Publications

Allergen-induced late asthmatic reactions are associated with elevation of exhaled nitric oxide.

The concentration of nitric oxide (NO) is increased in the exhaled air of asthmatic patients and may reflect cytokine-mediated inflammation in the airways. We investigated whether allergen-induced inflammation causes an elevation in the level of exhaled NO. Of 25 patients who underwent allergen challenge, 16 developed dual early and late responses, whereas eight had a single early response. In the patients with a dual response, the maximal fall in FEV1 during the late response was 26.8 +/- 4.2% at 9 h and there was a significant increase in the level of exhaled NO (maximal increase of 59.4 +/- 9.8%) 10 h after challenge. There was a significant relationship between the size of the late response and the increase in exhaled NO (r = 0.75, p < 0.01). In patients who have a single early response, there was no significant increase in exhaled NO, with the exception of a single time point at 21 h. In five patients given a control challenge with methacholine there was no change in exhaled NO. There was no increase in exhaled NO after inhaled histamine in any of the patient groups. We conclude that the late asthmatic response to allergen is associated with elevated exhaled NO concentrations and that this provides further evidence that exhaled NO may reflect allergic inflammation in asthmatic airways, and may be a useful marker in monitoring asthma and its response to anti-inflammatory treatments. Whether endogenously produced NO plays a pathophysiologic role in the late response remains to be determined.

Design of structural steel members by advanced inelastic analysis with strain limits

Increased nitric oxide in exhaled air of asthmatic patients

Combining Baseline Distal-to-Aortic Pressure Ratio and Fractional Flow Reserve in the Assessment of Coronary Stenosis Severity

Objectives This study sought to understand the physiological basis of baseline distal-to-aortic pressure ratio (Pd/Pa) and fractional flow reserve (FFR) agreement and discordance, using coronary flow reserve (CFR), stenosis resistance, and microcirculatory resistance measurements, and form there, to investigate the potential value of combining Pd/Pa with FFR in the diagnostic rationale. Background Pd/Pa is always available before FFR assessment, and emerging data supports the notion that baseline indices can determine the ischemic potential of coronary stenosis in selected subsets. Methods A total of 467 stenosed vessels from 363 patients were investigated with pressure and flow sensors during baseline and hyperemia: 168 vessels (135 patients) with thermodilution-derived flow, and 299 vessels (228 patients) with Doppler-derived flow. Results Pd/Pa correlated more strongly with CFR than FFR (ρ difference = 0.129; p for ρ comparison <0.001). Although Pd/Pa and FFR were closely correlated (ρ = 0.798; 95% confidence interval: 0.767 to 0.828), categorical discordance was observed in 19.3% of total vessels. Such discordance was associated with the patients’ clinical profile and was characterized by contrastive changes in stenosis resistance, microcirculatory resistance, and the underlying CFR. Notably, all stenosis with Pd/Pa ≤0.83 (n = 74, 15.8%) progressed to FFR ≤0.80, and although no Pd/Pa cutoff was able to exclude the development of FFR ≤0.80 in the high end of values, only 15 (10.1%) vessels with Pd/Pa ≥0.96 (n = 149, 31.9%) developed FFR ≤0.80, from which none had definite ischemia, as defined by CFR ≤1.74. Conclusions Combining baseline Pd/Pa with FFR seems to provide a more comprehensive physiological examination of stenosed coronary arteries and a closer pressure-based appraisal of the flow reserve of the downstream myocardial bed.

Radioligand binding studies of adrenergic receptors and their clinical relevance.

Ahlquist in 1948 first recognised that there were two distinct types of adrenoceptor, which he was able to differentiate by comparing the rank order of potency of several adrenergic agonists in various tissues.1 Alpha-adrenoceptors which mediate smooth muscle contraction were characterised by the potency order adrenaiine> noradrenaline >isoprenaline and beta adrenoceptors, mediating relaxation, by the rank order isoprenaline > adrenaline > noradrenaline. Since then specific antagonists such as phentolamine, which blocks a-adrenorecep tors, and propranalol, which blocks ?-adrenoreceptors3 have been developed. Beta-adrenoceptors have been subclassified into ?x-receptors, which mediate positive inotropic cardiac re? sponses and lipolysis and for which adrenaline and noradrena? line are equipotent, and ?o-receptors, which mediate relaxation in vascular, bronchial, and uterine smooth muscle for which adrenaline is more potent than noradrenaline.2 Antagonists such as practolol, atenolol, and metroprolol are more potent at ?x than ?2-receptors (and are therefore termed cardioselective), whereas agonists such as salbutamol and terbutaline are more potent at ?2than ?rreceptors (and are therefore termed bronchodilators). Some tissues show a response intermediate between ?A and ?2-receptors, which may be explained by the co-existence of both types of ?-receptor. More recently, the existence of a-receptor subtypes has been recognised, based on the development of selective agents.3 Alphai-receptors are the classical post-synaptic a-receptors which mediate smooth muscle contraction, whereas a2-receptors, located presynaptically, reduce the amount of noradrenaline released from the nerve ending?that is, an autoinhibitory effect. There is some evidence that a2-receptors may also be located post-synaptically and on platelets. Prazosin is a selective antagonist of aj-receptors and the plant alkaloid yohimbine a selective antagonist of a2-receptors, whereas phento lamine is equipotent at ax and a2-receptors. Clonidine is a more potent agonist at a2 than ax-receptors.

