decreased 76%, 56%, 45%, (each at p<0.0001), and 28% (p<0.01) secondary to vessel dilator, LANP, kaliuretic peptide and ANP, respectively., Conclusion: These results indicate that four cardiac hormones are significant inhibitors (by up to 89%) of JNK2 in human small cell lung cancer cells and up to 76% in human prostate adenocarcinoma cells as part of their anticancer mechanism(s) of action.

We report an inelastic neutron scattering study of the spin fluctuations in the nearly ferromagnetic element palladium. Dispersive over-damped collective magnetic excitations or "paramagnons" are observed up to 128 meV. We analyze our results in terms of a Moriya-Lonzarich-type spin-fluctuation model and estimate the contribution of the spin fluctuations to the low-temperature heat capacity. In spite of the paramagnon excitations being relatively strong, their relaxation rates are large. This leads to a small contribution to the low-temperature electronic specific heat.

An alumina-supported nickel catalyst has been used to effect the 'dry' reforming of methane, using CO(2) as the oxidant. After 6 hours on-stream, reaction was stopped and the sample analysed by inelastic neutron scattering (INS). The INS spectrum reveals the presence of hydrocarbonaceous species as well as hydroxyl species present at the catalyst surface. Through the use of appropriate reference compounds, calibration procedures have been developed to determine the concentration of the retained hydrocarbon and hydroxyl moieties. Ancillary temperature programmed oxidation experiments establish the total carbon content. This approach not only enables the extent of overall carbon laydown to be determined but it also identifies the degree to which hydrogen is associated with carbon and oxygen atoms. The methodology described is generic and should be applicable to a wide number of heterogeneously catalysed systems.

We use inelastic neutron scattering to measure the magnetic excitations in underdoped La2-xSrxCuO4 (x=0.085, T&#95;{c}=22 K) for large energy (5

Recovery of hydrocarbons commonly is associated with coproduction of water. This water may be put to beneficial use or may be reinjected into subsurface aquifers. In either case, it would be helpful to establish a fingerprint for that coproduced water so that it may be tracked following discharge on the surface or reintroduction to geologic reservoirs. This study explores the potential of using delta(13)C of dissolved inorganic carbon (DIC) of coalbed natural gas (CBNG)-coproduced water as a fingerprint of its origin and to trace its fate once it is disposed on the surface. Our initial results for water samples coproduced with CBNG from the Powder River Basin show that this water has strongly positive delta(13)C(DIC) (12 per thousand to 22 per thousand) that is readily distinguished from the negative delta(13)C of most surface and ground water (-8 per thousand to -11 per thousand). Furthermore, the DIC concentrations in coproduced water samples are also high (more than 100 mg C/L) compared to the 20 to 50 mg C/L in ambient surface and ground water of the region. The distinctively high delta(13)C and DIC concentrations allow us to identify surface and ground water that have incorporated CBNG-coproduced water. Accordingly, we suggest that the delta(13)C(DIC) and DIC concentrations of water can be used for long-term monitoring of infiltration of CBNG-coproduced water into ground water and streams. Our results also show that the delta(13)C(DIC) of CBNG-coproduced water from two different coal zones are distinct leading to the possibility of using delta(13)C(DIC) to distinguish water produced from different coal zones.

Water introduced to surface drainages, such as agricultural and roadway runoff, mine drainage, or coalbed natural gas (CBNG)-produced water, potentially can be of environmental concern. In order to mitigate potential environmental effects, it may be important to be able to trace water discharged to the surface as it infiltrates and interacts with near-surface aquifers. We have chosen to study water withdrawn during CBNG production for isotope tracing in the hyporheic zone because it poses a variety of economic, environmental, and policy issues in the Rocky Mountain states. Ground water quality must be protected as CBNG water is added to semiarid ecosystems. Strontium (Sr) isotopes are effective fingerprints of the aquifer from which water originates. In this study, CBNG water was found to have a higher (87)Sr/(86)Sr ratio than the local alluvial aquifer water. This measurable difference allows the strontium isotope ratio and concentration to be used as tracers of CBNG water following its discharge to the surface. The dissolution and mobilization of salts from soil are an important contributor to ground water quality degradation. In the Powder River basin of Wyoming, the soils are calcium carbonate-buffered systems. The chemical similarity of strontium to calcium allows it to substitute into calcium minerals and enabled us to use strontium isotopes to identify calcium salts mobilized from the soil. Strontium isotopes are an effective monitor of the source of ions and the volume and direction of introduced water flow in the hyporheic zone.

