Background
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by necrotizing inflammation of small- and medium-sized blood vessels and the ...presence of circulating ANCA. Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic ANCA-associated vasculitis, characterized by peripheral eosinophilia, neuropathy, palpable purpuras or petechiae, renal and cardiac involvement, sinusitis, asthma, and transient pulmonary infiltrates. Middle lobe syndrome (MLS) is defined as recurrent or chronic atelectasis of the right middle lobe of the lung, and it is a potential complication of asthma.
Case presentation
Herein, we describe a case of MLS in a 51-year-old woman, never-smoker, affected by EGPA, presenting exclusively with leukocytosis and elevated concentrations of acute-phase proteins, without any respiratory symptom, cough, or hemoptysis. Chest computed tomography (CT) imaging documented complete atelectasis of the middle lobe, together with complete obstruction of lobar bronchial branch origin. Fiberoptic bronchoscopy (FOB) revealed complete stenosis of the middle lobar bronchus origin, thus confirming the diagnosis of MLS, along with distal left main bronchus stenosis. Bronchoalveolar lavage (BAL) did not detect any infection. Bronchial biopsies included plasma cells, neutrophil infiltrates, only isolated eosinophils, and no granulomas, providing the hypothesis of vasculitic acute involvement less likely. First-line agents directed towards optimizing pulmonary function (mucolytics, bronchodilators, and antibiotic course) were therefore employed. However, the patient did not respond to conservative treatment; hence, endoscopic management of airway obstruction was performed, with chest CT documenting resolution of middle lobe atelectasis.
Conclusion
To the best of our knowledge, this is the first detailed description of MLS in EGPA completely resolved through FOB. Identification of MLS in EGPA appears essential as prognosis, longitudinal management, and treatment options may differ from other pulmonary involvement in AAV patients.
Background
We aimed to train and test a deep learning classifier to support the diagnosis of coronavirus disease 2019 (COVID-19) using chest x-ray (CXR) on a cohort of subjects from two hospitals in ...Lombardy, Italy.
Methods
We used for training and validation an ensemble of ten convolutional neural networks (CNNs) with mainly bedside CXRs of 250 COVID-19 and 250 non-COVID-19 subjects from two hospitals (Centres 1 and 2). We then tested such system on bedside CXRs of an independent group of 110 patients (74 COVID-19, 36 non-COVID-19) from one of the two hospitals. A retrospective reading was performed by two radiologists in the absence of any clinical information, with the aim to differentiate COVID-19 from non-COVID-19 patients. Real-time polymerase chain reaction served as the reference standard.
Results
At 10-fold cross-validation, our deep learning model classified COVID-19 and non-COVID-19 patients with 0.78 sensitivity (95% confidence interval CI 0.74–0.81), 0.82 specificity (95% CI 0.78–0.85), and 0.89 area under the curve (AUC) (95% CI 0.86–0.91). For the independent dataset, deep learning showed 0.80 sensitivity (95% CI 0.72–0.86) (59/74), 0.81 specificity (29/36) (95% CI 0.73–0.87), and 0.81 AUC (95% CI 0.73–0.87). Radiologists’ reading obtained 0.63 sensitivity (95% CI 0.52–0.74) and 0.78 specificity (95% CI 0.61–0.90) in Centre 1 and 0.64 sensitivity (95% CI 0.52–0.74) and 0.86 specificity (95% CI 0.71–0.95) in Centre 2.
Conclusions
This preliminary experience based on ten CNNs trained on a limited training dataset shows an interesting potential of deep learning for COVID-19 diagnosis. Such tool is in training with new CXRs to further increase its performance.
To assess whether urine protein-to-creatinine (UPC) ratios determined in urine samples collected by cystocentesis versus those collected by free catch provide similar diagnostic information for dogs.
...Evaluation study.
115 client-owned dogs evaluated because of various health problems requiring urinalysis or to screen for proteinuria in an area endemic for leishmaniasis.