Cost‐effectiveness of percutaneous coronary intervention with cobalt‐chromium everolimus eluting stents versus bare metal stents: Results from a patient level meta‐analysis of randomized trials

Background Second‐generation drug eluting stents (DES) may reduce costs and improve clinical outcomes compared to first‐generation DES with improved cost‐effectiveness when compared to bare metal stents (BMS). We aimed to conduct an economic evaluation of a cobalt‐chromium everolimus eluting stent (Co‐Cr EES) compared with BMS in percutaneous coronary intervention (PCI). Objective To conduct a cost‐effectiveness analysis (CEA) of a cobalt‐chromium everolimus eluting stent (Co‐Cr EES) versus BMS in PCI. Methods A Markov state transition model with a 2‐year time horizon was applied from a US Medicare setting with patients undergoing PCI with Co‐Cr EES or BMS. Baseline characteristics, treatment effects, and safety measures were taken from a patient level meta‐analysis of 5 RCTs ( n = 4,896). The base‐case analysis evaluated stent‐related outcomes; a secondary analysis considered the broader set of outcomes reported in the meta‐analysis. Results The base‐case and secondary analyses reported an additional 0.018 and 0.013 quality‐adjusted life years (QALYs) and cost savings of $236 and $288, respectively with Co‐Cr EES versus BMS. Results were robust to sensitivity analyses and were most sensitive to the price of clopidogrel. In the probabilistic sensitivity analysis, Co‐Cr EES was associated with a greater than 99% chance of being cost saving or cost effective (at a cost per QALY threshold of $50,000) versus BMS. Conclusions Using data from a recent patient level meta‐analysis and contemporary cost data, this analysis found that PCI with Co‐Cr EES is more effective and less costly than PCI with BMS. © 2016 The Authors. Catheterization and Cardiovascular Interventions Published by Wiley Periodicals, Inc.

Comparative Assessment of Predictive Performance of PRECISE-DAPT, CRUSADE, and ACUITY Scores in Risk Stratifying 30-Day Bleeding Events

Background The utility of the PRECISE-DAPT score in predicting short-term major bleeding, either alone, or in comparison with the CRUSADE and ACUITY scores, has not been investigated. This analysis compared the predictive performances of the three bleeding scores in stratifying the risk of 30-day major bleeding postpercutaneous coronary intervention in patients with dual-antiplatelet therapy. Methods In this post hoc subanalysis of the GLOBAL LEADERS trial, the primary safety objective (bleeding according to the Bleeding Academic Research Consortium [BARC] criteria [type 3 or 5]) was assessed at 30 days according to the three scores in the overall population, and in patients with acute (ACS) and chronic coronary syndrome (CCS). Results In a total of 15,968 patients, we calculated all three scores in 14,709 (92.1%). Irrespective of clinical presentation, the PRECISE-DAPT (c-statistics: 0.648, 0.653, and 0.641, respectively), CRUSADE (c-statistics: 0.641, 0.639, and 0.644, respectively), and ACUITY (c-statistics: 0.633, 0.638, and 0.623, respectively) scores were no significant between-score differences in discriminatory performance for BARC 3 or 5 bleeding up to 30 days, and similarly the PRECISE-DAPT score had a comparable discriminative capacity according to the integrated discrimination improvement when compared with the other scores. In ACS, the CRUSADE score had a poor calibration ability (Hosmer–Lemeshow goodness-of-fit [GOF] chi-square = 15.561, p = 0.049), whereas in CCS, the PRECISE-DAPT score had poor calibration (GOF chi-square = 15.758, p = 0.046). Conclusion The PRECISE-DAPT score might be clinically useful in the overall population and ACS patients for the prediction of short-term major bleeding considering its discriminative and calibration abilities.

Anticholinergic Bronchodilators

Rescue Treatment in Asthma: Response

Nonlinear behaviour of short elastic cylindrical shells under global bending

Structural Response of Wire Arc Additively Manufactured Steel Bolted Connections under Single Shear

Abstract An experimental investigation into the structural performance of wire arc additively manufactured (WAAM) steel single‐lap shear bolted connections is presented in this paper. Sixty specimens of different thicknesses, printing strategies and geometric features, including end distances and plate widths, were manufactured using steel wire of a nominal yield strength of 420 MPa and subjected to single shear lap tests. The test results are analysed while the observed failure modes, featuring shear‐out, net section tension fracture, end‐splitting, localised tearing and curl‐bearing failure, are discussed. Digital image correlation (DIC) was used for detailed monitoring and visualisation of the surface strain fields that developed during testing, providing valuable insight into the developed failure mechanisms. The experimental results, which generally followed the anticipated trends, were used to assess the applicability of current design specifications developed for conventional steel bolted connections to WAAM steel bolted connections. It was found that both the cold‐formed steel specifications (AISI S100 and AS/NZS 4600) and the structural steel specifications (AISC 360 and EN 1993‐1) yield considerable overestimations or underestimations of the test capacities, depending on the specimen geometry. Further research is underway to underpin the development of improved design provisions.

