A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae.

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

Structure modeling hints at a granular organization of the Golgi ribbon.

BACKGROUND: In vertebrate cells, the Golgi functional subunits, mini-stacks, are linked into a tri-dimensional network. How this "ribbon" architecture relates to Golgi functions remains unclear. Are all connections between mini-stacks equal? Is the local structure of the ribbon of functional importance? These are difficult questions to address, without a quantifiable readout of the output of ribbon-embedded mini-stacks. Endothelial cells produce secretory granules, the Weibel-Palade bodies (WPB), whose von Willebrand Factor (VWF) cargo is central to hemostasis. The Golgi apparatus controls WPB size at both mini-stack and ribbon levels. Mini-stack dimensions delimit the size of VWF "boluses" whilst the ribbon architecture allows their linear co-packaging, thereby generating WPBs of different lengths. This Golgi/WPB size relationship suits mathematical analysis. RESULTS: WPB lengths were quantized as multiples of the bolus size and mathematical modeling simulated the effects of different Golgi ribbon organizations on WPB size, to be compared with the ground truth of experimental data. An initial simple model, with the Golgi as a single long ribbon composed of linearly interlinked mini-stacks, was refined to a collection of mini-ribbons and then to a mixture of mini-stack dimers plus long ribbon segments. Complementing these models with cell culture experiments led to novel findings. Firstly, one-bolus sized WPBs are secreted faster than larger secretory granules. Secondly, microtubule depolymerization unlinks the Golgi into equal proportions of mini-stack monomers and dimers. Kinetics of binding/unbinding of mini-stack monomers underpinning the presence of stable dimers was then simulated. Assuming that stable mini-stack dimers and monomers persist within the ribbon resulted in a final model that predicts a "breathing" arrangement of the Golgi, where monomer and dimer mini-stacks within longer structures undergo continuous linking/unlinking, consistent with experimentally observed WPB size distributions. CONCLUSIONS: Hypothetical Golgi organizations were validated against a quantifiable secretory output. The best-fitting Golgi model, accounting for stable mini-stack dimers, is consistent with a highly dynamic ribbon structure, capable of rapid rearrangement. Our modeling exercise therefore predicts that at the fine-grained level the Golgi ribbon is more complex than generally thought. Future experiments will confirm whether such a ribbon organization is endothelial-specific or a general feature of vertebrate cells.

Shrinking Weibel-Palade bodies prevents high platelet recruitment in assays using thrombotic thrombocytopenic purpura plasma.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP), caused by a genetic or autoimmune-driven lack of ADAMTS-13 activity, leads to high levels of the ultra-large von Willebrand factor (VWF) multimers produced by endothelial cells, causing excess platelet recruitment into forming thrombi, often with mortal consequences. Treatments include plasma infusion or replacement to restore ADAMTS-13 activity, or prevention of platelet recruitment to VWF. OBJECTIVES: We tested a different approach, exploiting the unique cell biology of the endothelium. Upon activation, the VWF released by exocytosis of Weibel-Palade bodies (WPBs), transiently anchored to the cell surface, unfurls as strings into flowing plasma, recruiting platelets. Using plasma from patients with TTP increases platelet recruitment to the surface of cultured endothelial cells under flow. WPBs are uniquely plastic, and shortening WPBs dramatically reduces VWF string lengths and the recruitment of platelets. We wished to test whether the TTP plasma-driven increase in platelet recruitment would be countered by reducing formation of the longest WPBs that release longer strings. METHODS: Endothelial cells grown in flow chambers were treated with fluvastatin, one of 37 drugs shown to shorten WPBs, then activated under flow in the presence of platelets and plasma of either controls or patients with TTP. RESULT: We found that the dramatic increase in platelet recruitment caused by TTP plasma is entirely countered by treatment with fluvastatin, shortening the WPBs. CONCLUSIONS: This potential approach of ameliorating the endothelial contribution to thrombotic risk by intervening far upstream of hemostasis might prove a useful adjunct to more conventional and direct therapies.

Comparison of Sensitivity and Specificity of Biparametric versus Multiparametric Prostate MRI in the Detection of Prostate Cancer in 431 Men with Elevated Prostate-Specific Antigen Levels.