Mesoscopic quantum phase coherence is important because it improves the prospects for handling quantum degrees of freedom in technology. Here we show that the development of such coherence can be monitored using magnetic neutron scattering from a one-dimensional spin chain of an oxide of nickel (Y2BaNiO5), a quantum spin fluid in which no classical static magnetic order is present. In the cleanest samples, the quantum coherence length is 20 nanometers, which is almost an order of magnitude larger than the classical antiferromagnetic correlation length of 3 nanometers. We also demonstrate that the coherence length can be modified by static and thermally activated defects in a quantitatively predictable manner.

Magnetic excitations for energies up to approximately 100 meV are studied for overdoped La(2-x)Sr(x)CuO(4) with x=0.25 and 0.30, using time-of-flight neutron spectroscopy. Comparison of spectra integrated over the width of an antiferromagnetic Brillouin zone demonstrates that the magnetic scattering at intermediate energies, 20

We have performed inelastic neutron scattering on the near ideal spin-ladder compound La4Sr10Cu24O41 as a starting point for investigating doped ladders and their tendency toward superconductivity. A key feature was the separation of one-triplon and two-triplon scattering. Two-triplon scattering is observed quantitatively for the first time and so access is realized to the important strong magnetic quantum fluctuations. The spin gap is found to be 26.4+/-0.3 meV. The data are successfully modeled using the continuous unitary transformation method, and the exchange constants are determined by fitting to be Jleg=186 meV and Jrung=124 meV along the leg and rung, respectively; a substantial cyclic exchange of Jcyc=31 meV is confirmed.

We use high-resolution inelastic neutron scattering to study the low-temperature magnetic excitations of the electron-doping superconductor Pr(0.88)LaCe(0.12)CuO(4-delta) (T(c) = 21 +/- 1 K) over a wide energy range (4 meV < or = homega < or = 330 meV). The effect of electron doping is to cause a wave vector (Q) broadening in the low-energy (homega < or = 80 meV) commensurate spin fluctuations at (0.5, 0.5) and to suppress the intensity of spin-wave-like excitations at high energies (homega > or = 100 meV). This leads to a substantial redistribution in the spectrum of the local dynamical spin susceptibility chi''(omega), and reveals a new energy scale similar to that of the lightly hole-doped YB2Cu3O(6.353) (T(c) = 18 K).

The intermediate valence compound YbAl3 exhibits a broad magnetic excitation in the inelastic neutron scattering spectrum with characteristic energy E1 approximately 50 meV, equal to the Kondo energy (T(K) approximately 600-700 K). In the low temperature (T < T(coh) approximately 40 K) Fermi liquid state, however, a new peak in the scattering occurs at E2 approximately 33 meV, which lies in the hybridization gap that exists in this compound. We report inelastic neutron scattering results for a single-crystal sample. The scattering at energies near E1 qualitatively has the momentum (Q) dependence expected for interband scattering across the indirect gap. The scattering near E2 has a very different Q dependence: it is a weak function of Q over a large fraction of the Brillouin zone and is smallest near (1/2,1/2, 1/2). A possibility is that the peak at E2 arises from a spatially localized excitation in the hybridization gap.