Report of an ESC-EAPCI Task Force on the evaluation and use of bioresorbable scaffolds for percutaneous coronary intervention: executive summary

A previous Task Force of the European Society of Cardiology (ESC) and European Association of Percutaneous Cardiovascular Interventions (EAPCI) provided a report on recommendations for the nonclinical and clinical evaluation of coronary stents.Following dialogue with the European Commission, the Task Force was asked to prepare an additional report on the class of devices known as bioresorbable scaffolds (BRS).Five BRS have CE-mark approval for use in Europe.Only one device -the Absorb bioresorbable vascular scaffold -has published randomized clinical trial data and this data show inferior outcomes to conventional drug-eluting stents (DES) at 2-3 years.For this reason, at present BRS should not be preferred to conventional DES in clinical practice.The Task Force recommends that new BRS devices should undergo systematic non-clinical testing according to standardized criteria prior to evaluation in clinical studies.A clinical evaluation plan should include data from a medium sized, randomized trial against DES powered for a surrogate end point of clinical efficacy.Manufacturers of successful devices receive CE-mark approval for use and must have an approved plan for a large-scale randomized clinical trial with planned long-term follow-up.

Length effects on interactive buckling in thin-walled rectangular hollow section struts

Interview: Interview with Peter Barnes

Peter Barnes first started his career in respiratory research in the late 1970s following studies at the Universities of Oxford and Cambridge. He is currently Professor of Thoracic Medicine at the National Heart and Lung Institute, Head of Respiratory Medicine at Imperial College and Honorary Consultant Physician at the Royal Brompton Hospital. He speaks to Future Medicinal Chemistry about the molecular mechanisms currently under investigation by his group, and discusses his views on the latest therapeutic breakthroughs and the future of respiratory research.

COPD and asthma: similarities and differences

Coronary fractional flow reserve measurements of a stenosed side branch: a computational study investigating the influence of the bifurcation angle

Coronary hemodynamics and physiology specific for bifurcation lesions was not well understood. To investigate the influence of the bifurcation angle on the intracoronary hemodynamics of side branch (SB) lesions computational fluid dynamics simulations were performed.A parametric model representing a left anterior descending-first diagonal coronary bifurcation lesion was created according to the literature. Diameters obeyed fractal branching laws. Proximal and distal main branch (DMB) stenoses were both set at 60 %. We varied the distal bifurcation angles (40°, 55°, and 70°), the flow splits to the DMB and SB (55 %:45 %, 65 %:35 %, and 75 %:25 %), and the SB stenoses (40, 60, and 80 %), resulting in 27 simulations. Fractional flow reserve, defined as the ratio between the mean distal stenosis and mean aortic pressure during maximal hyperemia, was calculated for the DMB and SB (FFRSB) for all simulations.The largest differences in FFRSB comparing the largest and smallest bifurcation angles were 0.02 (in cases with 40 % SB stenosis, irrespective of the assumed flow split) and 0.05 (in cases with 60 % SB stenosis, flow split 55 %:45 %). When the SB stenosis was 80 %, the difference in FFRSB between the largest and smallest bifurcation angle was 0.33 (flow split 55 %:45 %). By describing the ΔPSB-QSB relationship using a quadratic curve for cases with 80 % SB stenosis, we found that the curve was steeper (i.e. higher flow resistance) when bifurcation angle increases (ΔP = 0.451*Q + 0.010*Q (2) and ΔP = 0.687*Q + 0.017*Q (2) for 40° and 70° bifurcation angle, respectively). Our analyses revealed complex hemodynamics in all cases with evident counter-rotating helical flow structures. Larger bifurcation angles resulted in more pronounced helical flow structures (i.e. higher helicity intensity), when 60 or 80 % SB stenoses were present. A good correlation (R(2) = 0.80) between the SB pressure drop and helicity intensity was also found.Our analyses showed that, in bifurcation lesions with 60 % MB stenosis and 80 % SB stenosis, SB pressure drop is higher for larger bifurcation angles suggesting higher flow resistance (i.e. curves describing the ΔPSB-QSB relationship being steeper). When the SB stenosis is mild (40 %) or moderate (60 %), SB resistance is minimally influenced by the bifurcation angle, with differences not being clinically meaningful. Our findings also highlighted the complex interplay between anatomy, pressure drops, and blood flow helicity in bifurcations.

The load-bearing duct: biomimicry in structural design

The philosophical aspects of applying the principles of biomimicry are explored in a case study of structural design. Integrating structural engineering with services engineering can be regarded, to some extent, as taking principles from biological systems and applying them to large-scale conceptual design. The end-product discussed herein a so-called load-bearing duct, a functional naturally ventilated multi-storey office building that takes the applied loading efficiently both structurally and cost-effectively giving it the potential to be sustainable throughout its design life.

Mid-IR Spectrum of Supernova SN 2014J in M82