(1) Background: the study of dynamic contrast enhancement (DCE) has a limited role in the detection of prostate cancer (PCa), and there is a growing interest in performing unenhanced biparametric prostate-MRI (bpMRI) instead of the conventional multiparametric-MRI (mpMRI). In this study, we aimed to retrospectively compare the performance of the mpMRI, which includes DCE study, and the unenhanced bpMRI, composed of only T2-weighted imaging and diffusion-weighted imaging (DWI), in PCa detection in men with elevated prostate-specific-antigen (PSA) levels. (2) Methods: a 1.5 T MRI, with an endorectal-coil, was performed on 431 men (aged 61.5 ± 8.3 years) with a PSA ≥4.0 ng/mL. The bpMRI and mpMRI tests were independently assessed in separate sessions by two readers with 5 (R1) and 3 (R2) years of experience. The histopathology or ≥2 years follow-up served as a reference standard. The sensitivity and specificity were calculated with their 95% CI, and McNemar's and Cohen's κ statistics were used. (3) Results: in 195/431 (45%) of histopathologically proven PCa cases, 62/195 (32%) were high-grade PCa (GS ≥ 7b) and 133/195 (68%) were low-grade PCa (GS ≤ 7a). The PCa could be excluded by histopathology in 58/431 (14%) and by follow-up in 178/431 (41%) of patients. For bpMRI, the sensitivity was 164/195 (84%, 95% CI: 79-89%) for R1 and 156/195 (80%, 95% CI: 74-86%) for R2; while specificity was 182/236 (77%, 95% CI: 72-82%) for R1 and 175/236 (74%, 95% CI: 68-80%) for R2. For mpMRI, sensitivity was 168/195 (86%, 95% CI: 81-91%) for R1 and 160/195 (82%, 95% CI: 77-87%) for R2; while specificity was 184/236 (78%, 95% CI: 73-83%) for R1 and 177/236 (75%, 95% CI: 69-81%) for R2. Interobserver agreement was substantial for both bpMRI (κ = 0.802) and mpMRI (κ = 0.787). (4) Conclusions: the diagnostic performance of bpMRI and mpMRI were similar, and no high-grade PCa was missed with bpMRI.

Generalized chest CT and lab curves throughout the course of COVID-19.

A better understanding of temporal relationships between chest CT and labs may provide a reference for disease severity over the disease course. Generalized curves of lung opacity volume and density over time can be used as standardized references from well before symptoms develop to over a month after recovery, when residual lung opacities remain. 739 patients with COVID-19 underwent CT and RT-PCR in an outbreak setting between January 21st and April 12th, 2020. 29 of 739 patients had serial exams (121 CTs and 279 laboratory measurements) over 50 ± 16 days, with an average of 4.2 sequential CTs each. Sequential volumes of total lung, overall opacity and opacity subtypes (ground glass opacity [GGO] and consolidation) were extracted using deep learning and manual segmentation. Generalized temporal curves of CT and laboratory measurements were correlated. Lung opacities appeared 3.4 ± 2.2 days prior to symptom onset. Opacity peaked 1 day after symptom onset. GGO onset was earlier and resolved later than consolidation. Lactate dehydrogenase, and C-reactive protein peaked earlier than procalcitonin and leukopenia. The temporal relationships of quantitative CT features and clinical labs have distinctive patterns and peaks in relation to symptom onset, which may inform early clinical course in patients with mild COVID-19 pneumonia, or may shed light upon chronic lung effects or mechanisms of medical countermeasures in clinical trials.

Federated semi-supervised learning for COVID region segmentation in chest CT using multi-national data from China, Italy, Japan.

The recent outbreak of Coronavirus Disease 2019 (COVID-19) has led to urgent needs for reliable diagnosis and management of SARS-CoV-2 infection. The current guideline is using RT-PCR for testing. As a complimentary tool with diagnostic imaging, chest Computed Tomography (CT) has been shown to be able to reveal visual patterns characteristic for COVID-19, which has definite value at several stages during the disease course. To facilitate CT analysis, recent efforts have focused on computer-aided characterization and diagnosis with chest CT scan, which has shown promising results. However, domain shift of data across clinical data centers poses a serious challenge when deploying learning-based models. A common way to alleviate this issue is to fine-tune the model locally with the target domains local data and annotations. Unfortunately, the availability and quality of local annotations usually varies due to heterogeneity in equipment and distribution of medical resources across the globe. This impact may be pronounced in the detection of COVID-19, since the relevant patterns vary in size, shape, and texture. In this work, we attempt to find a solution for this challenge via federated and semi-supervised learning. A multi-national database consisting of 1704 scans from three countries is adopted to study the performance gap, when training a model with one dataset and applying it to another. Expert radiologists manually delineated 945 scans for COVID-19 findings. In handling the variability in both the data and annotations, a novel federated semi-supervised learning technique is proposed to fully utilize all available data (with or without annotations). Federated learning avoids the need for sensitive data-sharing, which makes it favorable for institutions and nations with strict regulatory policy on data privacy. Moreover, semi-supervision potentially reduces the annotation burden under a distributed setting. The proposed framework is shown to be effective compared to fully supervised scenarios with conventional data sharing instead of model weight sharing.

