Safety, feasibility, and hemodynamic response of regadenoson for stress perfusion CMR

Owing to its pharmacodynamics and posology, the use of regadenoson for stress cardiac magnetic resonance (CMR) has potential advantages over other vasodilators. We sought to evaluate the safety, hemodynamic response and diagnostic performance of regadenoson stress-CMR in routine clinical practice. All regadenoson stress-CMR examinations performed between May 2017 and July 2020 at our institution were retrospectively reviewed. A total of 698 studies were included for the final analysis. A conventional stress/rest protocol was performed using a 1.5T MRI scanner (Magnetom Aera, Siemens Healthineers, Erlangen, Germany). Adverse events, clinical symptoms, and hemodynamic response were assessed. Diagnostic accuracy of the test was evaluated in patients who underwent invasive coronary angiography. Nearly half of patients (48.5%) remained asymptomatic. Most common clinical symptoms included dyspnea (137, 19.6%), chest pain (116, 16.6%) and flushing (44, 6.3%). Two patients (0.28%) could not complete the examination due to severe hypotension or unbearable chest pain. Overall, an increase in heart rate (HR) response (36.2% [IQR: 22.5–50.9]) and a decrease in systolic and diastolic blood pressure (BP) (median systolic BP response of -5% [IQR: -11.5-0.6]; median diastolic BP response of -6.3 mmHg [IQR: -13.4-0]) was observed. Patients with symptoms induced by regadenoson showed higher HR response (40.3%, IQR: 26.4–56.1 vs. 32.4%, IQR: 19-45.6, p<0.001), whereas a blunted HR response was observed in diabetic (29.6%, IQR: 18.4–42 p<0.001), obese (31.7%, IQR: 20.7–46.2 p=0.005) and patients aged 70 years or older (32.9%, IQR: 22.6–43.1 p<0.001). Overall, regadenoson stress-CMR showed 95.65% (IQ 91.49–99.81) sensitivity, 54.84% (IQ 35.71–73.97) specificity, 86.99% (IQ 82.74–94.68) positive predictive value, and 77.27% (IQ 57.49–97.06) negative predictive value for detecting significant coronary stenosis as compared with invasive coronary angiography. Regadenoson is a well-tolerated vasodilator that can be safely employed for stress perfusion CMR, with high diagnostic performanc

Nocturnal Hypoxemia and CT Determined Pulmonary Artery Enlargement in Smokers

Background: Pulmonary artery enlargement (PAE) detected using chest computed tomography (CT) is associated with poor outcomes in chronic obstructive pulmonary disease (COPD). It is unknown whether nocturnal hypoxemia occurring in smokers, with or without COPD, obstructive sleep apnoea (OSA) or their overlap, may be associated with PAE assessed by chest CT. Methods: We analysed data from two prospective cohort studies that enrolled 284 smokers in lung cancer screening programs and completing baseline home sleep studies and chest CT scans. Main pulmonary artery diameter (PAD) and the ratio of the PAD to that of the aorta (PA:Ao ratio) were measured. PAE was defined as a PAD >= 29 mm in men and >= 27 mm in women or as a PA:Ao ratio > 0.9. We evaluated the association of PAE with baseline characteristics using multivariate logistic models. Results: PAE prevalence was 27% as defined by PAD measurements and 11.6% by the PA:Ao ratio. A body mass index >= 30 kg/m(2) (OR 2.01; 95%CI 1.06-3.78), lower % predicted of forced expiratory volume in one second (FEV1) (OR 1.03; 95%CI 1.02-1.05) and higher % of sleep time with O-2 saturation < 90% (T90) (OR 1.02; 95%CI 1.00-1.03), were associated with PAE as determined by PAD. However, only T90 remained significantly associated with PAE as defined by the PA:Ao ratio (OR 1.02; 95%CI 1.01-1.03). In the subset group without OSA, only T90 remains associated with PAE, whether defined by PAD measurement (OR 1.02; 95%CI 1.01-1.03) or PA:Ao ratio (OR 1.04; 95%CI 1.01-1.07). Conclusions: In smokers with or without COPD, nocturnal hypoxemia was associated with PAE independently of OSA coexistence

Development of a novel splice array platform and its application in the identification of alternative splice variants in lung cancer