Quantum effects dominate the behaviour of many diverse materials. Of particular current interest are those systems in the vicinity of a quantum critical point (QCP). Their physical properties are predicted to reflect those of the nearby QCP with universal features independent of the microscopic details. The prototypical QCP is the Luttinger liquid (LL), which is of relevance to many quasi-one-dimensional materials. The magnetic material KCuF3 realizes an array of weakly coupled spin chains (or LLs) and thus lies close to but not exactly at the LL quantum critical point. By using inelastic neutron scattering we have collected a complete data set of the magnetic correlations of KCuF3 as a function of momentum, energy and temperature. The LL description is found to be valid over an extensive range of these parameters, and departures from this behaviour at high and low energies and temperatures are identified and explained.

We have investigated the spin dynamics in the strongly correlated chain copper oxide SrCuO2 for energies up to greater, similar 0.6 eV using inelastic neutron scattering. We observe a gapless continuum of magnetic excitations, which is well described by the "Müller ansatz" for the two-spinon continuum in the S=1/2 antiferromagnetic Heisenberg spin chain. The lower boundary of the continuum extends up to approximately 360 meV, which corresponds to an exchange constant J=226(12) meV.

We present neutron scattering spectra taken from a single crystal of Na0.75CoO2, the precursor to a novel cobalt-oxide superconductor. The data contain a prominent inelastic signal at low energies ( approximately 10 meV), which is localized in wave vector about the origin of two-dimensional reciprocal space. The signal is highly dispersive, and decreases in intensity with increasing temperature. We interpret these observations as direct evidence for the existence of ferromagnetic spin fluctuations within the cobalt-oxygen layers.

87Sr/86Sr ratios of ground waters in the Bighorn and Laramie basins' carbonate and carbonate-cemented aquifer systems, Wyoming, United States, reflect the distinctive strontium isotope signatures of the minerals in their respective aquifers. Well water samples from the Madison Aquifer (Bighorn Basin) have strontium isotopic ratios that match their carbonate host rocks. Casper Aquifer ground waters (Laramie Basin) have strontium isotopic ratios that differ from the bulk host rock; however, stepwise leaching of Casper Sandstone indicates that most of the strontium in Casper Aquifer ground waters is acquired from preferential dissolution of carbonate cement. Strontium isotope data from both Bighorn and Laramie basins, along with dye tracing experiments in the Bighorn Basin and tritium data from the Laramie Basin, suggest that waters in carbonate or carbonate-cemented aquifers acquire their strontium isotope composition very quickly--on the order of decades. Strontium isotopes were also used successfully to verify previously identified mixed Redbeds-Casper ground waters in the Laramie Basin. The strontium isotopic compositions of ground waters near Precambrian outcrops also suggest previously unrecognized mixing between Casper and Precambrian aquifers. These results demonstrate the utility of strontium isotopic ratio data in identifying ground water sources and aquifer interactions.

Aims: To establish by case note review how people with newly diagnosed asthma were treated in general practice., Methods: A retrospective cross-sectional survey was carried out in twelve general practices from the MRC General Practice Research Framework. Children between their 3rd and 8th birthdays and adults 16 years and over were identified with newly diagnosed or treated asthma from computer records with further details obtained from a case record search. The main outcome measure was the time of recorded asthma diagnosis and the time of first prescriptions for inhaled corticosteroids., Results: For 41% of children and 53% of adults with a diagnosis of asthma and inhaled corticosteroids, inhaled corticosteroids were prescribed before or on the same day as the diagnosis of asthma was recorded. Diagnosis tended to be made on the basis of a patient's medical history with fewer than 20% of patients having results of any tests recorded in their medical notes. The time from first respiratory consultation to inhaled corticosteroid prescription was statistically significantly shorter in those children for whom a diagnosis of asthma was recorded (p=0.038) compared to those children without a recorded diagnosis of asthma., Conclusions: Inhaled corticosteroids are frequently prescribed before a diagnosis of asthma is recorded. A diagnostic label of asthma in children significantly reduces the length of time from the date of first respiratory consultation to inhaled corticosteroid prescription. If inhaled corticosteroids are to be prescribed early there must be an improvement in the diagnosis of asthma in primary care, including the recording of results in patient's medical notes., (Copyright © 2002 General Practice Airways Group.)