Modulation of endothelial organelle size as an antithrombotic strategy.

BACKGROUND: It is long established that von Willebrand factor (VWF) is central to hemostasis and thrombosis. Endothelial VWF is stored in cell-specific secretory granules, Weibel-Palade bodies (WPBs), organelles generated in a wide range of lengths (0.5-5.0 µm). WPB size responds to physiological cues and pharmacological treatment, and VWF secretion from shortened WPBs dramatically reduces platelet and plasma VWF adhesion to an endothelial surface. OBJECTIVE: We hypothesized that WPB-shortening represented a novel target for antithrombotic therapy. Our objective was to determine whether compounds exhibiting this activity do exist. METHODS: Using a microscopy approach coupled to automated image analysis, we measured the size of WPB bodies in primary human endothelial cells treated with licensed compounds for 24 hours. RESULTS AND CONCLUSIONS: A novel approach to identification of antithrombotic compounds generated a significant number of candidates with the ability to shorten WPBs. In vitro assays of two selected compounds confirm that they inhibit the pro-hemostatic activity of secreted VWF. This set of compounds acting at a very early stage of the hemostatic process could well prove to be a useful adjunct to current antithrombotic therapeutics. Further, in the current SARS-CoV-2 pandemic, with a considerable fraction of critically ill COVID-19 patients affected by hypercoagulability, these WPB size-reducing drugs might also provide welcome therapeutic leads for frontline clinicians and researchers.

Artificial intelligence for the detection of COVID-19 pneumonia on chest CT using multinational datasets.

Chest CT is emerging as a valuable diagnostic tool for clinical management of COVID-19 associated lung disease. Artificial intelligence (AI) has the potential to aid in rapid evaluation of CT scans for differentiation of COVID-19 findings from other clinical entities. Here we show that a series of deep learning algorithms, trained in a diverse multinational cohort of 1280 patients to localize parietal pleura/lung parenchyma followed by classification of COVID-19 pneumonia, can achieve up to 90.8% accuracy, with 84% sensitivity and 93% specificity, as evaluated in an independent test set (not included in training and validation) of 1337 patients. Normal controls included chest CTs from oncology, emergency, and pneumonia-related indications. The false positive rate in 140 patients with laboratory confirmed other (non COVID-19) pneumonias was 10%. AI-based algorithms can readily identify CT scans with COVID-19 associated pneumonia, as well as distinguish non-COVID related pneumonias with high specificity in diverse patient populations.

RGS4 controls secretion of von Willebrand factor to the subendothelial matrix.

The haemostatic protein von Willebrand factor (VWF) exists in plasma and subendothelial pools. The plasma pools are secreted from endothelial storage granules, Weibel-Palade bodies (WPBs), by basal secretion with a contribution from agonist-stimulated secretion, and the subendothelial pool is secreted into the subendothelial matrix by a constitutive pathway not involving WPBs. We set out to determine whether the constitutive release of subendothelial VWF is actually regulated and, if so, what functional consequences this might have. Constitutive VWF secretion can be increased by a range of factors, including changes in VWF expression, levels of TNF and other environmental cues. An RNA-seq analysis revealed that expression of regulator of G protein signalling 4 (RGS4) was reduced in endothelial cells (HUVECs) grown under these conditions. siRNA RGS4 treatment of HUVECs increased constitutive basolateral secretion of VWF, probably by affecting the anterograde secretory pathway. In a simple model of endothelial damage, we show that RGS4-silenced cells increased platelet recruitment onto the subendothelial matrix under flow. These results show that changes in RGS4 expression alter levels of subendothelial VWF, affecting platelet recruitment. This introduces a novel control over VWF function.

Myths and facts about artificial intelligence: why machine- and deep-learning will not replace interventional radiologists.

