Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled β -agonist treatment

AbstractThere is uncertainty about the development of airway tolerance to β -agonists and the phenomenon of rebound bronchoconstriction on β -agonist withdrawal. We have recently completed a study of the regular terbutaline and budesonide treatment in asthma. We report our observations on the effect of starting and stopping terbutaline treatment on morning and evening peak flows.The study was a randomized four-way, double-dummy, cross-over comparison of regular inhaled terbutaline (500–1000 μ g four times daily), budesonide, combined treatment and matching placebo. Each treatment was given for 6 weeks following a 4 week single-blind placebo washout. Ipratropium was used for symptom relief. No other asthma medication was permitted during either the treatment or wash-out periods. Evaluable data were obtained from 52 subjects for both placebo and terbutaline treatment. Changes in mean morning and evening peak flows during terbutaline treatment were compared to the baseline peak flows during the last 2 weeks of the preceding washout. The peak flow changes on stopping terbutaline were also analysed.Mean morning peak flow was not significantly different during terbutaline treatment when compared to either baseline or placebo treatment. Evening peak flows were significantly higher during terbutaline treatment [mean increase 23·1l min−1(95%CI=18·8, 27·4)]. Analysis of the peak flow changes on a day-by-day basis revealed an initial increase in morning peak flows for the first 2 days of treatment of 19·2 and 13·4l min−1[increases of 25·0 and 17·3l min−1in comparison with the corresponding values during placebo (P<0·01)] followed by a return to baseline. The increase in evening peak flows was also greater for the first 2 days of treatment than for the remainder of the treatment period (P<0·01). On ceasing terbutaline treatment there was a fall in mean morning peak flow below the baseline on the following morning of 21·6l min−1(P<0·05 compared to placebo).The temporary increase in morning peak flows and greater than expected rise in evening peak flows for the first 2 days of treatment suggest the development of tolerance to the bronchodilator effect of terbutaline. Similarly, the fall in morning peak flows on treatment withdrawal suggests rebound bronchoconstriction. These effects are likely to be mediated by downregulation of the β -receptor during treatment. The clinical significance of these changes is uncertain in view of the stability of overall asthma control during terbutaline treatment, but sudden withdrawal of β -agonist treatment could conceivably lead to a deterioration in asthma control

Possible origins of macroscopic left-right asymmetry in organisms

I consider the microscopic mechanisms by which a particular left-right (L/R) asymmetry is generated at the organism level from the microscopic handedness of cytoskeletal molecules. In light of a fundamental symmetry principle, the typical pattern-formation mechanisms of diffusion plus regulation cannot implement the "right-hand rule"; at the microscopic level, the cell's cytoskeleton of chiral filaments seems always to be involved, usually in collective states driven by polymerization forces or molecular motors. It seems particularly easy for handedness to emerge in a shear or rotation in the background of an effectively two-dimensional system, such as the cell membrane or a layer of cells, as this requires no pre-existing axis apart from the layer normal. I detail a scenario involving actin/myosin layers in snails and in C. elegans, and also one about the microtubule layer in plant cells. I also survey the other examples that I am aware of, such as the emergence of handedness such as the emergence of handedness in neurons, in eukaryote cell motility, and in non-flagellated bacteria.Comment: 42 pages, 6 figures, resubmitted to J. Stat. Phys. special issue. Major rewrite, rearranged sections/subsections, new Fig 3 + 6, new physics in Sec 2.4 and 3.4.1, added Sec 5 and subsections of Sec

