Publications

1. Prostaglandins are important regulatory mediators of cardiovascular and pulmonary functions which may become disordered in patients with sepsis. The mechanisms controlling their synthesis and release under these circumstances remain unclear. Cyclo-oxygenase (COX, prostaglandin G/H synthase) is a key enzyme in prostaglandin synthesis and has two isoforms (COX-1 and COX-2). COX-1 is constitutively expressed and is probably responsible for prostaglandin release under physiological conditions, whereas COX-2 is expressed at high levels upon induction. 2. We investigated the effect of lipopolysaccharide treatment in vivo on differential COX-1 and COX-2 mRNA expression in the rat. 3. The 2.8 kb COX-1 message was detected in all lungs and seven hearts of eight control rats. In lipopolysaccharide-treated animals, COX-1 expression was reduced by approximately 5-fold in lungs and 2-fold in hearts as quantified by densitometry. In parallel, a marked upregulation of COX-2 mRNA expression was observed. The 4.4 kb COX-2 transcript was absent or expressed at low level in control lungs and hearts, but was increased by approximately 7- and 12-fold in lipopolysaccharide-treated lungs and hearts respectively. Neither the down-regulation of COX-1 nor the upregulation of COX-2 mRNA induced by lipopolysaccharide was significantly affected by pretreatment with dexamethasone in lung and heart, although expression of inducible nitric oxide synthase, induced by lipopolysaccharide, was markedly inhibited in the same tissues. 4. The down-regulation of COX-1 and upregulation of COX-2 may contribute to the multi-organ failure seen in sepsis.

Background— Pathology studies on fatal cases of very late stent thrombosis have described incomplete neointimal coverage as common substrate, in some cases appearing at side-branch struts. Intravascular ultrasound studies have described the association between incomplete stent apposition (ISA) and stent thrombosis, but the mechanism explaining this association remains unclear. Whether the neointimal coverage of nonapposed side-branch and ISA struts is delayed with respect to well-apposed struts is unknown. Methods and Results— Optical coherence tomography studies from 178 stents implanted in 99 patients from 2 randomized trials were analyzed at 9 to 13 months of follow-up. The sample included 38 sirolimus-eluting, 33 biolimus-eluting, 57 everolimus-eluting, and 50 zotarolimus-eluting stents. Optical coherence tomography coverage of nonapposed side-branch and ISA struts was compared with well-apposed struts of the same stent by statistical pooled analysis with a random-effects model. A total of 34 120 struts were analyzed. The risk ratio of delayed coverage was 9.00 (95% confidence interval, 6.58 to 12.32) for nonapposed side-branch versus well-apposed struts, 9.10 (95% confidence interval, 7.34 to 11.28) for ISA versus well-apposed struts, and 1.73 (95% confidence interval, 1.34 to 2.23) for ISA versus nonapposed side-branch struts. Heterogeneity of the effect was observed in the comparison of ISA versus well-apposed struts (H=1.27; I 2 =38.40) but not in the other comparisons. Conclusions— Coverage of ISA and nonapposed side-branch struts is delayed with respect to well-apposed struts in drug-eluting stents, as assessed by optical coherence tomography. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00389220, NCT00617084.

Introduction: Cyclic plaque structural stress has been hypothesized as a mechanism for plaque fatigue and eventually plaque rupture. A novel approach to derive cyclic plaque stress in vivo from optical coherence tomography (OCT) is hereby developed. Materials and Methods: All intermediate lesions from a previous OCT study were enrolled. OCT cross-sections at representative positions within each lesion were selected for plaque stress analysis. Detailed plaque morphology, including plaque composition, lumen and internal elastic lamina contours, were automatically delineated. OCT-derived vessel and plaque morphology were included in a 2-dimensional finite element analysis, loaded with patient-specific intracoronary pressure tracing data, to calculate the changes in plaque structural stress (ΔPSS) on vessel wall over the cardiac cycle. Results: A total of 50 lesions from 41 vessels were analyzed. A significant ΔPSS gradient was observed across the plaque, being maximal at the proximal shoulder (45.7 [32.3, 78.6] kPa), intermediate at minimal lumen area (MLA) (39.0 [30.8, 69.1] kPa) and minimal at the distal shoulder (35.1 [28.2, 72.3] kPa; p = 0.046). The presence of lipidic plaques were observed in 82% of the diseased segments. Larger relative lumen deformation and ΔPSS were observed in diseased segments, compared with normal segments (percent diameter change: 8.2 ± 4.2% vs. 6.3 ± 2.3%, p = 0.04; ΔPSS: 59.3 ± 48.2 kPa vs. 27.5 ± 8.2 kPa, p < 0.001). ΔPSS was positively correlated with plaque burden (r = 0.37, p < 0.001) and negatively correlated with fibrous cap thickness (r = -0.25, p = 0.004). Conclusions: ΔPSS provides a feasible method for assessing plaque biomechanics in vivo from OCT images, consistent with previous biomechanical and clinical studies based on different methodologies. Larger ΔPSS at proximal shoulder and MLA indicates the critical sites for future biomechanical assessment.

