Substantial uptake of nitrous oxide (N2O) by shoots of mature European beech.

Similar to soils, tree stems emit and consume nitrous oxide (N2O) from the atmosphere. Although tree leaves dominate tree surface area, they have been completely excluded from field N2O flux measurements and therefore their role in forest N2O exchange remains unknown. We explored the contribution of leaf fluxes to forest N2O exchange. We determined the N2O exchange of mature European beech (Fagus sylvatica) stems and shoots (i.e., terminal branches) and of adjacent forest floor, in a typical temperate upland forest in Germany. The beech stems, and particularly the shoots, acted as net N2O sinks (-0.254 ±â€¯0.827 µg N2O m-2 stem area h-1 and - 4.54 ±â€¯1.53 µg N2O m-2 leaf area h-1, respectively), while the forest floor was a net source (2.41 ±â€¯1.08 µg N2O m-2 soil area h-1). The unstudied tree shoots were identified as a significant contributor to the net ecosystem N2O exchange. Moreover, we revealed for the first time that tree leaves act as substantial N2O sinks. Although this is the first study of its kind, it is of global importance for the proper design of future flux studies in forest ecosystems worldwide. Our results demonstrate that excluding tree leaves from forest N2O flux measurements can lead to misinterpretation of tree and forest N2O exchange, and thus global forest greenhouse gas flux inventories.

Dry and wet periods determine stem and soil greenhouse gas fluxes in a northern drained peatland forest.

Greenhouse gas (GHG) fluxes from peatland soils are relatively well studied, whereas tree stem fluxes have received far less attention. Simultaneous year-long measurements of soil and tree stem GHG fluxes in northern peatland forests are scarce, as previous studies have primarily focused on the growing season. We determined the seasonal dynamics of tree stem and soil CH4, N2O and CO2 fluxes in a hemiboreal drained peatland forest. Gas samples for flux calculations were manually collected from chambers at different heights on Downy Birch (Betula pubescens) and Norway Spruce (Picea abies) trees (November 2020-December 2021) and analysed using gas chromatography. Environmental parameters were measured simultaneously with fluxes and xylem sap flow was recorded during the growing season. Birch stems played a greater role in the annual GHG dynamics than spruce stems. Birch stems were net annual CH4, N2O and CO2 sources, while spruce stems constituted a CH4 and CO2 source but a N2O sink. Soil was a net CO2 and N2O source, but a sink of CH4. Temporal dynamics of stem CH4 and N2O fluxes were driven by isolated emissions' peaks that contributed significantly to net annual fluxes. Stem CO2 efflux followed a seasonal trend coinciding with tree growth phenology. Stem CH4 dynamics were significantly affected by the changes between wetter and drier periods, while N2O was more influenced by short-term changes in soil hydrologic conditions. We showed that CH4 emitted from tree stems during the wetter period can offset nearly half of the soil sink capacity. We presented for the first time the relationship between tree stem GHG fluxes and sap flow in a peatland forest. The net CH4 flux was likely an aggregate of soil-derived and stem-produced CH4. A dominating soil source was more evident for stem N2O fluxes.

PET-determined myocardial perfusion and flow in coronary artery disease characterization.

Positron emission tomography (PET) myocardial perfusion imaging in conjunction with tracer-kinetic modeling enables the concurrent assessment of myocardial perfusion and regional myocardial blood flow (MBF) of the left ventricle in absolute terms in milliliters per gram per minute (mL/g/min). The non-invasive quantification of MBF during pharmacologically induced hyperemia, at rest, and corresponding myocardial flow reserve (MFR) opens a new avenue for the identification and characterization of classical or endogen type of coronary microvascular dysfunction (CMD) as functional substrate for microvascular angina in patients with non-obstructive coronary artery disease (CAD) and/or no CAD at all. Further, PET-MBF quantification expands the scope of conventional myocardial perfusion imaging from the identification of advanced, and flow-limiting, epicardial CAD to early stages of atherosclerosis and/or CMD. Adding MBF assessment to myocardial perfusion may also reliably unravel diffuse ischemia owing to significant left main stenosis and/or multivessel CAD, commonly confirmed by peak stress transient ischemic cavity dilation of the left ventricle during maximal vasomotor stress compared to rest on gated PET images. Owing to high spatial and contrast resolution in conjunction with photon-attenuation free myocardial perfusion PET images, PET is preferentially used for CAD detection in advanced obesity and women with pronounced breast habitus. With increasing clinical use of cardiac PET perfusion and MBF assessment, individualized, and image-guided cardiovascular treatment decisions in CAD patients is likely to ensue, while its translation into improved cardiovascular outcome remains to be investigated.

Total-Body PET/CT Applications in Cardiovascular Diseases: A Perspective Document of the SNMMI Cardiovascular Council.