Abstract Background Microarrays strategies, which allow for the characterization of thousands of alternative splice forms in a single test, can be applied to identify differential alternative splicing events. In this study, a novel splice array approach was developed, including the design of a high-density oligonucleotide array, a labeling procedure, and an algorithm to identify splice events. Results The array consisted of exon probes and thermodynamically balanced junction probes. Suboptimal probes were tagged and considered in the final analysis. An unbiased labeling protocol was developed using random primers. The algorithm used to distinguish changes in expression from changes in splicing was calibrated using internal non-spliced control sequences. The performance of this splice array was validated with artificial constructs for CDC6, VEGF, and PCBP4 isoforms. The platform was then applied to the analysis of differential splice forms in lung cancer samples compared to matched normal lung tissue. Overexpression of splice isoforms was identified for genes encoding CEACAM1, FHL-1, MLPH, and SUSD2. None of these splicing isoforms had been previously associated with lung cancer. Conclusions This methodology enables the detection of alternative splicing events in complex biological samples, providing a powerful tool to identify novel diagnostic and prognostic biomarkers for cancer and other pathologies

Somatotypes trajectories during adulthood and their association with COPD phenotypes

Rationale: Chronic obstructive pulmonary disease (COPD) comprises distinct phenotypes, all characterised by airflow limitation. Objectives: We hypothesised that somatotype changes – as a surrogate of adiposity – from early adulthood follow different trajectories to reach distinct phenotypes. Methods: Using the validated Stunkard’s Pictogram, 356 COPD patients chose the somatotype that best reflects their current body build and those at ages 18, 30, 40 and 50 years. An unbiased group-based trajectory modelling was used to determine somatotype trajectories. We then compared the current COPD-related clinical and phenotypic characteristics of subjects belonging to each trajectory. Measurements and main results: At 18 years of age, 88% of the participants described having a lean or medium somatotype (estimated body mass index (BMI) between 19 and 23 kg·m−2 ) while the other 12% a heavier somatotype (estimated BMI between 25 and 27 kg·m−2 ). From age 18 onwards, five distinct trajectories were observed. Four of them demonstrating a continuous increase in adiposity throughout adulthood with the exception of one, where the initial increase was followed by loss of adiposity after age 40. Patients with this trajectory were primarily females with low BMI and DLCO (diffusing capacity of the lung for carbon monoxide). A persistently lean trajectory was seen in 14% of the cohort. This group had significantly lower forced expiratory volume in 1 s (FEV1), DLCO, more emphysema and a worse BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) score thus resembling the multiple organ loss of tissue (MOLT) phenotype. Conclusions: COPD patients have distinct somatotype trajectories throughout adulthood. Those with the MOLT phenotype maintain a lean trajectory throughout life. Smoking subjects with this lean phenotype in early adulthood deserve particular attention as they seem to develop more severe COPD

Characterization of the lncRNA Transcriptome in Multiple Myeloma

Multiple myeloma (MM) is an hematological neoplasm characterized by uncontrolled clonal proliferation of plasma cells in the bone marrow. MM is an incurable and very heterogeneous disease, whose clinical variability makes its management challenging, highlighting the need for biological features to improve the therapy and survival of MM patients. There are many studies about genetic and epigenetic alterations in MM; however, the magnitude of the heterogeneity of this neoplasm is still unknown. New approaches about the deregulation of specific long non-coding RNAs (lncRNAs) have been shown in MM; nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we have described the complete lncRNA transcriptome of MM patients in the context of B-cell differentiation. Thanks to our work, we identified 40,511 novel lncRNAs expressed in MM samples. We added to our group of novel lncRNAs all the coding genes and lncRNAs annotated before, detecting that 82% of the MM transcriptome corresponded to lncRNAs; and remarkably, 56% corresponded to the novel lncRNAs detected in MM patients. Furthermore, we identified that lncRNAs were more heterogeneously expressed than coding-genes. After a comparison between MM samples and their healthy counterpart, bone marrow plasma cells (BMPCs) from healthy donors, we identified a group of 10,351 overexpressed and 9,535 downregulated lncRNAs in MM patients. Transcriptional dynamics study of those deregulated lncRNAs in the context of normal B-cell differentiation revealed a group of 989 lncRNAs with specific expression in MM samples, among which 89 showed de novo epigenomic activation. From those 89 lncRNAs with specific expression and de novo gain active chromatin marks in MM, we selected SMILO for functional assays. Knockdown studies on SMILO (Specific Myeloma Intergenic LOng non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. These results showed the relevance of SMILO in the biology of MM cells, and that could be a potential therapeutic target. We also analyzed the expression of lncRNAs in the context of the clinical of MM patients, looking for a better stratification and survival of patients. We studied the expression of the 89 lncRNAs with specific expression and de novo gain active chromatin marks in MM, together with high risk genetic and clinical alterations. Results revealed that lncRNAs together with different genetic and clinical factors could better stratify MM patients into different risk groups for progression-free survival and overall survival. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease

