Publications

We determined whether the loop diuretic, piretanide, had a similar inhibitory action against sodium metabisulphite (MBS)-induced bronchoconstriction in asthmatic subjects as frusemide and, if so, its duration of action. In the first study, we compared the effect of inhaled placebo, piretanide (24 mg), or frusemide (40 mg), on the provocative concentration of MBS needed to cause a 20% fall in baseline forced expiratory volume in one second (FEV1) (PC20MBS) in 12 mild asthmatic subjects before, immediately after, and at 1.5, 3, 6, and 24 h, after inhalation. Both piretanide and frusemide induced a significant diuresis lasting at least 24 h. Frusemide caused a mean 3.8 fold (95% confidence interval: 2.3-6.3 fold), piretanide a 2.5 fold (1.8-3.4 fold) and placebo a 1.7 fold (1.5-1.9 fold) increase in PC20MBS. The effects of frusemide and piretanide were significantly greater than that of placebo. At later time points, tachyphylaxis to the bronchoconstrictor effects of MBS was observed during the placebo limb. In the second study, we measured PC20MBS at 90 min after inhalation of either placebo, piretanide (24 mg), or frusemide (40 mg). No significant difference in PC20MBS was observed. We conclude that piretanide in addition to frusemide significantly inhibits MBS-induced bronchoconstriction and that this action is short-lived over less than 90 min. Frusemide was more potent in inhibiting MBS-induced bronchoconstriction despite causing a smaller diuretic effect than piretanide. The basic mechanism of action of the loop diuretics in the airways remains unclear.

No abstract is provided for this article.

Background The optimal duration of dual antiplatelet therapy after coronary drug-eluting stent placement in adults with stable coronary artery disease (SCAD) versus acute coronary syndromes (ACS) remains uncertain. Methods and Results This was a prespecified subgroup analysis of the GLOBAL LEADERS trial. Participants were randomly assigned 1:1 to the experimental or reference strategy, stratified by ACS (experimental, n=3750; reference, n=3737) versus SCAD (experimental, n=4230; reference, n=4251). The experimental strategy was 75 to 100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy. The reference strategy was 75 to 100 mg aspirin daily plus either 75 mg clopidogrel daily (for SCAD) or 90 mg ticagrelor twice daily (for ACS) for 12 months, followed by aspirin monotherapy for 12 months. The primary end point at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction. The key secondary safety end point was site-reported Bleeding Academic Research Consortium grade 3 or 5 bleeding. The primary end point occurred in 147 (3.92%) versus 169 (4.52%) patients with ACS (rate ratio [RR], 0.86; 95% CI, 0.69-1.08; P=0.189), and in 157 (3.71%) versus 180 (4.23%) patients with SCAD (RR, 0.87; 95% CI, 0.71-1.08; P=0.221) with experimental and reference strategy, respectively (P-interaction=0.926). Bleeding Academic Research Consortium grade 3 or 5 bleeding occurred in 73 (1.95%) versus 100 (2.68%) patients with ACS (RR, 0.73; 95% CI, 0.54-0.98; P=0.037), and in 90 (2.13%) versus 69 (1.62%) patients with SCAD (RR, 1.32; 95% CI, 0.97-1.81; P=0.081; P-interaction=0.007). Conclusions While there was no evidence for differences in efficacy between treatment strategies by subgroup, the experimental strategy appeared to reduce bleeding risk in patients with ACS but not in patients with SCAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.

The data available in this article include 3D mechanical designs used for the computer-aided fabrication of metal honeycombs produced by additive manufacturing and studied in [1]. In addition, the force-displacement data utilized to evaluate the mechanical performance of the metal used in this study are available via the digital image correlation technique. Further, the surface features obtained using 3D scanning microscopy of the fabricated parts are available as raw files and processed data. Finally, the impact test data are presented as high-frame-rate videos showing the time-displacement numerical values. This information has been provided in this data article to complement the related research, serve as a guide for future studies, and ensure the data's repeatability and reliability of the related research paper. The research article [1] investigates the mechanical performance and failure mechanism of additively manufactured metallic honeycombs under various scenarios, from quasi-static to dynamic loading. It also investigates the design optimization of these energy-absorbing hollow structures by comparing hollow structures made of three distinct novel cell designs (triangular, diamond-shaped, and diamond-shaped with curved walls) with traditional honeycombs made of hexagonal cells.

