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The aim of the study was to evaluate the effect of strut protrusion (SP) on wall shear stress (WSS) and neointimal growth (NG) one and five years after implantation of an Absorb bioresorbable vascular scaffold.Eight patients were selected from a first-in-man study. Following three-dimensional (3D) reconstruction of coronaries, WSS was quantified using Newtonian steady-flow simulation in each cross-section at 5° subunits (sectors) of the circumferential luminal surface. At one year, neointimal thickness (NT) was measured by optical coherence tomography (OCT) and correlated to WSS and SP post procedure. Median SP was 112.9 (90.8, 133.1) µm post implantation. Post procedure, a logarithmic inverse relationship between SP and post-implantation WSS (r=-0.425, p<0.001; correlation coefficients in a range from -0.143 to -0.553) was observed, whereas a correlation between baseline logarithm-transformed WSS (log-WSS) and NT (r=-0.451, p<0.001; correlation coefficients ranged from -0.140 to -0.662) was documented at one year. Mixed-effects analysis between baseline log-WSS and NT at follow-up yielded a slope of 30 µm/ln Pascal (Pa) and a y-intercept of 98 µm. As a result of NG, median flow area decreased from 6.91 (6.53, 7.48) mm2 post implantation to 5.65 (5.47, 6.02) mm2 at one-year follow-up (p=0.01) and to 5.75±1.37 mm2 at five-year follow-up (p=0.024). However, the vessel surface exposed to low WSS (<1 Pa) decreased significantly post procedure (42%) to one year (35.9%) and five years (15.2%) (p-overall <0.0001).SP disturbs laminar flow, creates regions of low WSS (<1.0 Pa) that are associated with NG and lumen area reduction. Low WSS post implantation reduced significantly at long-term follow-up. Thin struts with effective embedment would substantially reduce NG and accelerate homogenisation of WSS towards physiological values.

Over 5.4 million adults receive treatment for asthma in the UK. Asthma is a chronic allergic disorder characterised by chronic inflammation. Type 2 T helper (T H 2) are an important component in the development of the asthma and the response to allergens, producing the cytokines interleukin (IL) -4 and IL-13. In T H 2 cells, production of the cytokines IL-4, IL-5, and IL-13 in a co-ordinate manner. Th2 cytokine expression is controlled by cooperation between transcription factors GATA-3 and Nuclear factor of activated T-cells -1 (NFAT1). The genes encoding these cytokines are located together the same chromosomal region, 5q31.1 in humans. We have investigated the co-ordinated expression of IL4 and IL13 in the T H 2 model cell line HUT78. Using chromatin immunoprecipitation (ChIP) and re-ChIP analysis we have shown that in HUT78 cells GATA-3 is associated with the IL4 and IL13 promoter regions. Additionally, following stimulation CD3/28 antibodies NFAT1 rapidly translocates to the nucleus and becomes associated with the promoter regions and GATA3. Finally, using Chromatin Conformation Capture (3C) we demonstrate looping of DNA at the IL4 and IL13 promoters to bring them into close proximity with each other. This suggests that the formation of a transcriptional hub under the control of GATA-3 and NF-AT drives co-ordinate T H 2 cytokine production.

Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms and clinical consequences remain incompletely defined.Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences, and potential for therapeutic manipulation of these defects.Methods: We isolated AMs and monocyte-derived macrophages (MDMs) from a cohort of patients with COPD and control subjects within the Medical Research Council COPDMAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.Measurements and Main Results: COPD AMs and MDMs have impaired phagocytosis of Streptococcus pneumoniae. COPD AMs have a selective defect in uptake of opsonized bacteria, despite the presence of antipneumococcal antibodies in BAL, not observed in MDMs or healthy donor AMs. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria, and health-related quality-of-life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AMs was not reduced. COPD AMs have reduced transcriptional responses to opsonized bacteria, such as cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2 (nuclear factor erythroid 2–related factor 2)-regulated genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and compound 7) reverse defects in phagocytosis of S. pneumoniae and nontypeable Haemophilus influenzae by COPD AMs.Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AMs, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.

