Publications

<h3>BACKGROUND</h3> Expiratory flow rate, soft palate closure, and dead space air may influence exhaled levels of nitric oxide (NO). These factors have not been evaluated in the reservoir collection of NO. <h3>METHODS</h3> Exhaled NO was collected into a reservoir during a single flow and pressure controlled exhalation. <h3>RESULTS</h3> NO collected in a reservoir containing silica gel was stable for 24 hours. Nasally delivered 4.8% argon measured by mass spectrometry did not contaminate exhaled argon levels (0.1 (0.02)%) in five volunteers during exhalation against a resistance (10 (0.5) cmH₂O), hence proving an effective soft palate closure. Exhaled NO in the reservoir was 11 (0.2) ppb, 8.6 (0.1) ppb, 7.1 (0.6) ppb, and 6.6 (0.4) ppb in five normal subjects and 48.3 (18) ppb, 20.3 (12) ppb, 16.9 (0.3) ppb and 10.1 (0.4) ppb in 10 asthmatic subjects at four studied expiratory flows (5–6, 7–8, 10–11, and 12–13 l/min, respectively), with NO levels equal to direct measurement (7.3 (0.5) ppb and 17.4 (0.5) ppb for normal and asthmatic subjects respectively, p&lt;0.05) at the flow rate 10–11 l/min. Elimination of dead space proved necessary to provide NO levels comparable to the direct measurement. Exhaled NO collected into the reservoir without dead space during flow controlled exhalation against mild resistance provided close agreement (mean (SD) difference –0.21 (0.68), coefficient of variation 4.58%) with direct measurement in 74 patients (NO range 1–69 ppb). <h3>CONCLUSIONS</h3> Flow and pressure controlled collection of exhaled NO into a reservoir with silica gel provides values identical to the direct measurement and may be used to monitor asthma at home and where analysers are not on site.

The purpose of this preclinical feasibility study was to evaluate a novel integrated platform in which magnetic navigation is used to remotely guide electromechanical mapping of the left ventricle (LV) and transendocardial cell injections. Using an integrated remote system would greatly facilitate intramyocardial delivery of stem cells for treating ischaemic heart disease.We used the computer-controlled Stereotaxis magnetic navigation system to guide the NOGA electromechanical mapping system in mapping viable myocardium in the LV of seven pigs. We then tested the feasibility of this system to perform transendocardial injections in three of the pigs and to deliver mesenchymal precursor cells (MPCs) to targeted myocardial segments in four of the pigs. The success or failure of each injection was determined by myocardial contrast staining in the first group and by histopathologic analysis in the last group. The mean time (+/-SD) spent mapping the LV for each pig was 49.3+/-10.6 min. The success rate for transendocardial injections was 94.4%, as indicated by myocardial contrast staining. There was a 95.8% success rate for targeted injections of MPCs, and 4',6-diamidino-2-phenylindole-labeled MPCs were detected in all but one segment of one pig. No epicardial haemorrhage or injury was observed, although there was some venous drainage.The integrated Stereotaxis/NOGA system has excellent remote navigability inside the LV cavity while sparing the operator from radiation exposure. This system also allows transendocardial cell injections to be performed with a high success rate. Further studies are needed to define the safety profile of this system for clinical use.

Abstract Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating novel therapies. Here, we show that COPD patients have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared to control subjects. IL-36γ is derived mainly from small airway epithelial cells (SAEC) and further induced by a viral mimetic, whereas IL-36RA is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, that was inhibited by exogenous IL-36RA. The use of a therapeutic antibody that inhibits binding to the IL-36 receptor (IL-36R) attenuated IL-36γ driven inflammation and cellular cross talk. We have demonstrated a novel mechanism for the amplification and propagation of neutrophilic inflammation in COPD and that blocking this cytokine family via a IL-36R neutralising antibody could be a promising new therapeutic strategy in the treatment of COPD.

No abstract is provided for this article.

