Efficacy of oral amantadine among patients hospitalised with COVID-19: A randomised, double-blind, placebo-controlled, multicentre study.

BACKGROUND: Amantadine has been proposed as a treatment for COVID-19 because it shows anti-SARS-CoV-2 activity in vitro. However, to date, no controlled study has assessed the safety and efficacy of amantadine in COVID-19. RESEARCH QUESTION: Whether amantadine is effective and safe among patients with different COVID-19 severity classifications. STUDY DESIGN: and Methods: This was multi-centre, randomised, placebo-controlled study.Patients with oxygen saturation ≤94% and no need for high-flow oxygen or ventilatory support were randomly allocated to receive oral amantadine or placebo (1:1) for 10 days in addition to standard care. The primary endpoint was time to recovery assessed over 28 days since randomisation, defined as discharge from hospital or no need for supplemental oxygen. RESULTS: The study was terminated early due to a lack of efficacy after an interim analysis. Final data from 95 patients who received amantadine (mean age, 60.2 years; 65% male; 66% with comorbidities) and 91 patients who received placebo (mean age, 55.8 years; 60% male; 68% with comorbidities) were obtained. The median (95% CI) time to recovery was 10 days both in the amantadine (9-11) and placebo arms (8-11; subhazard ratio = 0.94 [95%CI 0.7-1.3]). The percentage of deaths and percentage of patients who required intensive care at 14 and 28 days did not significantly differ between the amantadine and placebo groups. INTERPRETATION: Adding amantadine to standard care in patients hospitalised with COVID-19 did not increase the likelihood of recovery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04952519; www. CLINICALTRIALS: gov.

AQM based on the queue length: A real-network study.

Active Queue Management (AQM) is recommended by Internet Engineering Task Force to mitigate the bufferbloat phenomenon in the Internet. In this paper, we show the results of comprehensive measurements carried out in our university network, in which a device with an AQM algorithm, designed and programmed for this purpose, was running. The implemented AQM algorithm was based on the dropping function, i.e. arriving packets were dropped randomly, with the probability being a function of the queue length. Several different dropping function forms, proposed in the networking literature, were used, in addition to the classic FIFO queue (no AQM). The experiment lasted over a month, during which the state of the network was measured and recorded several thousand times. This made the results independent of the natural fluctuations of the users' behavior and the network load. Conclusions on the general performance improvement offered by the implemented AQM, as well as the differences in the performance between particular forms of the dropping function, were reached. Some of these conclusions differ from those drawn previously from simulations. This underlines the need for carrying measurements of new AQMs in real, operating networks, with complex, natural traffic.

Asthma-COPD Overlap-A Discordance Between Patient Populations Defined by Different Diagnostic Criteria.

BACKGROUND: The concordance between asthma-chronic obstructive pulmonary disease overlap (ACO) defined according to Global Inititative for Asthma (GINA)/Global Initiative for Chronic Obstructive Lung Disease (GOLD) and other diagnostic criteria is unknown. OBJECTIVE: To assess the concordance between different ACO definitions and to estimate the definition-based ACO prevalence and characteristics. METHODS: A prospective, real-life study based on a 32-item data set was performed in a mixed population of patients with asthma and chronic obstructive pulmonary disease (COPD). Five different definitions of ACO, including the GINA/GOLD criteria, were analyzed. RESULTS: A total of 1609 patients were included in the final analysis. Application of Venn diagram for ACO populations resulted in 31 ACO subpopulations, which were further reduced to 6 separate populations by introducing a rank order for the analyzed definitions to classify patients from intersecting groups. Overall, the level of agreement between different ACO definitions was poor. Cohen kappa coefficient for the agreement between ACO GINA/GOLD definition and other ACO definitions varied from 0.06 to 0.21. Only 2 patients (0.12%) met all the ACO definitions. Definition-based ACO prevalence ranged between 3.8% (Spanish criteria) and 18.4% (clinician's diagnosis). A total of 573 (33.4%) patients met the criteria from at least 1 ACO definition. Patients who could not be classified as suffering from "pure" asthma, "pure" COPD, or ACO accounted for as much as 27.5% of the whole investigated group. The most severe symptoms were observed in patients with ACO defined as COPD and asthma diagnosed at age less than 40 years. CONCLUSIONS: The current ACO definitions identify distinct populations that share only a small number of common features and present with different disease phenotypes. ACO prevalence is highly variable, depending on the definition applied.

Stem Cell-Based Therapy in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a progressive fibrosing disorder for which there is no cure and no pharmacological treatment capable of increasing in a meaningful way the survival rate. Lung transplantation remains the only possible treatment for patients with advanced disease, although the increase in 5-year survival is only 45 %. Some preclinical studies have generated promising results about the therapeutic potential of exogenous stem cells. However, two initial clinical trials involving the endobronchial or systemic delivery of autologous adipose tissue-derived or unrelated-donor, placenta-derived mesenchymal stem cells have not convincingly demonstrated that these treatments are acceptably safe. The results of other ongoing clinical trials may help to identify the best source and delivery route of mesenchymal stem cells and to estimate the risk of unwanted effects related to the mesenchymal nature of the transplanted cells. Considering that most of the therapeutic potential of these cells has been ascribed to paracrine signaling, the use of mesenchymal stem cell-derived secretome as an alternative to the transplantation of single cell suspension may circumvent many regulatory and clinical problems. Technical and safety concerns still limit the possibility of clinical applications of other promising interventions that are based on the use of human amnion stem cells, embryonic stem cells or induced pluripotent stem cells to replace or regenerate the dysfunctional alveolar epithelium. We summarize the current status of the field and identify major challenges and opportunities for the possible future integration of stem cell-based treatments into the currently recommended clinical management strategy for idiopathic pulmonary fibrosis.

Extracellular matrix remodelling properties of human fibrocytes.

The fibrocytes are thought to serve as a source of newly deposited collagens I and III during reparative processes and in certain fibrotic disorders, but their matrix remodelling properties are incompletely understood. We evaluated their ability to produce several extracellular matrix (ECM) components, in comparison with fibroblasts, and to participate in collagen turnover. The collagen gene expression profile of fibrocytes differed from that of fibroblasts because fibrocytes constitutively expressed relatively high levels of the mRNA encoding collagen VI and significantly lower levels of the mRNA encoding collagens I, III and V. The proteoglycan (PG) gene expression profile was also different in fibrocytes and fibroblasts because fibrocytes constitutively expressed the mRNA encoding perlecan and versican at relatively high levels and the mRNA encoding biglycan and decorin at low and very low levels, respectively. Moreover, fibrocytes expressed the mRNA for hyaluronan synthase 2 at higher level than fibroblasts. Significant differences between the two cell populations were also demonstrated by metabolic labelling and analysis of the secreted collagenous proteins, PGs and hyaluronan. Fibrocytes constitutively expressed the scavenger receptors CD163 and CD204 as well as the mannose receptors CD206 and Endo180, and internalized and degraded collagen fragments through an Endo180-mediated mechanism. The results of this study demonstrate that human fibrocytes exhibit ECM remodelling properties previously unexplored, including the ability to participate in collagen turnover. The observed differences in collagen and PG expression profile between fibrocytes and fibroblasts suggest that fibrocytes may predominantly have a matrix-stabilizing function.