<h3></h3> We present a 50-year-old lady with 6-months’ history of episodes of feeling weak with legs giving way triggered by sudden change of position or head-turning and no loss of consciousness. She had left tinnitus for years and one year worsening migraines with fortification spectra, visual blurring, and vertigo. ENT made a diagnosis of vestibular migraines. Her neurological examination was normal and attempted provocation of attacks with sudden changes in position and Dix-Hallpike was unsuccessful. Brain MRI revealed a large lesion obstructing foramina of Luschka-Magendie giving rise to obstructive hydrocephalus. Neuro-ophthalmology review showed bilateral papilledema and no evidence of Parinaud’s syndrome (no convergence retraction nystagmus or tectal pupils). Tumour biomarkers (bHCG-AFP-AlkPh-LDH) and body CT scan were normal. She underwent urgent CSF diversion. MDTs confirmed radiological diagnosis of epidermoid cyst awaiting debulking. Episodic headaches/vertigo with head-turning are described in Bruns syndrome manifesting as abrupt headaches, vertigo, vomiting provoked by changes in head position due to intermittent obstructive hydrocephalous (mass lesion and ball-valve mechanism). We propose patient’s acute episodes of lower limb weakness were similar phenomenon highlighting importance of imaging in stereotypical attacks after triggers.

GATA-3 plays a critical role in allergic diseases by regulating the release of cytokines from Th2 lymphocytes. However, the molecular mechanisms involved in the regulation of GATA-3 in human T lymphocytes are not yet understood. Using small interfering RNA to knock down GATA-3, we have demonstrated its critical role in regulating IL-4, IL-5, and IL-13 release from a human T cell line. Specific stimulation of T lymphocytes by costimulation of CD3 and CD28 to mimic activation by APCs induces translocation of GATA-3 from the cytoplasm to the nucleus, with binding to the promoter region of Th2 cytokine genes, as determined by chromatin immunoprecipitation. GATA-3 nuclear translocation is dependent on its phosphorylation on serine residues by p38 MAPK, which facilitates interaction with the nuclear transporter protein importin-alpha. This provides a means whereby allergen exposure leads to the expression of Th2 cytokines, and this novel mechanism may provide new approaches to treating allergic diseases.

Transcatheter aortic valve replacement (TAVR) is a recommended intervention for selected population with severe aortic stenosis (AS). Bicuspid aortic valve (BAV) anatomy has been categorized as an unfavorable anatomy for TAVR due to multiple considerations as exclusion from randomized trials in addition to the challenging and unpredictable anatomy. The anatomical constraints of BAV include the large anatomy of the annulus, sinus of Valsalva, and aorta (aortopathy), in addition to significant calcifications of the device landing zone. Most commercial transcatheter heart valves (THV) have upper dimension limits of the annulus and area in which the device can be implanted safely without significant oversizing. Myval-XL THVs (Meril Life Sciences Pvt. Ltd., India) are balloon-expandable valves (BEV) that have been developed with two new sizes, 30.5 and 32 mm, aiming to treat patients with large annulus dimensions and that exceed the upper limit of an ordinary device's sizing matrix. This case series report describes TAVR using the XL-Myval 32 mm THV in three European patients with symptomatic severe bicuspid aortic stenosis with significant calcifications and large annular dimensions exceeding the limits of the other THVs.

Abstract The primary aim of the present study is to explore the use, advantages and potential of two advanced data acquisition techniques – 3D scanning and digital image correlation (DIC), in the testing of metallic structures. 3D scanning is a novel method for capturing the full outer geometry of an object. It is being increasingly used in experimental studies for the determination of dimensional parameters and the characterisation of local and global imperfections, examples of which are given and discussed. Digital image correlation (DIC) is a rapidly evolving technology for the full‐field measurement of the displacements and strains over a surface. A brief introduction to DIC and its workflow is firstly provided. Example applications of DIC in various scales of experiments, including material tests, structural element tests and full‐scale structural system tests, are subsequently discussed. These new‐generation data acquisition techniques enable structural researchers to gain a deeper insight into the behaviour of metallic structures in experimental research.

