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<b>Introduction:</b> Janus kinases (JAK) regulate inflammatory gene expression through phosphorylation of signal transducer and activator of transcription (STAT) proteins. Expression of STAT proteins is increased in chronic obstructive pulmonary disease (COPD) and may be involved in driving chronic inflammation. Oral JAK inhibitors are effective as anti-inflammatory therapy but exhibit dose-limiting adverse effects. <b>Aims:</b> Development of inhaled compounds would be enhanced by robust biomarkers that directly reflect the anti-inflammatory and pharmacological activity in the lung. <b>Methods:</b> A novel flow cytometry assay was developed to measure STAT1 phosphorylation in sputum inflammatory cells. The standard sputum processing method was refined to improve sputum cell viability. The flow cytometric assay was used to assess the reproducibility of the measurement of STAT1 phosphorylation and the <i>in vitro</i> activity of a pan JAK-inhibitor on three separate visits in COPD subjects. <b>Results:</b> Up-regulation of STAT1 phosphorylation was measured following <i>in vitro</i> IFNγ stimulation of sputum macrophages (stimulated/unstimulated ratio 1.57; P&lt;0.0001). Up-regulation was inhibited following <i>in vitro</i> pre-incubation with a pan JAK-inhibitor (inhibited+stimulated/unstimulated ratio 0.97). STAT1 phosphorylation activity could only be measured in macrophages. <b>Conclusions:</b> Sputum from COPD patients can be used to reproducibly measure phospho-STAT expression in sputum macrophages. The flow cytometry based methods can be used to evaluate kinase inhibitors <i>in vitro</i> and subsequently in <i>ex vivo</i> studies. The assay is particularly useful for the assessment of inhaled compounds where whole blood assays may not be relevant.

Introduction: We have recently found that impaired protein tyrosine phosphatase PTPRR and serine/threonine phosphatase PP2A expression and activity lead to lower dephosphorylation of glucocorticoid receptor (GR)-Ser 226 via c-Jun N-terminal kinase 1 (JNK1), and to lower nuclear translocation of GR, resulting in corticosteroid insensitivity. Aims: To elucidate the association between PTPRR and PP2A in regulation of corticosteroid sensitivity. Methods: Protein expression of PTPRR and PP2A catalytic subunit (PP2A C ) and phosphorylation levels of PP2A C -Tyr 307 were evaluated by Western-Blot in monocytic U937 cell line or peripheral blood mononuclear cells (PBMCs). Effects of PTPRR and PP2A knock down using siRNA were evaluated in U937 cells. Phosphatase activities of immunopurified PTPRR and PP2A C were analyzed by fluorescence-based assay. Results: In PBMCs from severe asthmatics, PTPRR and PP2A C expression were reduced and positively correlated to each other. PTPRR was associated with PP2A C in the cytoplasm. PTPRR reduction attenuated PP2A C expression and activity with concomitant enhancement of PP2A C -Tyr 307 phosphorylation whereas PP2A reduction did not alter PTPRR expression or activity. In addition, PTPRR expression positively correlated with PP2A C -Tyr 307 phosphorylation and negatively with PP2A C activity. Interestingly, PTPRR was activated by formoterol, independently of β 2 adrenoceptor. Conclusion: We have demonstrated that reduction of PTPRR down-regulates PP2A C via enhancement of PP2A C -Tyr 307 phosphorylation that may lead to corticosteroid insensitivity. This novel mechanism may be a new therapeutic target for restoration of corticosteroid sensitivity in patients with severe asthma.

The morphology of the Milky Way is still a matter of debate. In order to shed light on uncertainties surrounding the structure of the Galaxy, in this paper, we study the imprint of spiral arms on the distribution and properties of its molecular gas. To do so, we take full advantage of the SEDIGISM survey that observed a large area of the inner Galaxy in the $^{13}$CO(2-1) line at an angular resolution of 28. We analyse the influences of the spiral arms by considering the features of the molecular gas emission as a whole across the longitude-velocity map built from the full survey. Additionally, we examine the properties of the molecular clouds in the spiral arms compared to the properties of their counterparts in the inter-arm regions. Through flux and luminosity probability distribution functions, we find that the molecular gas emission associated with the spiral arms does not differ significantly from the emission between the arms. On average, spiral arms show masses per unit length of $\sim10^5-10^6$ M$_{\odot} $kpc$^{-1}$. This is similar to values inferred from data sets in which emission distributions were segmented into molecular clouds. By examining the cloud distribution across the Galactic plane, we infer that the molecular mass in the spiral arms is a factor of 1.5 higher than that of the inter-arm medium, similar to what is found for other spiral galaxies in the local Universe. We observe that only the distributions of cloud mass surface densities and aspect ratio in the spiral arms show significant differences compared to those of the inter-arm medium; other observed differences appear instead to be driven by a distance bias. By comparing our results with simulations and observations of nearby galaxies, we conclude that the measured quantities would classify the Milky Way as a flocculent spiral galaxy, rather than as a grand-design one.