230 paired urine samples, 1 collected by cystocentesis and 1 by free catch, were collected from the 115 dogs. The UPC ratio was determined in paired urine samples (n = 162) from 81 dogs with no indication of active inflammation according to urine sediment analysis. On the basis of the UPC ratio of urine sample collected by cystocentesis, dogs were classified as nonproteinuric (UPC ratio < 0.2), borderline proteinuric (UPC ratio of 0.2 to 0.5), or proteinuric (UPC ratio > 0.5), according to the International Renal Interest Society (IRIS).
The correlation between UPC ratio in urine samples collected by cystocentesis and by free catch was strong (r(2) = 0.90); 75 of 81 (92.6%) dogs had UPC ratios from both urine samples that resulted in classification in the same IRIS substage with a kappa coefficient of 0.83.
The UPC ratio in dogs was minimally affected in urine samples collected by free catch, thus allowing correct grading of proteinuria with this method. The high reliability of the UPC ratio in free-catch urine samples coupled with the ease of collection should increase the use of this value for assessment of proteinuria.
Abstract
Background
Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients.
Objectives
To evaluate the pharmacokinetics of ...remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients.
Methods
Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method.
Results
We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure.
Conclusions
We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.
CDCP1, a transmembrane protein with tumor pro-metastatic activity, was recently identified as a prognostic marker in TNBC, the most aggressive breast cancer subtype still lacking an effective ...molecular targeted therapy. The mechanisms driving CDCP1 over-expression are not fully understood, although several stimuli derived from tumor microenvironment, such as factors present in Wound Healing Fluids (WHFs), reportedly increase CDCP1 levels. The expression of CDCP1, PDGFRbeta and ERK1/2cell was tested by Western blot after stimulation of MDA-MB-231 cells with PDGF-BB and, similarly, in presence or not of ERK1/2 inhibitor in a panel of TNBC cell lines. Knock-down of PDGFRbeta was established in MDA-MB-231 cells to detect CDCP1 upon WHF treatment. Immunohistochemical staining was used to detect the expression of CDCP1 and PDGFRbeta in TNBC clinical samples. We discovered that PDGF-BB-mediated activation of PDGFRbeta increases CDCP1 protein expression through the downstream activation of ERK1/2. Inhibition of ERK1/2 activity reduced per se CDCP1 expression, evidence strengthening its role in CDCP1 expression regulation. Knock-down of PDGFRbeta in TNBC cells impaired CDCP1 increase induced by WHF treatment, highlighting the role if this receptor as a central player of the WHF-mediated CDCP1 induction. A significant association between CDCP1 and PDGFRbeta immunohistochemical staining was observed in TNBC specimens, independently of CDCP1 gene gain, thus corroborating the relevance of the PDGF-BB/PDGFRbeta axis in the modulation of CDCP1 expression. We have identified PDGF-BB/PDGFRbeta-mediated pathway as a novel player in the regulation of CDCP1 in TNCBs through ERK1/2 activation. Our results provide the basis for the potential use of PDGFRbeta and ERK1/2 inhibitors in targeting the aggressive features of CDCP1-positive TNBCs.
The role of some chemical elements in neurodegeneration was suggested by various authors. To obtain a profile of chemical elements and oxidative status in complex neurological diseases, an unbiased ...“omics” approach, i.e., quantification of 26 elements and oxidative stress parameters (serum oxidative status (SOS) and serum anti-oxidant capacity (SAC)), combined with multivariate statistical procedures (forward discriminant analysis, FDA) to analyse the vast amount of data, was applied to four groups of subjects (53 patients with Alzheimer's disease (AD), 71 with Parkinson disease (PD), 60 with multiple sclerosis (MS) and 124 healthy individuals).
Descriptive statistics revealed numerous differences between each disease and healthy status. A concordant imbalance (reduction in Fe, Zn and SAC, and increase in SOS) was shared by AD, PD and MS. The FDA yielded three significant discriminant functions based on age, SOS, Ca, Fe, Si, Sn, V, Zn and Zr, and identified disease-specific profiles of element imbalances, thus showing the appropriateness of the “omics” approach. It may help assess the contribution of chemical elements and oxidative stress to disease causation and may provide complex predictors of disease evolution or treatment response.
