Receptor activity-modifying protein-dependent effects of mutations in the calcitonin receptor-like receptor:implications for adrenomedullin and calcitonin gene-related peptide pharmacology

Background and Purpose Receptor activity-modifying proteins (RAMPs) define the pharmacology of the calcitonin receptor-like receptor (CLR). The interactions of the different RAMPs with this class B GPCR yield high-affinity calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors. However, the mechanism for this is unclear. Experimental Approach Guided by receptor models, we mutated residues in the N-terminal helix of CLR, RAMP2 and RAMP3 hypothesized to be involved in peptide interactions. These were assayed for cAMP production with AM, AM2 and CGRP together with their cell surface expression. Binding studies were also conducted for selected mutants. Key Results An important domain for peptide interactions on CLR from I32 to I52 was defined. Although I41 was universally important for binding and receptor function, the role of other residues depended on both ligand and RAMP. Peptide binding to CLR/RAMP3 involved a more restricted range of residues than that to CLR/RAMP1 or CLR/RAMP2. E101 of RAMP2 had a major role in AM interactions, and F111/W84 of RAMP2/3 was important with each peptide. Conclusions and Implications RAMP-dependent effects of CLR mutations suggest that the different RAMPs control accessibility of peptides to binding residues situated on the CLR N-terminus. RAMP3 appears to alter the role of specific residues at the CLR-RAMP interface compared with RAMP1 and RAMP2

Large-scale cosmic flows and moving dark energy

Large-scale matter bulk flows with respect to the cosmic microwave background have very recently been detected on scales 100 Mpc/h and 300 Mpc/h by using two different techniques showing an excellent agreement in the motion direction. However, the unexpectedly large measured amplitudes are difficult to understand within the context of standard LCDM cosmology. In this work we show that the existence of such a flow could be signaling the presence of moving dark energy at the time when photons decoupled from matter. We also comment on the relation between the direction of the CMB dipole and the preferred axis observed in the quadrupole in this scenario.Comment: 11 pages, 2 figures. New comments and references included. Final version to appear in JCA

The association of smoking and socioeconomic status on cutaneous melanoma: a population‐based, data‐linkage, case–control study

BACKGROUND: Previous studies have identified an inverse association between melanoma and smoking; however, data from population-based studies are scarce. OBJECTIVES: To determine the association between smoking and socioeconomic (SES) on the risk of development of melanoma. Furthermore, we sought to determine the implications of smoking and SES on survival. METHODS: We conducted a population-based case-control study. Cases were identified from the Welsh Cancer Intelligence and Surveillance Unit (WCISU) during 2000-2015 and controls from the general population. Smoking and SES were obtained from data linkage with other national databases. The association of smoking status and SES on the incidence of melanoma were assessed using binary logistic regression. Multivariate survival analysis was performed on a melanoma cohort using a Cox proportional hazard model using survival as the outcome. RESULTS: During 2000-2015, 9636 patients developed melanoma. Smoking data were obtained for 7124 (73·9%) of these patients. There were 26 408 controls identified from the general population. Smoking was inversely associated with melanoma incidence [odds ratio (OR) 0·70, 95% confidence interval (CI) 0·65-0·76]. Smoking was associated with an increased overall mortality [hazard ratio (HR) 1·30, 95% CI 1·09-1·55], but not associated with melanoma-specific mortality. Patients with higher SES had an increased association with melanoma incidence (OR 1·58, 95% CI 1·44-1·73). Higher SES was associated with an increased chance of both overall (HR 0·67, 95% CI 0·56-0·81) and disease-specific survival (HR 0·69, 95% CI 0·53-0·90). CONCLUSIONS: Our study has demonstrated that smoking appeared to be associated with reduced incidence of melanoma. Although smoking increases overall mortality, no association was observed with melanoma-specific mortality. Further work is required to determine if there is a biological mechanism underlying this relationship or an alternative explanation, such as survival bias. What's already known about this topic? Previous studies have been contradictory with both negative and positive associations between smoking and the incidence of melanoma reported. Previous studies have either been limited by publication bias because of selective reporting or underpowered. What does this study add? Our large study identified an inverse association between smoking status and melanoma incidence. Although smoking status was negatively associated with overall disease survival, no significant association was noted in melanoma-specific survival. Socioeconomic status remains closely associated with melanoma. Although higher socioeconomic populations are more likely to develop the disease, patients with lower socioeconomic status continue to have a worse prognosis