Animal studies suggest that the neuropeptides, substance P and vasoactive intestinal peptide (VIP), may influence carotid body chemoreceptor activity and that substance P may take part in the carotid body response to hypoxia. The effects of these peptides on resting ventilation and on ventilatory responses to hypoxia and to hypercapnia have been investigated in six normal humans. Infusions of substance P (1 pmol.kg-1.min-1) and of VIP (6 pmol.kg-1.min-1) were compared with placebo and with nitroprusside (5 micrograms.kg-1.min-1) as a control for the hypotensive action of the peptides. Both peptides caused significantly less hypotension than nitroprusside. Substance P and nitroprusside caused significantly greater increases in ventilation and in the hypoxic ventilatory response than VIP. No changes were seen in hypercapnic sensitivity. The stimulation of ventilation and the differential effects on ventilatory chemosensitivity that accompanied hypotension are consistent either with stimulation of carotid body chemoreceptor activity or with an interaction with peripheral chemoreceptor input to the respiratory center, as is seen in animals. The similar cardiovascular but different ventilatory effects of the peptides suggest that substance P may also stimulate the carotid body in a manner independent of the effect of hypotension. This is consistent with a role of substance P in the hypoxic ventilatory response in humans.

Objectives The study sought to evaluate the efficacy and safety of the Absorb everolimus-eluting bioresorbable vascular scaffold (BVS) (Abbott Vascular, Abbott Park, Illinois) in patients with diabetes mellitus. Background Randomized, controlled trials have demonstrated comparable clinical outcomes following percutaneous coronary intervention with either Absorb BVS or metallic Xience everolimus-eluting stent. However, these trials lack power required to provide reliable treatment effect estimates in this high-risk population. Methods In a pre-specified, powered analysis, patients with diabetes who received ≥1 Absorb were pooled from the ABSORB II, III, and JAPAN randomized trials and from the single arm ABSORB EXTEND registry. The study composite primary endpoint was target lesion failure (TLF) at 1 year following Absorb BVS compared with a performance goal of 12.7%. Results Among 754 diabetic patients included in analysis (27.3% insulin treated), the 1-year TLF rate was 8.3% (upper 1-sided 95% confidence limit: 10.1%; p = 0.0001 vs. performance goal). Scaffold thrombosis (definite or probable) was observed in 2.3% of patients. Multivariable regression identified older age, insulin treatment, and smaller pre-procedure reference vessel diameter as significant independent predictors of 1-year TLF. Conclusions The Absorb diabetic substudy suggests efficacy and safety of the Absorb BVS for treatment of patients with diabetes mellitus.

Three-dimensional (3-D) reconstruction of intracoronary ultrasound (ICUS) images has an increasing application as the applicability of systems of on-line analysis provides a superior guidance by coupling the advantages of a high-resolution cross-sectional imaging with an overview of stenosis and reference segments. Detection of the external contour of the vessel which is a prerequisite for measurements of coronary plaques is currently not provided by the algorithms for automated on-line analysis. Thus, off-line reconstruction is required for studies aiming at the assessment of progression/regression of atherosclerosis and of mechanisms of interventions or restenosis. Various 3-D reconstruction methods with specific advantages and limitations are able to meet the different requirements concerning applicability, quality of visualization, and accuracy of quantification. The use of 3-D ICUS in the assessment of cardiac transplant recipients permits a more reliable and accurate quantification of intimal hyperplasia as seen in cardiac allograft arteriopathy. In patients undergoing bypass surgery it may influence the therapeutic decision, since it allows to determine the longitudinal extent of calcification and frequently discovers atherosclerosis in angiographically normal segments. Vessel stenoses both of native coronary arteries and bypass grafts can be studied by 3-D ICUS and additional information can be obtained during catheter based interventions. Despite some remaining technical limitation 3-D reconstruction of ICUS images has the potential of becoming a practical tool to simplify the interpretation and quantification of ICUS images.