No abstract is provided for this article.

BACKGROUND: Inhaled medications are central to treating asthma and chronic obstructive pulmonary disease (COPD), yet critical inhaler technique errors are made by up to 90% of patients. In the clinical research setting, recruitment of subjects with poor inhaler technique may give a false impression of both the benefits and the necessity of add-on treatments such as biologic therapies. OBJECTIVE: To assess the frequency with which inhaler technique is assessed and reliably optimized before and during patient enrollment into randomized controlled trials (RCTs) addressing the efficacy of topical therapy, and the escalation of therapy for asthma and COPD. METHODS: Systematic searches were conducted of PubMed and Embase for RCTs published in the past 10 years involving patients with a diagnosis of asthma or COPD undergoing escalation of baseline inhaled therapy (stepping up, changing, adding, switching, increasing, etc) or the introduction of biologic agents. RESULTS: Searches highlighted 1,014 studies, 118 of which were eligible after the removal of duplicates as well as screening and full text review. Of these, only 14 (11.9%) included accessible information in the methods section or referred to such information in online supplements or protocols concerning assessment of participants' inhaler technique. We therefore developed the proposed Best Practice Inhaler Technique Assessment and Reporting Checklist. CONCLUSIONS: Our study identifies a concerning lack of checking and correcting inhaler technique, or at least reporting that this was undertaken, before enrollment in asthma and COPD RCTs, which may affect the conclusions drawn. Mandating the use of a standardized checklist in RCT protocols and ensuring all published RCTs report checking and correcting inhaler technique before enrollment are important next steps.

Background The functional SYNTAX score (FSS) has been shown to improve the discrimination for major adverse cardiac events compared with the anatomic SYNTAX score (SS) while reducing interobserver variability. However, evidence supporting the noninvasive FSS in patients with multivessel coronary artery disease (CAD) is scarce. Objectives The purpose of this study was to assess the feasibility of and validate the noninvasive FSS derived from coronary computed tomography angiography (CTA) with fractional flow reserve (FFRCT) in patients with 3-vessel CAD. Methods The CTA-SS was calculated in patients with 3-vessel CAD included in the SYNTAX II (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery II) study. The noninvasive FSS was determined by including only ischemia-producing lesions (FFRCT ≤0.80). SS derived from different imaging modalities were compared using the Bland-Altman and Passing-Bablok method, and the agreement on the SS tertiles was investigated with Cohen’s Kappa. The risk reclassification was compared between the noninvasive and invasive physiological assessment, and the diagnostic accuracy of FFRCT was assessed by the area under the receiver-operating characteristic curve using instantaneous wave-free ratio as a reference. Results The CTA-SS was feasible in 86% of patients (66 of 77), whereas the noninvasive FSS was feasible in 80% (53 of 66). The anatomic SS was overestimated by CTA compared with conventional angiography (27.6 ± 6.4 vs. 25.3 ± 6.9; p < 0.0001) whereas the calculation of the FSS yielded similar results between the noninvasive and invasive imaging modalities (21.6 ± 7.8 vs. 21.2 ± 8.8; p = 0.589). The noninvasive FSS reclassified 30% of patients from the high- and intermediate-SS tertiles to the low-risk tertile, whereas invasive FSS reclassified 23% of patients from the high- and intermediate-SS tertiles to the low-risk tertile. The agreement on the classic SS tertiles based on Kappa statistics was slight for the anatomic SS (Kappa = 0.19) and fair for the FSS (Kappa = 0.32). The diagnostic accuracy of FFRCT to detect functional significant stenosis based on an instantaneous wave-free ratio ≤0.89 revealed an area under the receiver-operating characteristics curve of 0.85 (95% CI: 0.79 to 0.90) with a sensitivity of 95% (95% CI: 89% to 98%), specificity of 61% (95% CI: 48% to 73%), positive predictive value of 81% (95% CI: 76% to 86%), and negative predictive value of 87% (95% CI: 74% to 94%). Conclusions Calculation of the noninvasive FSS is feasible and yielded similar results to those obtained with invasive pressure-wire assessment. The agreement on the SYNTAX score tertile classification improved with the inclusion of the functional component from slight to fair agreement. FFRCT has good accuracy in detecting functionally significant lesions in patients with 3-vessel CAD. (A Trial to Evaluate a New Strategy in the Functional Assessment of 3-Vessel Disease Using SYNTAX II Score in Patients Treated With PCI; NCT02015832)