The magnetic excitations of the square-lattice spin-1/2 antiferromagnet and high- T(c) parent compound La2CuO4 are determined using high-resolution inelastic neutron scattering. Sharp spin waves with absolute intensities in agreement with theory including quantum corrections are found throughout the Brillouin zone. The observed dispersion relation shows evidence for substantial interactions beyond the nearest-neighbor Heisenberg term which can be understood in terms of a cyclic or ring exchange due to the strong hybridization path around the Cu4O4 square plaquettes.

Magnetic neutron scattering provides evidence for nucleation of antiferromagnetic droplets around impurities in a doped nickel oxide-based quantum magnet. The undoped parent compound contains a spin liquid with a cooperative singlet ground state and a gap in the magnetic excitation spectrum. Calcium doping creates excitations below the gap with an incommensurate structure factor. We show that weakly interacting antiferromagnetic droplets with a central phase shift of pi and a size controlled by the correlation length of the quantum liquid can account for the data. The experiment provides a quantitative impression of the magnetic polarization cloud associated with holes in a doped transition metal oxide.

Objective: To evaluate the safety of a non-chlorofluorocarbon metered dose salbutamol inhaler., Design: This was a postmarketing surveillance study, conducted under formal guidelines for company sponsored safety assessment of marketed medicines (SAMM). A non-randomised, non-interventional, observational design compared patients prescribed metered doses of salbutamol delivered by inhalers using either hydrofluoroalkane or chlorofluorocarbon as the propellant. Follow up was three months., Setting: 646 general practices throughout the United Kingdom., Subjects: 6614 patients with obstructive airways disease (1667 patient years of exposure)., Main Outcome Measures: Proportions of patients who were: admitted to hospital for respiratory diseases, reported adverse side effects, or withdrew because of adverse affects., Results: There were no significant differences between the hydrofluoroalkane (HFA 134a) and chlorofluorocarbon inhaler groups in relation to the proportions of patients admitted to hospital for respiratory diseases (odds ratio 0.75; 95% confidence interval 0.51 to 1.08) or the proportions who reported adverse events (1.01; 0.88 to 1.17). However, more patients using the hydrofluoroalkane inhaler than the chlorofluorocarbon inhaler withdrew because of adverse events (3.8% and 0.9% respectively)., Conclusion: The hydrofluoroalkane inhaler was as safe as the chlorofluorocarbon inhaler when judged by hospital admissions and adverse affects. The study design successfully fulfilled the recommendations of the guidelines. Differences between postmarketing surveillance studies and randomised clinical trials in assessing safety were identified. These may lead to difficulties in the design of postmarketing surveillance studies.

We have previously shown that the association between salt intake and blood pressure is large and of substantial public health importance. Analysis of the average blood pressure and average sodium intake in different communities yielded estimates of the decrease in blood pressure for a given reduction in dietary sodium according to age and blood pressure centile that successfully predicted both the association between sodium and blood pressure in observational studies and the reduction in blood pressure obtained in trials of dietary salt reduction. Here we consider the validity of criticisms of the appraisal. The fact that the observed blood pressure reductions in individual trials closely mirrored predicted values for individuals trials that varied widely (from 2.6 to 25.2 mmHg systolic according to age, existing blood pressure and the extent of salt restriction) renders bias implausible since it would be too great a coincidence for a source of error to reproduce such close matching. If the analysis is restricted to trials that avoided possible bias because (1) the high- and low-salt diets were otherwise identical, (2) the order of the diet avoided regression to the mean or (3) the trials were double-blind with diets that were otherwise identical and the order was random, the matching between observed and predicted blood pressure reductions is equally close. Our results are consistent with the Intersalt study. A reduction in dietary salt could be a simple change, yet the reduction in mortality would be large.

