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PurposeTo develop a pipeline that automatically classifies patients for pulmonary embolism (PE) in CT pulmonary angiography (CTPA) examinations with high sensitivity and specificity.Materials and MethodsSeven hundred non-ECG-gated CTPA examinations from 652 patients (median age 72 years, range 16-100 years; interquartile range 18 years; 353 women) performed at a single institution between 2014 and 2018, of which 149 examinations contained PE, were used for model development. The nnU-Net deep learning-based segmentation framework was trained and validated in 5-fold cross-validation. To enhance classification, we applied logical rules based on PE volume and probability thresholds. External model testing was then performed in 770 and 34 CTPAs from two independent datasets.ResultsFor patient-level classification, a threshold PE volume of 20 mm³ resulted in the best balance between sensitivity and specificity. In internal cross-validation and test set, the trained model correctly classified 123 of 128 examinations as positive for PE (sensitivity 96%; 95% C.I. 91-98%) and 521 of 551 as negative (specificity 95%; 95% C.I. 92-96%). In the first external test dataset, the trained model correctly classified 31 of 32 examinations as positive (sensitivity 97%; 95% C.I. 84-99%) and 2 of 2 as negative (specificity 100%; 95% C.I. 34-100%). In the second external test dataset, the trained model correctly classified 379 of 385 examinations as positive (sensitivity 98%; 95% C.I. 97-99%) and 346 of 385 as negative (specificity 90%; 95% C.I. 86-93%).ConclusionBeyond state-of-art classification for PE in CTPA was achieved using nnU-Net for deep learning-based segmentation in combination with volume- and probability-based classification.

Highlights • Pericardial effusion with acute cardiac tamponade may be a potential complication of severe SARS-CoV-2 infection. • This should be kept in mind especially when facing mechanically ventilated patients with acute hemodynamic collapse. • Bedside TTE is a valuable tool for prompt diagnosis and life-saving therapeutic pericardiocentesis., Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently evolved as a pandemic disease. Although the respiratory system is predominantly affected, cardiovascular complications have been frequently identified, including acute myocarditis, myocardial infarction, acute heart failure, arrhythmias and venous thromboembolic events. Pericardial disease has been rarely reported. We present a case of acute life-threatening cardiac tamponade caused by a small pericardial effusion in a mechanically ventilated patient with severe COVID-19 associated pneumonia. The patient presented acute circulatory collapse with hemodynamic features of cardiogenic or obstructive shock. Bedside echocardiography permitted prompt diagnosis and life-saving pericardiocentesis. Further investigation revealed no other apparent cause of pericardial effusion except for SARS-CoV-2 infection. Cardiac tamponade may complicate COVID-19 and should be included in the differential diagnosis of acute hemodynamic deterioration in mechanically ventilated COVID-19 patients.

Cigarette smoking is one of the risk factors for coronary artery disease. Although conditioning decreases infarct size in hearts from healthy animals, comorbidities may render it ineffective. We investigated the effects of cigarette smoke (CS) exposure on intracellular myocardial signaling, infarct size after ischemia-reperfusion, and the potential interference with ischemic conditioning. Exposure of mice to CS increased blood pressure, caused cardiac hypertrophy, and upregulated the nitric oxide synthatse (NOS)/soluble guanylate cyclase (sGC)/cGMP pathway. To test the effect of CS exposure on the endogenous cardioprotective mechanisms, mice were subjected to regional myocardial ischemia and reperfusion with no further intervention or application of preconditioning (PreC) or postconditioning (PostC). Exposure to CS did not increase the infarction compared with the room air (RA)-exposed group. PreC was beneficial for both CS and RA vs. nonconditioned animals. PostC was effective only in RA animals, while the infarct size-limiting effect was not preserved in the CS group. Differences in oxidative stress markers, Akt, and endothelial NOS phosphorylation and cGMP levels were observed between RA and CS groups subjected to PostC. In conclusion, exposure to CS does not per se increase infarct size. The beneficial effect of ischemic PreC is preserved in mice exposed to CS, as it does not affect the cardioprotective signaling; in contrast, PostC fails to protect CS-exposed mice due to impaired activation of the Akt/eNOS/cGMP axis that occurs in parallel to enhanced oxidative stress.

Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-κB (BAY-11–7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-κB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-α, IL-10, IL-2, IL-1β) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-κB. Inhibition of NF-κB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-κB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-κB/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-κB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-κB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm.

Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation.To determine the effects of resistive breathing on the healthy lung.Anesthetized rats breathed through a two-way nonrebreathing valve. The inspiratory line was connected to a resistance setting peak inspiratory tracheal pressure at 50% of maximum (inspiratory resistive breathing), while 100% oxygen was supplied to prevent hypoxemia. Quietly breathing animals (100% oxygen) served as controls. Lung injury was evaluated after 3 and 6 hours of resistive breathing.After both 3 and 6 hours of resistive breathing, lung permeability was increased, as assessed by (99m)Tc-diethylenetriaminepentaacetic acid scintigraphy and Evans blue dye extravasation. Tissue elasticity, measured on the basis of static pressure-volume curves and by the low-frequency forced oscillation technique, was also increased. After both 3 and 6 hours of resistive breathing, gravimetric measurements revealed the presence of pulmonary edema and analysis of bronchoalveolar lavage showed increased total protein content, whereas the total cell count was elevated only after 6 hours of resistive breathing. Cytokine levels were assessed in bronchoalveolar lavage fluid and lung tissue by ELISA and were increased after 6 hours compared with controls. Western blot analysis showed early activation of Src kinase via phosphorylation (at 30 min), and Erk1/2 and IκBα (nuclear factor-κB inhibitor) were phosphorylated at 3 and 6 hours. Pathology revealed the presence of lung injury after resistive breathing.Resistive breathing induces acute lung injury and inflammation.