Digital PET/CT systems with a long axial field of view have become available and are emerging as the current state of the art. These new camera systems provide wider anatomic coverage, leading to major increases in system sensitivity. Preliminary results have demonstrated improvements in image quality and quantification, as well as substantial advantages in tracer kinetic modeling from dynamic imaging. These systems also potentially allow for low-dose examinations and major reductions in acquisition time. Thereby, they hold great promise to improve PET-based interrogation of cardiac physiology and biology. Additionally, the whole-body coverage enables simultaneous assessment of multiple organs and the large vascular structures of the body, opening new opportunities for imaging systemic mechanisms, disorders, or treatments and their interactions with the cardiovascular system as a whole. The aim of this perspective document is to debate the potential applications, challenges, opportunities, and remaining challenges of applying PET/CT with a long axial field of view to the field of cardiovascular disease.

Early diagnosis and management of cardiac amyloidosis: A clinical perspective.

Cardiac amyloidosis multidisciplinary team (MDT). We propose the creation of a multidisciplinary team (MDT) for cardiac amyloidosis in which internal medicine physicians could take a lead role in coordinating other specialists involved in patient care. Created with BioRender.com.

Total Soil CO2 Efflux from Drained Terric Histosols.

Histosols cover about 8-10% of Lithuania's territory and most of this area is covered with nutrient-rich organic soils (Terric Histosols). Greenhouse gas (GHG) emissions from drained Histosols contribute more than 25% of emissions from the Land Use, Land Use Change and Forestry (LULUCF) sector. In this study, as the first step of examining the carbon dioxide (CO2) fluxes in these soils, total soil CO2 efflux and several environmental parameters (temperature of air and topsoil, soil chemical composition, soil moisture, and water table level) were measured in drained Terric Histosols under three native forest stands and perennial grasslands in the growing seasons of 2020 and 2021. The drained nutrient-rich organic soils differed in terms of concentrations of soil organic carbon and total nitrogen, as well as soil organic carbon and total nitrogen ratio. The highest rate of total soil CO2 efflux was found in the summer months. Overall, the rate was statistically significant and strongly correlated only with soil and air temperature. A trend emerged that total soil CO2 efflux was 30% higher in perennial grassland than in forested land. Additional work is still needed to estimate the net CO2 balance of these soils.

Rationale and design of the RAPID-WATER-FLOW trial: Radiolabeled perfusion to identify coronary artery disease using water to evaluate responses of myocardial FLOW.

OBJECTIVES: The objective of this study was to determine the diagnostic performance of 15O-water positron emission tomography (PET) myocardial perfusion imaging to detect coronary artery disease (CAD) using the truth-standard of invasive coronary angiography (ICA) with fractional flow reserve (FFR) or instantaneous wave-Free Ratio (iFR) or coronary computed tomography angiogram (CCTA). BACKGROUND: 15O-water has a very high first-pass extraction that allows accurate quantification of myocardial blood flow and detection of flow-limiting CAD. However, the need for an on-site cyclotron and lack of automated production at the point of care and relatively complex image analysis protocol has limited its clinical use to date. METHODS: The RAPID WATER FLOW study is an open-label, multicenter, prospective investigation of the accuracy of 15O-water PET to detect obstructive angiographic and physiologically significant stenosis in patients with suspected CAD. The study will include the use of an automated system for producing, dosing, and injecting 15O-water and enrolling approximately 215 individuals with suspected CAD at approximately 10 study sites in North America and Europe. The primary endpoint of the study is the diagnostic sensitivity and specificity of the 15O-water PET study using the truth-standard of ICA with FFR or iFR to determine flow-limiting stenosis, or CCTA to rule out CAD and incorporating a quantitative analytic platform developed for the 15O-water PET acquisitions. Sensitivity and specificity are to be considered positive if the lower bound of the 95% confidence interval is superior to the threshold of 60% for both, consistent with prior registration studies. Subgroup analyses include assessments of diagnostic sensitivity, specificity, and accuracy in female, obese, and diabetic individuals, as well as in those with multivessel disease. All enrolled individuals will be followed for adverse and serious adverse events for up to 32 hours after the index PET scan. The study will have >90% power (one-sided test, α = 0.025) to test the hypothesis that sensitivity and specificity of 15O-water PET are both >60%. CONCLUSIONS: The RAPID WATER FLOW study is a prospective, multicenter study to determine the diagnostic sensitivity and specificity of 15O-water PET as compared to ICA with FFR/iFR or CCTA. This study will introduce several novel aspects to imaging registration studies, including a more relevant truth standard incorporating invasive physiologic indexes, coronary CTA to qualify normal individuals for eligibility, and a more quantitative approach to image analysis than has been done in prior pivotal studies. CLINICAL TRIAL REGISTRATION INFORMATION: Clinical-Trials.gov (#NCT05134012).