Artificial intelligence (AI) is revolutionizing healthcare and transforming the clinical practice of physicians across the world. Radiology has a strong affinity for machine learning and is at the forefront of the paradigm shift, as machines compete with humans for cognitive abilities. AI is a computer science simulation of the human mind that utilizes algorithms based on collective human knowledge and the best available evidence to process various forms of inputs and deliver desired outcomes, such as clinical diagnoses and optimal treatment options. Despite the overwhelmingly positive uptake of the technology, warnings have been published about the potential dangers of AI. Concerns have been expressed reflecting opinions that future medicine based on AI will render radiologists irrelevant. Thus, how much of this is based on reality? To answer these questions, it is important to examine the facts, clarify where AI really stands and why many of these speculations are untrue. We aim to debunk the 6 top myths regarding AI in the future of radiologists.

Quantification of heterogeneity to classify benign parotid tumors: a feasibility study on most frequent histotypes.

Aim: To differentiate Warthin tumors (WTs) and pleomorphic adenomas (PAs) measuring heterogeneity of intravoxel incoherent motion (IVIM) and dynamic-contrast enhanced-magnetic resonance imaging biomarkers. Methods: Volumes of interest were traced on 18 WT and 18 PA in 25 patients. For each IVIM and dynamic-contrast enhanced biomarker, histogram parameters were calculated and then compared using the Wilcoxon-signed-rank test. Receiver operating characteristic curves and multivariate analysis were employed to identify the parameters and their pairs with the best accuracy. Results: Most of the biomarkers exhibited significant difference (p < 0.05) between PA and WT for histogram parameters. Time to peak median and skewness, and D* median and entropy showed the highest area under the curve. No meaningful improvement of accuracy was obtained using two features. Conclusion: IVIM and dynamic-contrast enhanced histogram descriptors may help in the classification of WT and PA.

Gd-EOB-DTP-enhanced MRC in the preoperative percutaneous management of intra and extrahepatic biliary leakages: does it matter?

Postoperative bile leakage is a common complication of abdominal surgical procedures and a precise localization of is important to choose the best management. Many techniques are available to correctly identify bile leaks, including ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI), being the latter the best to clearly depict "active" bile leakages. This paper presents the state of the art algorithm in the detection of biliary leakages in order to plan a percutaneous biliary drainage focusing on widely available and safe contrast agent, the Gb-EOB-DPA. We consider its pharmacokinetic properties and impact in biliary imaging explain current debates to optimize image quality. We report common sites of leakage after surgery with special considerations in cirrhotic liver to show what interventional radiologists should look to easily detect bile leaks.

Assessment of the response of hepatocellular carcinoma to interventional radiology treatments.

According to Barcelona Clinic Liver Cancer (BCLC) guidelines, interventional radiology procedures are valuable treatment options for many hepatocellular carcinomas (HCCs) that are not amenable to resection or transplantation. Accurate assessment of the efficacy of therapies at earlier stages enables completion of treatment, optimal follow-up and to prevent potentially unnecessary treatments, side effects and costly failure. The goal of this review is to summarize and describe the radiological strategies that have been proposed to predict survival and to stratify HCC responses after interventional radiology therapies. New techniques currently in development are also described.

Endothelial cell-derived nidogen-1 inhibits migration of SK-BR-3 breast cancer cells.

BACKGROUND: The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood. METHODS: We have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro. RESULTS: Upon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression. CONCLUSION: The identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.

Early cross-sectional imaging following open and laparoscopic cholecystectomy: a primer for radiologists.