A multicentre randomised feasibility STUdy evaluating the impact of a prognostic model for management of BLunt chest wall trauma patients : STUMBL Trial

Objective: A new prognostic model has been developed and externally validated, the aim of which is to assist in the management of the blunt chest wall trauma patient in the emergency department (ED). The aim of this trial is to assess the feasibility and acceptability of a definitive impact trial investigating the clinical and cost-effectiveness of a new prognostic model for the management of patients with blunt chest wall trauma in the ED. Design: Stepped wedge feasibility trial. Setting: Four EDs in England and Wales. Participants: Adult blunt chest wall trauma patients presenting to the ED with no concurrent, life-threatening injuries. Intervention: A prognostic model (the STUMBL score) to guide clinical decision-making. Outcome measures: Primary: participant recruitment rate and clinicians’ use of the STUMBL score. Secondary: composite outcome measure (mortality, pulmonary complications, delayed upgrade in care, unplanned representations to the ED), physical and mental components of quality of life, clinician feedback and health economic data gathering methodology for healthcare resource utilisation. Results: Quantitative data were analysed using the intention-to-treat principle. 176 patients were recruited; recruitment targets were achieved at all sites. Clinicians used the model in 96% of intervention cases. All feasibility criteria were fully or partially met. After adjusting for predefined covariates, there were no statistically significant differences between the control and intervention periods. Qualitative analysis highlighted that STUMBL was well-received and clinicians would support a definitive trial. Collecting data on intervention costs, health-related quality of life and healthcare resource use was feasible. Discussion: We have demonstrated that a fully powered randomised clinical trial of the STUMBL score is feasible and desirable to clinicians. Minor methodological modifications will be made for the full trial. Trial registration number: ISRCTN95571506; Post-results

Early exercise in blunt chest wall trauma: protocol for a mixed-methods, multicentre, parallel randomised controlled trial (ELECT2 trial)

Introduction: Chronic pain and disability are now well-recognised long-term complications of blunt chest wall trauma. Limited research exists regarding therapeutic interventions that can be used to address these complications. A recent feasibility study was completed testing the methods of a definitive trial. This protocol describes the proposed definitive trial, the aim of which is to investigate the impact of an early exercise programme on chronic pain and disability in patients with blunt chest wall trauma. Methods/analysis: This mixed-methods, multicentre, parallel randomised controlled trial will run in four hospitals in Wales and one in England over 12-month recruitment period. Patients will be randomised to either the control group (routine physiotherapy input) or the intervention group (routine physiotherapy input plus a simple exercise programme completed individually by the patient). Baseline measurements including completion of two surveys (Brief Pain Inventory and EuroQol 5-dimensions, 5-Levels) will be obtained on initial assessment. These measures and a client services receipt inventory will be repeated at 3-month postinjury. Analysis of outcomes will focus on rate and severity of chronic pain and disability, cost-effectiveness and acceptability of the programme by patients and clinicians. Qualitative feedback regarding acceptability will be obtained through patient and clinician focus groups. Ethics/dissemination: London Riverside Research Ethics Committee (Reference number: 21/LO/0782) and the Health Research Authority granted approval for the trial in December 2021. Patient recruitment will commence in February 2022. Planned dissemination is through publication in a peer-reviewed Emergency Medicine Journal, presentation at appropriate conferences and to stakeholders at professional meetings. Trial registration number: ISRCTN65829737; Pre-results