Kidney Outcomes and Preservation of Kidney Function With Obinutuzumab in Patients With Lupus Nephritis: A Post Hoc Analysis of the NOBILITY Trial.

OBJECTIVE: To determine whether adding obinutuzumab to standard-of-care lupus nephritis (LN) therapy could improve the likelihood of long-term preservation of kidney function and do so with less glucocorticoids. METHODS: Post hoc analyses of the phase II NOBILITY trial were performed. Time to unfavorable kidney outcome (a composite of treatment failure, doubling of serum creatinine, or death), LN flare, first 30% and 40% declines in estimated glomerular filtration rate (eGFR) from baseline, and chronic eGFR slope during the trial were compared between patients with active LN who were randomized to take obinutuzumab (n = 63) or placebo (n = 62) in combination with mycophenolate mofetil and glucocorticoids. The number of patients who achieved complete renal response (CRR) on 7.5 mg or less per day of prednisone was also determined. RESULTS: Obinutuzumab reduced the risk of developing the composite kidney outcome by 60%, LN flare by 57%, and first eGFR decline of 30% or 40% by 80% and 91%, respectively. Patients receiving obinutuzumab had a significantly slower decline in eGFR than patients receiving placebo, with an annualized eGFR slope advantage of 4.1 ml/min/1.73 m2 /year (95% confidence interval 0.14-8.08). Overall, 38% of patients receiving obinutuzumab compared with 16% of patients receiving placebo achieved CRR at week 76 while receiving 7.5 mg or less per day of prednisone (P < 0.01); at week 104, the difference did not achieve significance (38% vs 22%; P = 0.06). CONCLUSION: Post hoc analyses of NOBILITY demonstrated that compared with standard-of-care therapy, obinutuzumab treatment resulted in superior preservation of kidney function and prevention of LN flares. More patients achieved CRR at week 76 with less glucocorticoid use in the obinutuzumab group.

Transcriptional profiling upon T cell stimulation reveals down-regulation of inflammatory pathways in T and B cells in SLE versus Sjögren's syndrome.

Systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) share clinical as well as pathogenic similarities. Although previous studies suggest various abnormalities in different immune cell compartments, dedicated cell-type specific transcriptomic signatures are often masked by patient heterogeneity. Here, we performed transcriptional profiling of isolated CD4, CD8, CD16 and CD19 lymphocytes from pSS and SLE patients upon T cell stimulation, in addition to a steady-state condition directly after blood drawing, in total comprising 581 sequencing samples. T cell stimulation, which induced a pronounced inflammatory response in all four cell types, gave rise to substantial re-modulation of lymphocyte subsets in the two autoimmune diseases compared to healthy controls, far exceeding the transcriptomic differences detected at steady-state. In particular, we detected cell-type and disease-specific down-regulation of a range of pro-inflammatory cytokine and chemokine pathways. Such differences between SLE and pSS patients are instrumental for selective immune targeting by future therapies.

Systolic blood pressure ≤110 mm Hg is associated with severe coronary microvascular ischemia and higher risk for ventricular arrhythmias in hypertrophic cardiomyopathy.

Background: Coronary microvascular dysfunction (CMD) and hypertension (HTN) occur frequently in hypertrophic cardiomyopathy (HCM), but whether blood pressure (BP) influences CMD and outcomes is unknown. Objective: The purpose of this study was to test the hypothesis that HTN is associated with worse CMD and outcomes. Methods: This retrospective study included 690 HCM patients. All patients underwent cardiac magnetic resonance imaging, echocardiography, and rhythm monitoring; 127 patients also underwent rest/vasodilator stress 13NH3 positron emission tomography myocardial perfusion imaging. Patients were divided into 3 groups based on their rest systolic blood pressure (SBP) (group 1 ≤110 mm Hg; group 2 111-140; group 3 >140 mm Hg) and were followed for development of ventricular tachycardia (VT)/ventricular fibrillation (VF), heart failure (HF), death, and composite outcome. Results: Group 1 patients had the lowest age and left ventricular (LV) mass but the highest prevalence of nonobstructive hemodynamics and restrictive diastolic filling. LV scar was similar in the 3 groups. Group 1 had the lowest rest and stress myocardial blood flow (MBF) and highest SDS (summed difference score). Rest SBP was positively correlated with stress MBF and negatively correlated with SDS. Group 1 had the highest incidence of VT/VF, whereas the incidences of HF, death, and composite outcome were similar among the 3 groups. In multivariate analysis, rest SBP ≤110 mm Hg was independently associated with VT/VF (hazard ratio 2.6; 95% confidence interval 1.0-6.7; P = .04). Conclusion: SBP ≤110 mm Hg is associated with greater severity of CMD and coronary microvascular ischemia and higher incidence of ventricular arrhythmias in HCM.

Standardized Radiomics Analysis of Clinical Myocardial Perfusion Stress SPECT Images to Identify Coronary Artery Calcification.