The Valve Academic Research Consortium (VARC) endpoint definitions were established to standardise the reporting of clinical outcomes following transcatheter aortic valve implantation (TAVI). It remains unclear, however, to what extent and in which manner these definitions are applied. Therefore, we sought to investigate the utilisation and adherence to VARC guidelines since their introduction in 2011 across peerreviewed TAVI-related publications.We performed a systematic literature review to identify TAVI-related manuscripts published between February 2011 and February 2014. Manuscripts were categorised into three groups: a "compliant" group of manuscripts using only VARC-defined endpoints, a "non-compliant" group of manu scripts with only non-VARC-defined endpoints, and a "mixed compliant" group of manuscripts with both VARC- and non-VARC-defined endpoints. Multivariate analyses were performed to identify predictors of VARC use. Among 5,023 published manuscripts, 498 were included in the final analysis. At least one VARC definition was used in 275 (54%), while 223 (43%) did not use any VARC definitions. After publication of the first VARC manuscript (VARC-1, January 2011), VARC use increased from 31% (n=15) at six months to 69% (n=84) at 36 months. Following the publication of VARC-2 (October 2012), VARC-1 use declined (from 58% [n=47] to 36% [n=24]), while VARC-2 use increased from 4% (n=3) at six months to 35% (n=23) at 18 months. Of the manuscripts using VARC, 49 (10%) were classified as compliant and 226 (46%) as mixed compliant. The following endpoints were more often defined using VARC vs. non-VARC: myocardial infarction (64% vs. 36%); stroke (56% vs. 44%); bleeding (79% vs. 21%); vascular complications (70% vs. 30%); acute kidney injury (63% vs. 37%); reintervention (67% vs. 33%); and composite endpoints (52% vs. 48%). Mortality, valve dysfunction, TAVI-related complications, and quality of life were more often defined using non-VARC criteria.Implementation of VARC criteria in peer-reviewed manuscripts has increased over time. There remain, however, a considerable number (43%) of publications that do not report outcomes according to VARC. These data will inform the future development of VARC criteria.

Aims:The aim of this substudy was to determine the five-year correlates of non-TV-related adverse events (AE) in STEMI patients included in the EXAMINATION trial. Methods and results:The EXAMINATION trial randomised 1,498 STEMI patients to bare metal or everolimus-eluting stent implantation.In this substudy, patients were analysed according to non-TV-related AE, defined as the composite of either non-TV revascularisation (non-TVR) or non-TV-related myocardial infarction (MI).At five-year follow-up, 125 patients (8.3%) exhibited 136 non-TV-related AE (124 [8.3%] non-TVR, 12 [0.8%]non-TV-related MI), accounting for 47.1% of 289 non-fatal cardiac events overall.These patients had a higher incidence of diabetes mellitus (p<0.001),arterial hypertension (p=0.032),previous MI (p=0.073),multivessel disease (p<0.001), and incomplete revascularisation (p=0.049), and a lower rate of ST-segment resolution >70% (p=0.042) as compared to the rest.At Cox analysis, previous MI (HR 1.872, 95% CI: 1.004-3.489;p=0.048), incomplete revascularisation (HR 1.746, 95% CI: 1.029-2.963;p=0.039) and diabetes (HR 1.942, 95% CI: 1.292-2.919;p=0.001) were independent correlates of non-TVrelated AE. Conclusions:In STEMI patients undergoing primary percutaneous coronary intervention, previous MI, incomplete revascularisation and diabetes resulted in being independent correlates of five-year non-TVrelated AE.

Aims: Mucus expectoration is a common feature of chronic obstructive pulmonary disease (COPD). MUC5AC and MUC5B, the major mucins, are released predominantly from submucosal glands in the central airways. The aim was to investigate gland size and MUC5AC and MUC5B expression in bronchial rings from smokers with COPD compared with control groups. Methods and results: Bronchial rings from 10 non‐smoking subjects, 20 smokers with normal lung function and 20 smokers with COPD were studied. Periodic acid–Schiff (PAS) and Alcian blue histochemistry and MUC5AC and MUC5B immunohistochemistry followed by quantification of the immunoreactive area was performed. The area occupied by MUC5AC+ cells in bronchial submucosal glands was increased in COPD [20% (5.5–31.7%) gland area] compared with smokers with normal lung function [9.5% (2.5–17.5%); P &lt; 0.05] and non‐smoking subjects [2% (0.4–6.2%); P &lt; 0.05]. The area occupied by MUC5AC+ cells in the bronchial surface epithelium was also increased in smokers (with/without COPD) [73.5% (25–92%) epithelial area] compared with non‐smoking subjects [15% (2.7–32%); P &lt; 0.01]. Gland size, PAS, Alcian blue staining and MUC5B expression were not significantly different among groups. MUC5AC expression correlated with the degree of airflow obstruction. MUC5AC and MUC5B expression correlated with pack‐years. Conclusions: COPD is associated with increased MUC5AC expression in submucosal glands, indicating that MUC5AC may be involved in the pathophysiology of the disease.

The incidence of chronic obstructive pulmonary disease (COPD) is increasing throughout the world. Much less is known about the pathogenesis of COPD than that of asthma and there is little response to current therapy. Most patients with COPD have acquired their lung disease through smoking cigarettes, and the major step in management is to minimise further damage by stopping this habit. A number of therapies are being developed for the treatment of COPD; including new bronchodilators such as tiotropium bromide, agents to block inflammation induced by neutrophils and macrophages, as well as strategies to combat proteases and oxidants. The long-term goal is to provide therapy that retards the accelerated loss of lung function occurring in COPD. Development of novel therapies for COPD requires reliable Phase II decision making before entering large scale Phase III studies. The patient with COPD is often overlooked compared to their asthmatic counterpart, who benefit from an urgent need to identify novel targets and better therapy.