Treatment of coronary bifurcation lesions remains an ongoing challenge for interventional cardiologists. Stenting of coronary bifurcations carries higher risk for in-stent restenosis, stent thrombosis, and recurrent clinical events. This review summarizes the current evidence regarding application and use of biomechanical modeling in the study of stent properties, local flow dynamics, and outcomes after percutaneous coronary interventions in bifurcation lesions. Biomechanical modeling of bifurcation stenting involves computational simulations and in vitro bench testing using subject-specific arterial geometries obtained from in vivo imaging. Biomechanical modeling has the potential to optimize stenting strategies and stent design, thereby reducing adverse outcomes. Large-scale clinical studies are needed to establish the translation of pre-clinical findings to the clinical arena.

<b>Background:</b> In COPD, senescence of small airway fibroblasts (SAF) is closely related to the oxidative imbalance. The SAF secretome is characterised by a pro-inflammatory pattern that may drive small airway fibrosis. Molecular events leading to senescence are not clearly defined but <i>in vitro</i> studies suggest endoplasmic reticulum (ER) stress may be a key event in COPD pathogenesis. <b>Aim:</b> Assess the role of ER stress in SAF senescence. <b>Methods:</b> SAF were isolated from COPD lung tissue and age-matched non-smokers (NS) (n=6). Senescence (p21, γ-H2AX) and ER stress markers (p-IRE1, p-PERK, p-eIF2α, XBP1) were evaluated by Western blot. CXCL-8 and PAI-1 release were measured by ELISA. Co-expression of XBP1 and p21 was studied by immunochemistry. To link ER stress and senescence, SAF were exposed to ISRIB, a selective inhibitor of P-eIF2α and modification of senescence markers as well as the level of antioxidant markers (NRF2 stabilisation, <i>SOD3</i> expression, catalase activity) were evaluated. <b>Results:</b> At baseline, the expression of p21, γ-H2AX and CXCL-8 were increased in COPD SAF compared to NS (2.6, 3.2 and 2.7-fold-change). Phosphorylation of PERK and eIF2α was only observed in COPD SAF. XBP1 and p21 were co-expressed in the nucleus of ~35% of COPD SAF. ISRIB reduced expression of p21 and γ-H2AX (47% and 63% decrease, p&lt;0.01) as well as CXCL-8 and PAI-1 in COPD SAF supernatant compared to non-treated cells (29% and 22% decrease, p&lt;0.05). ISRIB also reduced NRF2 protein, <i>SOD3</i> mRNA expression and catalase activity in COPD SAF (47%, 53% and 63% decrease). <b>Conclusion:</b> These data imply a role for ER stress in SAF senescence in COPD and suggest p-eIF2α as a new target for therapeutic strategy.

No abstract is provided for this article.

The SYNTAX score II (SSII) was developed from the SYNTAX trial to predict the 4-year all-cause mortality after left main or multivessel disease revascularization and to facilitate the decision-making process. The SSII provides the following treatment recommendations: (i) coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) (equipoise risk), (ii) CABG preferred (excessive risk for PCI) or (iii) PCI preferred (excessive risk for CABG). We sought to externally validate SSII and to investigate the impact of not abiding by the SSII recommendations in the randomized EXCEL trial of PCI versus CABG for left main disease.The calibration plot of predicted versus observed 4-year mortality was constructed from individual values of SSII in EXCEL. To assess overestimation versus underestimation of predicted mortality risk, an optimal fit regression line with slope and intercept was determined. Prospective treatment recommendations based on SSII were compared with actual treatments and all-cause mortality at 4 years.SSII variables were available from EXCEL trial in 1807/1905 (95%) patients. For the entire cohort, discrimination was possibly helpful (C statistic = 0.670). SSII-predicted all-cause mortality at 4 years overestimated the observed mortality, particularly in the highest-risk percentiles, as confirmed by the fit regression line [intercept 2.37 (1.51-3.24), P = 0.003; slope 0.67 (0.61-0.74), P < 0.001]. When the SSII-recommended treatment was CABG, randomized EXCEL patients treated with PCI had a trend towards higher mortality compared with those treated with CABG (14.1% vs 5.3%, P = 0.07) in the as-treat population. In the intention-to-treat population, patients randomized to PCI had higher mortality compared with those randomized to CABG (15.1% vs 4.1%, P = 0.02), when SSII recommended CABG.In the EXCEL trial of patients with left main disease, the SSII-predicted 4-year mortality overestimated the 4-year observed mortality with a possibly helpful discrimination. Non-compliance with SSII CABG treatment recommendations (i.e. randomized to PCI) was associated with higher 4-year all-cause mortality.