Artificial intelligence, computational simulations, and extended reality, among other 21st century computational technologies, are changing the health care system. To collectively highlight the most recent advances and benefits of artificial intelligence, computational simulations, and extended reality in cardiovascular therapies, we coined the abbreviation AISER. The review particularly focuses on the following applications of AISER: 1) preprocedural planning and clinical decision making; 2) virtual clinical trials, and cardiovascular device research, development, and regulatory approval; and 3) education and training of interventional health care professionals and medical technology innovators. We also discuss the obstacles and constraints associated with the application of AISER technologies, as well as the proposed solutions. Interventional health care professionals, computer scientists, biomedical engineers, experts in bioinformatics and visualization, the device industry, ethics committees, and regulatory agencies are expected to streamline the use of AISER technologies in cardiovascular interventions and medicine in general.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

Budesonide-formoterol taken as needed is an emerging treatment for mild asthma. We used data from the SYGMA studies to assess the safety of As-needed budesonide-formoterol compared with As-needed terbutaline and compared with maintenance budesonide. SYGMA 1 and 2 were 52-week, double-blind, parallel-group studies in patients aged ≥ 12 years with physician-assessed mild asthma. Patients were randomized to As-needed budesonide-formoterol 200/6 μg, twice-daily budesonide 200 μg as maintenance plus As-needed terbutaline 0.5 mg, and As-needed terbutaline 0.5 mg (SYGMA 1 only). Adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs (DAEs), and study-defined asthma-related discontinuations from corresponding treatment groups in both studies were pooled. SYGMA 1 data were used for comparisons with As-needed terbutaline alone. The pooled analysis included 3366 patients in the As-needed budesonide-formoterol group and 3369 in the budesonide maintenance group, with AEs in 40.8% and 42.5% of patients, respectively. Common AEs included viral upper respiratory tract infection (viral URTI) and URTI. SAE, DAE, and asthma-related discontinuation rates were similar with As-needed budesonide-formoterol and maintenance budesonide. Potential local and systemic corticosteroid class effects were reported in ≤ 1% of patients for each budesonide-containing regimen. In SYGMA 1, AEs were more common in the As-needed terbutaline (n = 1277) than As-needed budesonide-formoterol (n = 1277) groups (42.7 vs. 38.0%), as were DAEs (2.9 vs. 0.8%) and asthma-related discontinuations (1.6 vs. 0.3%). Budesonide-formoterol anti-inflammatory reliever therapy is generally well-tolerated in patients with mild asthma and has a safety profile similar to that of daily budesonide. No new safety signals were identified. NCT02149199 (SYGMA 1) and NCT02224157 (SYGMA 2).

Background: Cardiovascular risk factors have an impact on coronary atherosclerosis evolution. However, there is only limited information about the relationship between risk and atherosclerotic plaque as measured invasively by Intravascular Ultrasound Radiofrequency (IVUS-RF) analysis. The Aim of this study was to assess the impact of cardiovascular risk factors not only on overall coronary plaque volume but on coronary plaque composition. Methods: 990 patients from 42 centers were enrolled in the prospective, multicenter, non randomized, global VH-IVUS registry. Coronary lesions were measured by conventional and IVUS-VH parameters using 20MHz Intravascular Ultrasound catheter. The four IVUS-VH plaque components (Dense Calcium-DC, Necrotic Core-NC, Fibrous tissue-F, Fibro Fatty-FF) were analyzed in every recorded frame. The results were expressed as mean cross-sectional areas, and percentage of total plaque volume. Risk factor assessment included correlation with family history of myocardial infarction, past or current smoking, diabetes mellitus, hypertension, and laboratory measurements. Results: Patients with diabetes have an increased relative amount of NC (6.47±0.28% vs. 5.86±0.14%, p=0.037) and DC (4.58±0.27% vs. 3.90±0.14%, p=0.017), Patients with hypertension have an increased relative amount of FF, DC (4.35±0.16% vs. 3.57±0.17%, p=0.02) and NC (6.24±0.17% vs. 5.60±0.19%, p=0.01). Compared with patients with LDL cholesterol 160 mg/dl had higher plaque volume (342.1±26.2mm 3 vs. 318.6±10.7mm 3 ). Linear Regression Analysis showed a correlation between the level of HDL and F (r=−0.149, p&lt;0.01), FF (r=−0 –106, p&lt; 0.01), and NC (r=−0.90, p&lt;0.05). The level of LDL correlated with F (r = 0.110, p &lt; 0.01). Patients with prior MI have an increased percentage of F (30.03±0.59 % vs. 28.20±0.37 %, p&lt;0.009). Smoking had no relevant effect on plaque composition. Conclusion: IVUS-RF analysis detects marked differences in coronary plaque depending on the risk factor profile with particular focus on lipid levels. Patients with greater amounts of necrotic core were associated with hypertension, myocardial infarction, and low HDL. This may have implications for prognosis and systemic treatment of patients with coronary artery disease.