Prioritising research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper

SCOPE: Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team, organisation and policy levels, evidence from the behavioural sciences is underutilised in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimising effective implementation of ASPs in hospital settings, using a behavioural perspective. METHODS: A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four high-income countries with publicly-funded health care systems (that is Canada, Germany, Norway and the UK), met face-to-face to agree on broad research priority areas using a structured consensus method. QUESTION ADDRESSED AND RECOMMENDATIONS: The consensus process on the 10 identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimise effective implementation of antibiotic stewardship programmes for hospital inpatients in HICs with publicly-funded health care systems. We suggest and detail, behavioural science evidence-guided research efforts in the following areas: 1) Comprehensively identifying barriers and facilitators to implementing antibiotic stewardship programmes and clinical recommendations intended to optimise antibiotic prescribing; 2) Identifying actors ('who') and actions ('what needs to be done') of antibiotic stewardship programmes and clinical teams; 3) Synthesising available evidence to support future research and planning for antibiotic stewardship programmes; 4) Specifying the activities in current antibiotic stewardship programmes with the purpose of defining a 'control group' for comparison with new initiatives; 5) Defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; 6) Conducting robust evaluations of antibiotic stewardship programmes with built-in process evaluations and fidelity assessments; 7) Defining and designing antibiotic stewardship programmes; 8) Establishing the evidence base for impact of antibiotic stewardship programmes on resistance; 9) Investigating the role and impact of government and policy contexts on antibiotic stewardship programmes; and 10) Understanding what matters to patients in antibiotic stewardship programmes in hospitals. Assessment, revisions and updates of our priority-setting exercise should be considered, at intervals of 2 years. To propose research priority areas in low- and medium income countries (LIMCs), the methodology reported here could be applied

Model-independent search for CP violation in D0→K−K+π−π+ and D0→π−π+π+π− decays

A search for CP violation in the phase-space structures of D0 and View the MathML source decays to the final states K−K+π−π+ and π−π+π+π− is presented. The search is carried out with a data set corresponding to an integrated luminosity of 1.0 fb−1 collected in 2011 by the LHCb experiment in pp collisions at a centre-of-mass energy of 7 TeV. For the K−K+π−π+ final state, the four-body phase space is divided into 32 bins, each bin with approximately 1800 decays. The p-value under the hypothesis of no CP violation is 9.1%, and in no bin is a CP asymmetry greater than 6.5% observed. The phase space of the π−π+π+π− final state is partitioned into 128 bins, each bin with approximately 2500 decays. The p-value under the hypothesis of no CP violation is 41%, and in no bin is a CP asymmetry greater than 5.5% observed. All results are consistent with the hypothesis of no CP violation at the current sensitivity

Measurement of the Bs0→J/ψKS0B_s^0\to J/\psi K_S^0 branching fraction

The $B_s^0\to J/\psi K_S^0$ branching fraction is measured in a data sample corresponding to 0.41$fb^{-1}$ of integrated luminosity collected with the LHCb detector at the LHC. This channel is sensitive to the penguin contributions affecting the sin2$\beta$ measurement from $B^0\to J/\psi K_S^0$ The time-integrated branching fraction is measured to be $BF(B_s^0\to J/\psi K_S^0)=(1.83\pm0.28)\times10^{-5}$. This is the most precise measurement to date

Measurement of the CP-violating phase \phi s in Bs->J/\psi\pi+\pi- decays

Measurement of the mixing-induced CP-violating phase phi_s in Bs decays is of prime importance in probing new physics. Here 7421 +/- 105 signal events from the dominantly CP-odd final state J/\psi pi+ pi- are selected in 1/fb of pp collision data collected at sqrt{s} = 7 TeV with the LHCb detector. A time-dependent fit to the data yields a value of phi_s=-0.019^{+0.173+0.004}_{-0.174-0.003} rad, consistent with the Standard Model expectation. No evidence of direct CP violation is found.Comment: 15 pages, 10 figures; minor revisions on May 23, 201