Characterization of the lncRNA Transcriptome in Multiple Myeloma

Multiple myeloma (MM) is an hematological neoplasm characterized by uncontrolled clonal proliferation of plasma cells in the bone marrow. MM is an incurable and very heterogeneous disease, whose clinical variability makes its management challenging, highlighting the need for biological features to improve the therapy and survival of MM patients. There are many studies about genetic and epigenetic alterations in MM; however, the magnitude of the heterogeneity of this neoplasm is still unknown. New approaches about the deregulation of specific long non-coding RNAs (lncRNAs) have been shown in MM; nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we have described the complete lncRNA transcriptome of MM patients in the context of B-cell differentiation. Thanks to our work, we identified 40,511 novel lncRNAs expressed in MM samples. We added to our group of novel lncRNAs all the coding genes and lncRNAs annotated before, detecting that 82% of the MM transcriptome corresponded to lncRNAs; and remarkably, 56% corresponded to the novel lncRNAs detected in MM patients. Furthermore, we identified that lncRNAs were more heterogeneously expressed than coding-genes. After a comparison between MM samples and their healthy counterpart, bone marrow plasma cells (BMPCs) from healthy donors, we identified a group of 10,351 overexpressed and 9,535 downregulated lncRNAs in MM patients. Transcriptional dynamics study of those deregulated lncRNAs in the context of normal B-cell differentiation revealed a group of 989 lncRNAs with specific expression in MM samples, among which 89 showed de novo epigenomic activation. From those 89 lncRNAs with specific expression and de novo gain active chromatin marks in MM, we selected SMILO for functional assays. Knockdown studies on SMILO (Specific Myeloma Intergenic LOng non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. These results showed the relevance of SMILO in the biology of MM cells, and that could be a potential therapeutic target. We also analyzed the expression of lncRNAs in the context of the clinical of MM patients, looking for a better stratification and survival of patients. We studied the expression of the 89 lncRNAs with specific expression and de novo gain active chromatin marks in MM, together with high risk genetic and clinical alterations. Results revealed that lncRNAs together with different genetic and clinical factors could better stratify MM patients into different risk groups for progression-free survival and overall survival. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease

Determination of hazardous zones for a generic hydrogen station - a case study

International audienceA method for determination of hazardous zones for hydrogen installations has been studied. This work has been carried out within the NoE HySafe. The method is based on the Italian Method outlined in Guide 31-30(2004), Guide 31-35(2001), Guide 31-35/A(2001), and Guide 31-35/A; V1(2003). Hazardous zones for a "generic hydrogen refuelling station"(HRS) are assessed, based on this method. The method is consistent with the EU directive 1999/92/EC "Safety and Health Protection of Workers potentially at risk from explosive atmospheres" which is the basis for determination of hazardous zones in Europe. This regulation is focused on protection of workers, and is relevant for hydrogen installations, such as hydrogen refuelling stations, repair shops and other stationary installations where some type of work operations will be involved. The method is also based on the IEC standard and European norm IEC/EN60079-10 "Electrical apparatus for explosive gas atmospheres. Part 10 Classification of hazardous areas". This is a widely acknowledged international standard/norm and it is accepted/approved by Fire and Safety Authorities in Europe and also internationally. Results from the HySafe work and other studies relevant for hydrogen and hydrogen installations have been included in the case study. Sensitivity studies have been carried out to examine the effect of varying equipment failure frequencies and leak sizes, as well as environmental condition (ventilation, obstacles, etc.). The discharge and gas dispersion calculations in the Italian Method are based on simple mathematical formulas. However, in this work also CFD (Computational Fluid Dynamics) and other simpler numerical tools have been used to quantitatively estimate the effect of ventilation and of different release locations on the size of the flammable gas cloud. Concentration limits for hydrogen to be used as basis for the extent of the hazardous zones in different situations are discussed