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure–volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC–cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.

Resistive breathing (encountered in chronic obstructive pulmonary disease and asthma) results in cytokine upregulation and decreased nitric oxide (NO) levels in the strenuously contracting diaphragm. NO can regulate gene expression. We hypothesized that endogenously produced NO downregulates cytokine production triggered by strenuous diaphragmatic contraction. Wistar rats treated with vehicle, the nonselective NO synthase inhibitor NG-nitro-l-arginine-methylester (l-NAME), or the NO donor diethylenetriamine-NONOate (DETA) were subjected to inspiratory resistive breathing (IRB; 50% of maximal inspiratory pressure) for 6 h or sham operation. Additional groups of rats were subjected to IRB for 6 h with concurrent administration of l-NAME and inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), or P38 (SB203580). Inhibition of NO production (with l-NAME) resulted in upregulation of IRB-induced diaphragmatic IL-6, IL-10, IL-2, TNF-α, and IL-1β levels by 50%, 53%, 60%, 47%, and 45%, respectively. In contrast, the NO donor (DETA) attenuated the IRB-induced cytokine upregulation to levels characteristic of quietly breathing animals. l-NAME augmented IRB-induced activation of MAPKs (P38 and ERK1/2) and NF-κB, whereas DETA triggered the opposite effect. NF-κB and ERK1/2 inhibition in l-NAME-treated animals blunted the l-NAME-induced cytokine upregulation except IL-6, whereas P38 inhibition blunted all (including IL-6) cytokine upregulation. NO downregulates IRB-induced cytokine production in the strenuously contracting diaphragm through its action on MAPKs and NF-κB.

Introduction and objectives Inspiratory resistive breathing (IRB), a hallmark of obstructive pulmonary diseases, is characterised by large negative intrathoracic pressures. IRB is shown to induce pulmonary inflammation in previously healthy rats. Src is a multifunctional kinase that is activated by phosphorylation upon mechanical stress and plays a significant role in inflammatory processes. The aim of our study was to investigate the role of Src in IRB-induced pulmonary inflammation. Methods Anaesthetised, tracheostomised rats were breathing spontaneously through a 2-way non rebreathing valve. The inspiratory port was connected to a resistance, setting peak tidal tracheal pressure at 50% of maximum (IRB). Quietly breathing animals served as controls. After 6 h of IRB, the mechanics of the respiratory system were assessed with the forced oscillation technique. Bronchoalveolar lavage (BAL) was performed to measure total and differential cell count and total protein levels. Phosphorylation of Src and ERK was detected in lung tissue samples by Western blot analysis at 30 min, 3 and 6 h of IRB. The Src inhibitor PP2 was administered intraperitoneally (1 mg/kg), 30 min prior to IRB, in a subgroup of animals. Results After 6 h of IRB, increased tissue elasticity was measured, compared to control. Increased BAL cellularity was also found (2-fold increase to control), due to raised numbers of both macrophages and neutrophils. Total protein levels were elevated in BAL fluid. Src activation was detected at 30 min of IRB (3-fold increase to control), while ERK was phosphorylated at 3 and 6 h. Inhibition of Src kinase attenuated the increase in tissue elasticity after 6 h of IRB. Following inhibition of Src kinase, the total cell number after 6 h of IRB was not increased compared to control. Neither macrophage nor neutrophil count was elevated after 6 h of IRB, following Src inhibition. Total protein levels were not altered by Src inhibition. Src inhibition attenuated the activation of ERK only at 3 h of IRB. Conclusion Src kinase activation partly mediates IRB-induced pulmonary inflammation.

Background & Objectives: During exacerbations of chronic obstructive pulmonary disease (COPD), increased airway inflammation and the accompanying bronchoconstriction lead to significant airway narrowing, i.e. resistive breathing (RB).To isolate the effects of mechanical stressor (i.e. RB) from the accompanying lung inflammation we developed an experimental model of RBthat exhibits both increased inspiratory and expiratory airway resistance, via tracheal banding . Since hydrogen sulphide (H 2 S) plays an important role in vasodilation and inflammation we hypothesized that the administration of a H 2 S fast releasing donor, Na 2 S, will attenuate the lung inflammation. Methods: C57BL/6 mice were studied: 1. Sham operated (controls) 2. Tracheal banded (TB) mice (tracheal surface area restricted to 50% of initial) 3. Sham operated mice treated with injected Na 2 S (10mg/kg) 4. Mice treated with injected Na 2 S 20 min prior to tracheal banding. Results: The proteinexpression of the three H 2 S synthesizing enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3MST), was the same between the TB and sham operated group in the lung. However, the lung mRNA level of CBS was decreased by 57% in TB mice (p=0.009). Finally interleukin IL-6 and IL-1β, were attenuated by 50% (p=0.004)and 45% (p=0.02)in the group of TB mice treated with Na 2 S compared to the TB mice, whereas the expression of TNF-α was the same among the groups. Conclusions: H 2 S ameliorates lung inflammation caused by airway narrowing. Our model of TB might offer new insights by which resistive breathing can enhance inflammation in obstructive lung disease.