No abstract is provided for this article.

We have investigated the relationship between changes in T-cell activation in the bronchial mucosa, airway responsiveness and eosinophilic inflammation in sensitized Brown-Norway rats exposed to ovalbumin (OVA). Rats sensitized intraperitoneally with OVA and exposed to OVA aerosol 21 days later showed an enhanced increase in lung resistance (RNL) to acetylcholine (P < 0.05), and a significant increase in the number of eosinophils, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BAL) (P < 0.05), compared with sensitized but saline-exposed controls. There was a significant increase in cells expressing the T-cell activation marker CD25 (P < 0.05) and the numbers of CD8+ T cells (P < 0.05), but not in the numbers of CD2+ and CD4+ cells. Eosinophil counts in airway submucosal tissue, as assessed by staining with BMK-13; a monoclonal antibody that binds to eosinophil major basic protein (MBP), were increased in rats receiving sensitization and exposure to OVA compared with naive controls (P < 0.002). There were significant positive correlations between the increase in RL to acetylcholine and the numbers of CD25+ (r = 0.92, P < 0.001), CD4+ (r = 0.77, P < 0.05), CD8+ (r = 0.71, P < 0.05) and MBP+ (r = 0.72, P < 0.03) cells in the OVA-sensitized and exposed group, but not in saline-exposed or naive animals. The number of MBP+ cells also correlated with CD25 expression (r = 0.71, P < 0.05). We conclude that airway hyper-responsiveness and inflammatory cell infiltration caused by OVA exposure of sensitized animals is associated with the presence of activated T cells in the airway mucosa. CD8+ T cells may play a role in the regulation of events leading to eosinophil inflammation and airway hyper-responsiveness.

<b>Introduction:</b> Exacerbations can occur even in mild asthma. The risk of exacerbations can be reduced with as-needed budesonide/formoterol (BUD/FORM) or BUD maintenance+as-needed terbutaline vs as-needed terbutaline alone (SYGMA 1; NCT02149199). <b>Aims and Objectives:</b> This <i>post-hoc</i> analysis of SYGMA 1 examined the NNT with as-needed BUD/FORM or BUD maintenance to have an additional patient (pt) free from a severe or moderate/severe exacerbation over 1 year. <b>Methods:</b> SYGMA 1 was a 52-week, double-blind trial of pts with mild asthma randomised to placebo bid+terbutaline 0.5mg as needed (n=1277), placebo bid+as-needed BUD/FORM 200/6µg (n=1277) or BUD 200µg bid+as-needed terbutaline (n=1282). The NNT for as-needed BUD/FORM and BUD maintenance vs as-needed terbutaline after 1 year of treatment were compared. <b>Results:</b> When compared with as-needed terbutaline, treating 16 pts with as-needed BUD/FORM, or 17 pts with maintenance BUD, for 1 year, prevented 1 additional pt having a severe exacerbation, reducing to 9 and 10 pts, respectively, for moderate/severe exacerbations (Table). <b>Conclusions:</b> The numbers needed to treat for a year with as-needed BUD/FORM to prevent one pt having a severe or moderate/severe exacerbation vs as-needed terbutaline were comparable to BUD maintenance, regardless of pre-study treatment, supporting a role for these therapies in mild asthma.

Exhaled nitric oxide (ENO), a marker of inflammation in airway diseases is decreased in cystic fibrosis (CF) patients, perhaps because nitric oxide (NO) is metabolized to oxidative end-products. A stable product, 3-nitrotyrosine, may indicate local formation of reactive nitrogen species. Whether NO metabolites in exhaled breath condensate may be increased in CF patients was investigated. The fractional concentration of ENO ( F eno ), nitrotyrosine and oxides of nitrogen in exhaled breath condensate from 36 stable CF patients were compared to 14 normal subjects using an enzyme immunoassay and fluorescence assay. Nitrotyrosine levels in breath condensate were increased significantly in stable CF patients, compared with normal subjects (25.3±1.5 versus 6.3±0.8 ng·mL −1 , p&lt;0.0001). There was an inverse correlation between the levels of nitrotyrosine and the severity of lung disease. F eno levels were significantly lower in CF patients than in normal subjects (4.4±0.3 versus 5.6±0.4 (parts per billion), p&lt;0.05). No correlation was found between nitrotyrosine and F eno levels in CF. There was no significant difference in the levels of nitrite and nitrate between CF patients and normals. The elevation in nitrotyrosine may reflect increased formation of reactive nitrogen species such as peroxynitrite or direct nitration by granulocyte peroxidases, indicating increased oxidative stress in airways of cystic fibrosis patients.