Opioid-induced constipation (OIC) is a common side effect of chronic opioid therapy that significantly impacts quality of life and healthcare costs. Naldemedine, a peripherally acting mu-opioid receptor antagonist, has shown efficacy in treating OIC. However, real-world evidence on naldemedine use in the United States is limited, particularly in older adults. We aimed to describe naldemedine use in real-world settings in the US, focusing on clinical characteristics, comorbidity profiles, co-prescribed medications, and healthcare resource utilization (HCRU), with a specific emphasis on older adults. This retrospective study analyzed data from the 2017–2022 Merative™ MarketScan® Commercial and Medicare Databases. We identified 2110 naldemedine users aged ≥ 30 years on chronic opioid therapy. Demographic and clinical characteristics, co-prescribed medications, and HCRU were evaluated. Subgroup analysis focused on patients aged ≥ 65 years. The study cohort (66% women, median age 56 years, 14% aged ≥ 65 years) presented a significant comorbidity burden, with 57% having hypertension, 36% diabetes, and 25% chronic pulmonary disease with a Charlson Comorbidity Index ≥ 2 in 38% of subjects. Polypharmacy (i.e., use of five or more distinct drugs, excluding naldemedine) was very common (76%, 82% in ≥ 65 years). The most frequent indications for naldemedine were chronic back pain and radiculopathy. Oxycodone, hydrocodone, and morphine were the most commonly prescribed opioids. After initiating naldemedine, 30% of patients showed a reduction in hospitalizations per patient per year, with a more pronounced effect in older adults (37%). Potential drug–drug interactions with CYP3A4 inducers or inhibitors were infrequent and did not appear to impact HCRU. This real-world study demonstrates that naldemedine is predominantly used in middle-aged adults with comorbidities and polypharmacy. Naldemedine use was associated with reduced HCRU, particularly in older adults, suggesting potential benefits in managing OIC. The findings support the safety and effectiveness of naldemedine in real-world settings, including in older patients with multiple comorbidities.

The role of shear stress in atherosclerosis has been well documented. However, its role in restenosis was underexposed. In this paper a novel in vivo measuring technique and several of its applications related to restenosis will be described. The technique consists of a combination of 3D reconstruction of blood vessels and computational fluid dynamics (CFD). The 3D imaging techniques use either of 3D intravascular ultrasound (IVUS) as a stand-alone technique or a fusion of biplane angiography and IVUS (ANGUS). CFD is applied in order to relate local shear stress distribution to the morphology of the vessel wall. In the applications of these techniques it will be demonstrated that shear stress plays a role in the prediction of neointimal formation in in-stent restenosis and in vascular remodeling after balloon angioplasty. Attempts to locally increase shear stress by a newly developed flow divider indicate that shear stress reduce in-stent neointimal formation by 50%.

Although transcatheter aortic-valve replacement (TAVR) is an accepted alternative to surgery in patients with severe aortic stenosis who are at high surgical risk, less is known about comparative outcomes among patients with aortic stenosis who are at intermediate surgical risk.We evaluated the clinical outcomes in intermediate-risk patients with severe, symptomatic aortic stenosis in a randomized trial comparing TAVR (performed with the use of a self-expanding prosthesis) with surgical aortic-valve replacement. The primary end point was a composite of death from any cause or disabling stroke at 24 months in patients undergoing attempted aortic-valve replacement. We used Bayesian analytical methods (with a margin of 0.07) to evaluate the noninferiority of TAVR as compared with surgical valve replacement.A total of 1746 patients underwent randomization at 87 centers. Of these patients, 1660 underwent an attempted TAVR or surgical procedure. The mean (±SD) age of the patients was 79.8±6.2 years, and all were at intermediate risk for surgery (Society of Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%). At 24 months, the estimated incidence of the primary end point was 12.6% in the TAVR group and 14.0% in the surgery group (95% credible interval [Bayesian analysis] for difference, -5.2 to 2.3%; posterior probability of noninferiority, >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic-valve areas than surgery. Structural valve deterioration at 24 months did not occur in either group.TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910 .).

Determining the optimal treatment strategy for revascularisation of coronary artery stenosis involves the use of fractional flow reserve (FFR). To improve the low clinical uptake of physiological lesion assessment to guide revascularisation, the instantaneous wave-free period (iFR) was proposed as a simpler alternative to FFR that does not require adenosine administration. iFR is calculated as the ratio of blood pressure distal and proximal to a coronary artery stenosis during the diastolic wave-free period. The wave-free period is a part of the cardiac cycle where generation of new pressure wavefronts does not occur and resting microvascular resistance is relatively minimised. iFR indicates the haemodynamic severity of a stenosis, by assessing the extent to which the epicardial stenosis depletes the microcirculatory, autoregulatory reserve. The introduction of iFR and the potential to assess haemodynamic stenosis severity without the need for administration of potent vasodilators such as adenosine sparked an interesting debate about the fundamentals of human coronary physiology. The outcomes of two randomised clinical trials investigating iFR are pending. These studies are designed to evaluate whether iFR-guided revascularisation is non-inferior to an FFR-guided approach. The purpose of this review article is to discuss the physiological concepts underlying iFR, examine the existing validation studies and discuss the advantages and disadvantages of iFR as compared to FFR.

No abstract is provided for this article.