Absolute luminosity measurements with the LHCb detector at the LHC

Absolute luminosity measurements are of general interest for colliding-beam experiments at storage rings. These measurements are necessary to determine the absolute cross-sections of reaction processes and are valuable to quantify the performance of the accelerator. Using data taken in 2010, LHCb has applied two methods to determine the absolute scale of its luminosity measurements for proton-proton collisions at the LHC with a centre-of-mass energy of 7 TeV. In addition to the classic "van der Meer scan" method a novel technique has been developed which makes use of direct imaging of the individual beams using beam-gas and beam-beam interactions. This beam imaging method is made possible by the high resolution of the LHCb vertex detector and the close proximity of the detector to the beams, and allows beam parameters such as positions, angles and widths to be determined. The results of the two methods have comparable precision and are in good agreement. Combining the two methods, an overall precision of 3.5% in the absolute luminosity determination is reached. The techniques used to transport the absolute luminosity calibration to the full 2010 data-taking period are presented.Comment: 48 pages, 19 figures. Results unchanged, improved clarity of Table 6, 9 and 10 and corresponding explanation in the tex

Measurement of the ratio of branching fractions BR(B0 -> K*0 gamma)/BR(Bs0 -> phi gamma) and the direct CP asymmetry in B0 -> K*0 gamma

The ratio of branching fractions of the radiative B decays B0 -> K*0 gamma and Bs0 phi gamma has been measured using an integrated luminosity of 1.0 fb-1 of pp collision data collected by the LHCb experiment at a centre-of-mass energy of sqrt(s)=7 TeV. The value obtained is BR(B0 -> K*0 gamma)/BR(Bs0 -> phi gamma) = 1.23 +/- 0.06(stat.) +/- 0.04(syst.) +/- 0.10(fs/fd), where the first uncertainty is statistical, the second is the experimental systematic uncertainty and the third is associated with the ratio of fragmentation fractions fs/fd. Using the world average value for BR(B0 -> K*0 gamma), the branching fraction BR(Bs0 -> phi gamma) is measured to be (3.5 +/- 0.4) x 10^{-5}. The direct CP asymmetry in B0 -> K*0 gamma decays has also been measured with the same data and found to be A(CP)(B0 -> K*0 gamma) = (0.8 +/- 1.7(stat.) +/- 0.9(syst.))%. Both measurements are the most precise to date and are in agreement with the previous experimental results and theoretical expectations.Comment: 21 pages, 3 figues, 4 table

Search for the lepton-flavor-violating decays Bs0→e±μ∓ and B0→e±μ∓

A search for the lepton-flavor-violating decays Bs0→e±μ∓ and B0→e±μ∓ is performed with a data sample, corresponding to an integrated luminosity of 1.0  fb-1 of pp collisions at √s=7  TeV, collected by the LHCb experiment. The observed number of Bs0→e±μ∓ and B0→e±μ∓ candidates is consistent with background expectations. Upper limits on the branching fractions of both decays are determined to be B(Bs0→e±μ∓)101  TeV/c2 and MLQ(B0→e±μ∓)>126  TeV/c2 at 95% C.L., and are a factor of 2 higher than the previous bounds

Absolute luminosity measurements with the LHCb detector at the LHC

Absolute luminosity measurements are of general interest for colliding-beam experiments at storage rings. These measurements are necessary to determine the absolute cross-sections of reaction processes and are valuable to quantify the performance of the accelerator. Using data taken in 2010, LHCb has applied two methods to determine the absolute scale of its luminosity measurements for proton-proton collisions at the LHC with a centre-of-mass energy of 7 TeV. In addition to the classic "van der Meer scan" method a novel technique has been developed which makes use of direct imaging of the individual beams using beam-gas and beam-beam interactions. This beam imaging method is made possible by the high resolution of the LHCb vertex detector and the close proximity of the detector to the beams, and allows beam parameters such as positions, angles and widths to be determined. The results of the two methods have comparable precision and are in good agreement. Combining the two methods, an overall precision of 3.5% in the absolute luminosity determination is reached. The techniques used to transport the absolute luminosity calibration to the full 2010 data-taking period are presented.Comment: 48 pages, 19 figures. Results unchanged, improved clarity of Table 6, 9 and 10 and corresponding explanation in the tex