PURPOSE: Myocardial perfusion (MP) stress single-photon emission computed tomography (SPECT) is an established diagnostic test for patients suspected of coronary artery disease (CAD). Meanwhile, coronary artery calcification (CAC) scoring obtained from diagnostic CT is a highly sensitive test, offering incremental diagnostic information in identifying patients with significant CAD yet normal MP stress SPECT (MPSS) scans. However, after decades of wide utilization of MPSS, CAC is not commonly reimbursed (e.g. by the CMS), nor widely deployed in community settings. We studied the potential of complementary information deduced from the radiomics analysis of normal MPSS scans in predicting the CAC score. METHODS: We collected data from 428 patients with normal (non-ischemic) MPSS (99mTc-sestamibi; consensus reading). A nuclear medicine physician verified iteratively reconstructed images (attenuation-corrected) to be free from fixed perfusion defects and artifactual attenuation. Three-dimensional images were automatically segmented into four regions of interest (ROIs), including myocardium and three vascular segments (left anterior descending [LAD]-left circumference [LCX]-right coronary artery [RCA]). We used our software package, standardized environment for radiomics analysis (SERA), to extract 487 radiomic features in compliance with the image biomarker standardization initiative (IBSI). Isotropic cubic voxels were discretized using fixed bin-number discretization (eight schemes). We first performed blind-to-outcome feature selection focusing on a priori usefulness, dynamic range, and redundancy of features. Subsequently, we performed univariate and multivariate machine learning analyses to predict CAC scores from i) selected radiomic features, ii) 10 clinical features, and iii) combined radiomics + clinical features. Univariate analysis invoked Spearman correlation with Benjamini-Hotchberg false-discovery correction. The multivariate analysis incorporated stepwise linear regression, where we randomly selected a 15% test set and divided the other 85% of data into 70% training and 30% validation sets. Training started from a constant (intercept) model, iteratively adding/removing features (stepwise regression), invoking the Akaike information criterion (AIC) to discourage overfitting. Validation was run similarly, except that the training output model was used as the initial model. We randomized training/validation sets 20 times, selecting the best model using log-likelihood for evaluation in the test set. Assessment in the test set was performed thoroughly by running the entire operation 50 times, subsequently employing Fisher's method to verify the significance of independent tests. RESULTS: Unsupervised feature selection significantly reduced 8×487 features to 56. In univariate analysis, no feature survived the false-discovery rate (FDR) to directly correlate with CAC scores. Applying Fisher's method to the multivariate regression results demonstrated combining radiomics with the clinical features to enhance the significance of the prediction model across all cardiac segments.  Conclusions: Our standardized and statistically robust multivariate analysis demonstrated significant prediction of the CAC score for all cardiac segments when combining MPSS radiomic features with clinical features, suggesting radiomics analysis can add diagnostic or prognostic value to standard MPSS for wide clinical usage.

Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart's energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage.

Novel Diagnostic Imaging Approach for Patients With Spontaneous Coronary Artery Dissection: The Utility of 18 F-FDG PET Imaging.

ABSTRACT: Spontaneous coronary artery dissection (SCAD) is an underdiagnosed etiology of acute coronary syndrome in women. Accurate diagnosis remains challenging but is imperative for treatment and prevention. We show here the utility of 18 F-FDG PET imaging in SCAD diagnosis. We present 1 representative case of 4 women with suspected SCAD on coronary angiography from the EVACS (Evolocumab in Acute Coronary Syndromes) clinical trial. 18 F-FDG PET imaging showed acute inflammation in the distribution of the suspected dissected coronary artery identified on angiography. Localized myocardial inflammation identified on 18 F-FDG PET imaging can aid in diagnosing SCAD suspected on coronary angiography.

Emerging role of PET/MR in the diagnosis and characterization of cardiotoxicity?

In cardiotoxicity, PET/MR affords an accurate evaluation of cardiovascular morphology, function, and also multi-parametric tissue characterization. A composite of several cardiac imaging parameters provided by the PET/MR scanner is likely to outperform a single parameter or imaging modality in the assessment and prediction of the severity and progression of cardiotoxicity but needing clinical investigations. Of particular interest, a heterogeneity map of single PET and CMR parameters could be perfectly correlated with the PET/MR scanner likely emerging as a promising marker of cardiotoxicity to monitor treatment response. While such functional and structural multiparametric imaging approach with cardiac PET/MR in the assessment and characterization of cardiotoxicity holds much promise, its validity and value in cancer patients treated with chemotherapy and/or radiation still needs to be assessed. The multi-parametric imaging approach with PET/MR, however, is likely to set new standards to develop predictive constellations of parameters for the severity and potential progression of cardiotoxicity that should afford timely and individualized treatment intervention to ascertain myocardial recovery and improved clinical outcome in these high-risk patients.