Performed on either an elective or urgent basis, cholecystectomy currently represents the most common abdominal operation due to the widespread use of laparoscopy and the progressively expanded indications. Compared to traditional open surgery, laparoscopic cholecystectomy minimised the duration of hospitalisation and perioperative mortality. Albeit generally considered safe, cholecystectomy may result in adverse outcomes with non-negligible morbidity. Furthermore, the incidence of worrisome haemorrhages and biliary complications has not been influenced by the technique shift. Due to the growing medico-legal concerns and the vast number of cholecystectomies, radiologists are increasingly requested to investigate recently operated patients. Aiming to increase familiarity with post-cholecystectomy cross-sectional imaging, this paper provides a brief overview of indications and surgical techniques and illustrates the expected early postoperative imaging findings. Afterwards, most iatrogenic complications following open, converted, laparoscopic and laparo-endoscopic rendezvous cholecystectomy are reviewed with examples, including infections, haematoma and active bleeding, residual choledocholithiasis, pancreatitis, biliary obstruction and leakage. Multidetector computed tomography (CT) represents the "workhorse" modality to rapidly investigate the postoperative abdomen in order to provide a reliable basis for an appropriate choice between conservative, interventional or surgical treatment. Emphasis is placed on the role of early magnetic resonance cholangiopancreatography (MRCP) and additional gadoxetic acid-enhanced MRCP to provide a non-invasive anatomic and functional assessment of the operated biliary tract. TEACHING POINTS: • Having minimised perioperative mortality and hospital stay, laparoscopy has now become the first-line approach to performing cholecystectomy, even in patients with acute cholecystitis. • Laparoscopic, laparo-endoscopic rendezvous, converted and open cholecystectomy remain associated with non-negligible morbidity, including surgical site infections, haemorrhage, residual lithiasis, pancreatitis, biliary obstruction and leakage. • Contrast-enhanced multidetector computed tomography (CT) is increasingly requested early after cholecystectomy and represents the "workhorse" modality that rapidly provides a comprehensive assessment of the operated biliary tract and abdomen. • Magnetic resonance cholangiopancreatography (MRCP) is the best modality to provide anatomic visualisation of the operated biliary tract and is indicated when biliary complications are suspected. • Additional gadoxetic acid (Gd-EOB-DTPA)-enhanced MRCP non-invasively provides functional biliary assessment, in order to confirm and visualise bile leakage.

DEB-TACE: a standard review.

Drug-eluting bead transarterial chemoembolization (DEB-TACE) is a relative new endovascular treatment based on the use of microspheres to release chemotherapeutic agents within a target lesion with controlled pharmacokinetics. This aspect justifies the immediate success of DEB-TACE, that nowadays represents one of the most used treatments for unresectable hepatocellular carcinoma. However, there is no consensus about the choice of the best embolotherapy technique. In this review, we describe the available microspheres and report the results of the main comparative studies, to clarify the role of DEB-TACE in the hepatocellular carcinoma management. We underline that there is no evidence about the superiority of DEB-TACE over conventional TACE in terms of efficacy, but there may be some benefits with respect to safety especially with the improvement of new technologies.

CT-MRI LI-RADS v2017: A Comprehensive Guide for Beginners.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second leading cause of cancer-related deceases worldwide. Early diagnosis is essential for correct management and improvement of prognosis. Proposed for the first time in 2011 and updated for the last time in 2017, the Liver Imaging-Reporting and Data System (LI-RADS) is a comprehensive system for standardized interpretation and reporting of computed tomography (CT) and magnetic resonance imaging (MRI) liver examinations, endorsed by the American College of Radiology to achieve congruence with HCC diagnostic criteria in at-risk populations. Understanding its algorithm is fundamental to correctly apply LI-RADS in clinical practice. In this pictorial review, we provide a guide for beginners, explaining LI-RADS indications, describing major and ancillary features and eventually elucidating the diagnostic algorithm with the use of some clinical examples.

The role of interventional radiology in the treatment of epiphora.

Epiphora is a relatively common ophthalmologic affection representing almost 5% of clinical consultations in ophthalmology and it consists in the complete or partial obstruction of nasolacrimal duct, leading to insufficient drainage of tears. The traditional treatment is represented by surgery namely, external dacryocystorhinostomy (DCR). Despite the high success rate DCR has many disadvantages and limitations since it requires general anesthesia, it may arise in a permanent facial scar and it is often affected by the reobstruction of the anastomotic tract by fibrotic scars and osteogenic activity. Fluoroscopically guided interventional procedures are a therapeutic alternative to surgery for lacrimal duct system obstructions that can consist either in balloon dacryocystoplasty or in nasolacrimal stent placement. In both cases, a pre-operative imaging characterization of the occlusion is needed for a correct treatment planning. In this review, we propose to highlight the role of interventional radiology in the treatment of epiphora and the role of computed tomography dacryocystography (CTD) in depiction and the pre-interventional planning.

State of the art of prostatic arterial embolization for benign prostatic hyperplasia.

Prostatectomy via open surgery or transurethral resection of the prostate (TURP) is the standard treatment for benign prostatic hyperplasia (BPH). Several patients present contraindication for standard approach, individuals older than 60 years with urinary tract infection, strictures, post-operative pain, incontinence or urinary retention, sexual dysfunction, and blood loss are not good candidates for surgery. Prostatic artery embolization (PAE) is emerging as a viable method for patients unsuitable for surgery. In this article, we report results about technical and clinical success and safety of the procedure to define the current status.