Measurement of the partial widths of the Z into up- and down-type quarks

Using the entire OPAL LEP1 on-peak Z hadronic decay sample, Z -> qbarq gamma decays were selected by tagging hadronic final states with isolated photon candidates in the electromagnetic calorimeter. Combining the measured rates of Z -> qbarq gamma decays with the total rate of hadronic Z decays permits the simultaneous determination of the widths of the Z into up- and down-type quarks. The values obtained, with total errors, were Gamma u = 300 ^{+19}_{-18} MeV and Gamma d = 381 ^{+12}_{-12} MeV. The results are in good agreement with the Standard Model expectation.Comment: 22 pages, 5 figures, Submitted to Phys. Letts.

Search for R-Parity Violating Decays of Scalar Fermions at LEP

A search for pair-produced scalar fermions under the assumption that R-parity is not conserved has been performed using data collected with the OPAL detector at LEP. The data samples analysed correspond to an integrated luminosity of about 610 pb-1 collected at centre-of-mass energies of sqrt(s) 189-209 GeV. An important consequence of R-parity violation is that the lightest supersymmetric particle is expected to be unstable. Searches of R-parity violating decays of charged sleptons, sneutrinos and squarks have been performed under the assumptions that the lightest supersymmetric particle decays promptly and that only one of the R-parity violating couplings is dominant for each of the decay modes considered. Such processes would yield final states consisting of leptons, jets, or both with or without missing energy. No significant single-like excess of events has been observed with respect to the Standard Model expectations. Limits on the production cross- section of scalar fermions in R-parity violating scenarios are obtained. Constraints on the supersymmetric particle masses are also presented in an R-parity violating framework analogous to the Constrained Minimal Supersymmetric Standard Model.Comment: 51 pages, 24 figures, Submitted to Eur. Phys. J.

Measurement of the Strong Coupling alpha s from Four-Jet Observables in e+e- Annihilation

Data from e+e- annihilation into hadrons at centre-of-mass energies between 91 GeV and 209 GeV collected with the OPAL detector at LEP, are used to study the four-jet rate as a function of the Durham algorithm resolution parameter ycut. The four-jet rate is compared to next-to-leading order calculations that include the resummation of large logarithms. The strong coupling measured from the four-jet rate is alphas(Mz0)= 0.1182+-0.0003(stat.)+-0.0015(exp.)+-0.0011(had.)+-0.0012(scale)+-0.0013(mass) in agreement with the world average. Next-to-leading order fits to the D-parameter and thrust minor event-shape observables are also performed for the first time. We find consistent results, but with significantly larger theoretical uncertainties.Comment: 25 pages, 15 figures, Submitted to Euro. Phys. J.

Measurement of the Hadronic Photon Structure Function F_2^gamma at LEP2

The hadronic structure function of the photon F_2^gamma is measured as a function of Bjorken x and of the factorisation scale Q^2 using data taken by the OPAL detector at LEP. Previous OPAL measurements of the x dependence of F_2^gamma are extended to an average Q^2 of 767 GeV^2. The Q^2 evolution of F_2^gamma is studied for average Q^2 between 11.9 and 1051 GeV^2. As predicted by QCD, the data show positive scaling violations in F_2^gamma. Several parameterisations of F_2^gamma are in agreement with the measurements whereas the quark-parton model prediction fails to describe the data.Comment: 4 pages, 2 figures, to appear in the proceedings of Photon 2001, Ascona, Switzerlan

A measurement of the tau mass and the first CPT test with tau leptons

We measure the mass of the tau lepton to be 1775.1+-1.6(stat)+-1.0(syst.) MeV using tau pairs from Z0 decays. To test CPT invariance we compare the masses of the positively and negatively charged tau leptons. The relative mass difference is found to be smaller than 3.0 10^-3 at the 90% confidence level.Comment: 10 pages, 4 figures, Submitted to Phys. Letts.