The aim of this study was to characterize the genome of a recombinant Enterovirus associated with severe and fatal nosocomial infection; it was typed as Echovirus 11 (E-11) according to the VP1 gene. ...Enterovirus infection is generally asymptomatic and self-limited, but occasionally it may progress to a more severe clinical manifestation, as in the case described here. Recombination plays a crucial role in the evolution of Enteroviruses (EVs) and has been recognized as the main driving force behind the emergence of epidemic strains associated with severe infection. Therefore, it is of utmost importance to monitor the circulation of recombinant strains for surveillance purposes.
Enterovirus-RNA was detected in the serum and liver biopsy of patients involved in the nosocomial cluster by commercial One-Step qRT-PCR method and the Enterovirus strains were isolated in vitro. The EVs typing was determined by analyzing the partial-length of the 5'UTR and VP1 sequences with the web-based open-access Enterovirus Genotyping Tool Version 0.1. The amplicons targeting 5'UTR, VP1 and overlapping fragments of the entire genome were sequenced with the Sanger method. Phylogenetic analysis was performed comparing the VP1 and the full-genome sequences of our strains against an appropriate reference set of Enterovirus prototypes of the Picornaviridae genera and species retrieved from the Enterovirus Genotyping Tool. Recombination analysis was performed using RDP4 software.
The Neighbor-Joining tree of the VP1 gene revealed that the 4 patients were infected with an identical molecular variant of Echovirus 11 (E-11). While the phylogenetic and the RDP4 analysis of the full-genome sequences provided evidence that it was a chimeric strain between an E-11 and a Coxsackievirus B (CV-B).
The chimeric structure of the E-11 genome might have contributed to the severe infection and epidemic feature of the strain, but further biological characterizations are needed. The evidence reported in this study, highlights the limit of typing techniques based on the VP1 gene, as they fail to identify the emergence of recombinant strains with potentially more pathogenic or epidemic properties, thus providing only partial information on the epidemiology and pathogenesis of Enteroviruses.
In Italy in 2016, acute flaccid myelitis developed in a woman who had received a hematopoietic stem cell transplant. Enterovirus D68 viral genome was detected in respiratory and cerebrospinal fluid ...samples, and the viral protein 1 sequence clustered with lineage B3. Immunocompromised adults may be at risk for enterovirus D68-associated neurologic complications.
At appropriate concentrations, selenium (Se) is beneficial for humans. Tomato appears to be one of the best commodities for producing Se-biofortified fruit for dietary supplementation. To assess the ...efficacy of different enrichment protocols, a total of four on-plant and off-plant trials were conducted. Hydroponically grown tomato plants were sprayed with: (i) chemically synthesized Se nanoparticles (SeNPs) at 0, 1, and 1.5 mg Se L−1 at blooming; (ii) sodium selenate (Na2SeO4) or SeNPs solution at 0, 5, and 10 mg Se L−1 when the fruit entered the immature green stage. With regard to the off-plant trials, harvested mature green fruit were immersed in Na2SeO4 solution: (iii) at 0, 5, 10, and 20 mg Se L−1 for 15 s under a vacuum; (iv) at 0, 40, and 80 mg Se L−1 for 1 h. Spraying Na2SeO4 induced higher Se accumulation in plant tissue than SeNPs: both protocols were effective in enriching tomatoes. Postharvest Se enrichment via vacuum infiltration caused textural damage, whereas passive immersion in solution induced fruit Se accumulation without causing any damage. SeNPs appear to be quantitatively less effective than Na2SeO4, but might be environmentally safer. Elemental Se carried by NPs may be more easily incorporated into organic forms, which are more bioavailable for humans. Passive immersion may represent an alternative Se-enrichment strategy, allowing for the biofortification of harvested tomato fruit directly, with lower risks of environmental pollution.
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