Current guidelines recommend a single inhaler maintenance and reliever therapy (SMART) regimen for moderate to severe asthma. However, evidence for the inhaled corticosteroid plus fast-onset-acting β2-agonist (ICS/FABA) as reliever therapy in management of intermittent and mild asthma patients is lacking. To systematically explore efficacy and safety of the proof-of-concept of the ICS plus FABA regimen in a single inhaler as reliever therapy across children and adults with intermittent and mild persistent asthma. We searched online bibliographic databases for randomized controlled trials (RCTs) involving the as-needed use of ICS/FABA as monotherapy in intermittent or mild asthma patients. The primary outcomes were exacerbations and the hazard ratio (HR) of the time to first exacerbation. Six RCTs (n = 1300) met the inclusion criteria. Compared with the as-needed FABA regimen, the as-needed use of ICS/FABA as monotherapy statistically reduced exacerbations (RR = 0.56, P = 0.001). Compared with regular ICS regimen, the as-needed ICS/FABA therapy had slightly higher risk of exacerbations (RR = 1.39, P = 0.011). The HR for time to first exacerbations in the ICS/FABA regimen was significant lower when compared with FABA regimen (HR = 0.52, P = 0.002) but had no difference when compared with ICS regimen (HR = 1.30, P = 0.286). The corticosteroid exposure in the daily ICS regimen was 2- to 5-fold compared with as-needed use of ICS/FABA regimen. Our analysis shows that the ICS/FABA as a symptom-driven therapy may be a promising alternative regimen for the patients with intermittent or mild asthma, but it needs further real-world RCTs to confirm these findings.

To assess the impact of the SYNTAX scores I and II in outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) for patients with diabetes and multivessel disease (MVD).We performed a patient-level pooled analysis of three large randomized trials of patients with MVD. The impact of coronary anatomic complexity as measured by the SYNTAX score in the differences in outcomes following PCI and CABG was assessed at a median follow-up of 5 years. We also assessed the performance of the SYNTAX II score model in patients with and without diabetes. From the 3280 patients enrolled in the three trials, a total of 1068 (32.6%) had diabetes. The rate of the composite of death, myocardial infarction (MI), or stroke was similar in the PCI and CABG arms in patients with low-intermediate (≤32) SYNTAX scores (15.1% vs. 14.9%, respectively; P = 0.93) while it was significantly higher in the PCI arm in patients with high (≥33) SYNTAX scores (24.5% vs. 13.2%, respectively; P = 0.018). The SYNTAX score II showed good calibration and moderate discrimination ability in patients with diabetes (c-index = 0.68) as well as in those without (c-index = 0.67).Differences in 5 years outcomes following PCI and CABG for patients with MVD and diabetes were influenced by anatomic complexity as measured by the SYNTAX score. The SYNTAX score II mortality prediction model showed similar performance regardless of the diabetes status.

• Hybrid X-joints with conventional CHS tubes and optimised DED-Arc nodes have been proposed. • A design-to-manufacture framework, encompassing topology optimisation and reengineering for manufacturability, has been developed. • Conventional and hybrid joint specimens have been tested under different chord-brace load combinations. • Hybrid joints with 3D-printed components showed disproportionate increases in capacity and stiffness over conventionally-welded joints. Relative to conventional formative or subtractive manufacturing techniques, additive manufacturing (AM) offers increased geometric freedom, and the potential for enhanced structural efficiency and greater automation. Hybrid construction, which combines conventionally produced structural components with AM parts, is considered the most practical way to deploy metal AM in construction. This study aims to develop an optimisation methodology for hybrid tubular joints, incorporating topology optimisation and printability considerations. The studied tubular joints have an X-shaped configuration, comprising conventionally produced circular hollow section (CHS) members and wire-arc directed energy deposited (DED-Arc) nodes. The DED-Arc nodes were topology optimised, with performance and printability enhanced by imposing stress and overhang constraints, preventing the formation of overly slender elements and excessive overhang angles. The printability was further improved by manual adjustments to satisfy manufacturing requirements. The structural performance of the hybrid joints, including the initial stiffness, ultimate load-bearing capacity, ductility and material efficiency, was assessed through geometrically and materially nonlinear numerical analyses and physical experiments on nine printed joints; five conventional X-joints were also fabricated and tested to provide benchmark results. Overall, the hybrid joints exhibited up to about 80 % higher initial stiffness, 20 % higher load-bearing capacity and 100 % higher capacity-to-mass ratios under biaxial compression compared with the conventionally produced joints, indicating markedly enhanced structural efficiency.

The introduction of biologics for the treatment of severe upper and lower (type 2) airway inflammation has been a gamechanger in the management of these diseases. Biologics are injectable medications targeting different molecules relevant in (type 2) inflammation in patients with severe (type 2) airway diseases, like asthma, eosinophilic chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis (CRS) and those who remain uncontrolled despite regular treatment (1-3). After the phase 3 trials, showing significant impact on symptoms, quality of life and interventions like surgery (for the upper airways) and exacerbations needing hospitalisation (for the lower airways), biologics are now used in daily practice in many parts of the world (4, 5). This pocket guide is aimed at all specialists treating adult patients with severe airway disease.