Objective: To determine whether the estimates of the size of the association between blood pressure and sodium intake derived from studies of individuals within populations can be quantitatively reconciled with our estimates derived from comparisons of the average blood pressure and sodium intake between different populations., Design: Examination of data from 14 published studies that correlated blood pressure recordings in individuals against measurements of their 24 hour sodium intake (within population studies)., Main Outcome Measure: Comparison of observed differences in blood pressure per 100 mmol/24 h difference in sodium intake in each within population study with predicted differences calculated from the between population data, after allowing for the underestimation of the true association of blood pressure with sodium intake caused by the large day to day variation in 24 hour sodium intake within individuals., Results: The underestimation bias inherent in the within populations studies reduced the regression slope of blood pressure on single measures of 24 hour sodium intake to between a half and a quarter of the true value (for example, in one study from 6.0 to 2.4 mm Hg/100 mmol/24 h). Estimates from between population comparisons of the regression slope of blood pressure on sodium intake, after adjustment to take this underestimation bias into account, were similar to the values actually observed in the within population studies., Conclusion: The within population studies confirm our estimates from between population comparisons of the magnitude of the association between blood pressure and sodium intake.

Objective: To determine whether the reduction in blood pressure achieved in trials of dietary salt reduction is quantitatively consistent with estimates derived from blood pressure and sodium intake in different populations, and, if so, to estimate the impact of reducing dietary salt on mortality from stroke and ischaemic heart disease., Design: Analysis of the results of 68 crossover trials and 10 randomised controlled trials of dietary salt reduction., Main Outcome Measure: Comparison of observed reductions in systolic blood pressure for each trial with predicted values calculated from between population analysis., Results: In the 45 trials in which salt reduction lasted four weeks or less the observed reductions in blood pressure were less than those predicted, with the difference between observed and predicted reductions being greatest in the trials of shortest duration. In the 33 trials lasting five weeks or longer the predicted reductions in individual trials closely matched a wide range of observed reductions. This applied for all age groups and for people with both high and normal levels of blood pressure. In people aged 50-59 years a reduction in daily sodium intake of 50 mmol (about 3 g of salt), attainable by moderate dietary salt reduction would, after a few weeks, lower systolic blood pressure by an average of 5 mm Hg, and by 7 mm Hg in those with high blood pressure (170 mm Hg); diastolic blood pressure would be lowered by about half as much. It is estimated that such a reduction in salt intake by a whole Western population would reduce the incidence of stroke by 22% and of ischaemic heart disease by 16% [corrected]., Conclusions: The results from the trials support the estimates from the observational data in the accompanying two papers. The effect of universal moderate dietary salt reduction on mortality from stroke and ischaemic heart disease would be substantial--larger, indeed, than could be achieved by fully implementing recommended policy for treating high blood pressure with drugs. However, reduction also in the amount of salt added to processed foods would lower blood pressure by at least twice as much and prevent some 75,000 [corrected] deaths a year in Britain as well as much disability.

Objective: To estimate the quantitative relation between blood pressure and sodium intake., Design: Data were analysed from published reports of blood pressure and sodium intake for 24 different communities (47 000 people) throughout the world., Main Outcome Measure: Difference in blood pressure for a 100 mmol/24 h difference in sodium intake. Allowance was made for differences in blood pressure between economically developed and undeveloped communities to minimise overestimation of the association through confounding with other determinants of blood pressure., Results: Blood pressure was higher on average in the developed communities, but the association with sodium intake was similar in both types of community. A difference in sodium intake of 100 mmol/24 h was associated with an average difference in systolic blood pressure that ranged from 5 mm Hg at age 15-19 years to 10 mm Hg at age 60-69. The differences in diastolic blood pressure were about half as great. The standard deviation of blood pressure increased with sodium intake implying that the association of blood pressure with sodium intake in individuals was related to the initial blood pressure--the higher the blood pressure the greater the expected reduction in blood pressure for the same reduction in sodium intake. For example, at age 60-69 the estimated systolic blood pressure reduction in response to a 100 mmol/24 h reduction in sodium intake was on average 10 mm Hg but varied from 6 mm Hg for those on the fifth blood pressure centile to 15 mm Hg for those on the 95th centile., Conclusions: The association of blood pressure with sodium intake is substantially larger than is generally appreciated and increases with age and initial blood pressure.