Patient-specific coronary endothelial shear stress (ESS) calculations using Newtonian and non-Newtonian rheological models were performed to assess whether the common assumption of Newtonian blood behavior offers similar results to a more realistic but computationally expensive non-Newtonian model. 16 coronary arteries (from 16 patients) were reconstructed from optical coherence tomographic (OCT) imaging. Pulsatile CFD simulations using Newtonian and the Quemada non-Newtonian model were performed. Endothelial shear stress (ESS) and other indices were compared. Exploratory indices including local blood viscosity (LBV) were calculated from non-Newtonian simulation data. Compared to the Newtonian results, the non-Newtonian model estimates significantly higher time-averaged ESS (1.69 (IQR 1.36)Pa versus 1.28 (1.16)Pa, p < 0.001) and ESS gradient (0.90 (1.20)Pa/mm versus 0.74 (1.03)Pa/mm, p < 0.001) throughout the cardiac cycle, under-estimating the low ESS (<1Pa) area (37.20 ± 13.57% versus 50.43 ± 14.16%, 95% CI 11.28-15.18, p < 0.001). Similar results were also found in the idealized artery simulations with non-Newtonian median ESS being higher than the Newtonian median ESS (healthy segments: 0.8238Pa versus 0.6618Pa, p < 0.001 proximal; 0.8179Pa versus 0.6610Pa, p < 0.001 distal; stenotic segments: 0.8196Pa versus 0.6611Pa, p < 0.001 proximal; 0.2546Pa versus 0.2245Pa, p < 0.001 distal) On average, the non-Newtonian model has a LBV of 1.45 times above the Newtonian model with an average peak LBV of 40-fold. Non-Newtonian blood model estimates higher quantitative ESS values than the Newtonian model. Incorporation of non-Newtonian blood behavior may improve the accuracy of ESS measurements. The non-Newtonian model also allows calculation of exploratory viscosity-based hemodynamic indices, such as local blood viscosity, which may offer additional information to detect underlying atherosclerosis.

Airway inflammation is important in the development and progression of many lung diseases, including bronchiectasis. Activation of inflammatory cells such as neutrophils, eosinophils, and macrophages induces a respiratory burst resulting in the production of reactive oxygen species such as hydrogen peroxide (H2O2). We have measured exhaled H2O2 in patients with documented bronchiectasis and investigated whether the concentration of H2O2 is related to the disease severity, as defined by lung function. We also investigated whether the concentrations of expired H2O2 were different in bronchiectatic patients who received inhaled corticosteroids compared with steroid-naı̈ve patients. In 37 patients with bronchiectasis (mean age, 45 ± 2.5 yr; FEV1, 59 ± 3% pred), mean H2O2 concentration in exhaled breath condensate was significantly elevated as compared with the values in 25 age-matched (mean age, 42 ± 2 yr) normal subjects (0.87 ± 0.01 versus 0.26 ± 0.04 μ M, p < 0.001). There was a significant negative correlation between H2O2 and FEV1 (r = − 0.76, p < 0.0001). Patients treated with inhaled corticosteroids had values of H2O2 similar to those of steroid-naı̈ve patients (0.8 ± 0.1 versus 0.9 ± 0.1, p > 0.05). We conclude that H2O2 is elevated in exhaled air condensate of patients with bronchiectasis and is correlated with disease severity. Measurement of H2O2 may be used as a simple noninvasive method to monitor airway inflammation and oxidative stress.