One quarter of the patients with COPD are colonized by PPMs during their stable periods. Exacerbation is associated with the overgrowth of PPMs and with the appearance of P aeruginosa in the lower airway, which is associated with exacerbation symptoms independent of load.

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Background We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. Methods We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. Results During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8–14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355–0.744], p < 0.001; weighted HR 0.741 (95% CI 0.619–0.887), p = 0.001. Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment [relative risk reduction (RRR) 46.7%]. We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in those treated with tocilizumab than in those treated with steroids alone [10.9% versus 40.2%, HR 0.511 (95% CI 0.352–0.741), p = 0.036; weighted HR 0.6 (95% CI 0.449–0.804), p < 0.001] (interaction p = 0.094). Conclusions These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. Trial registration European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415 Electronic supplementary material The online version of this article (10.1007/s40121-020-00373-8) contains supplementary material, which is available to authorized users.

ORTHOUNION is a multicentre, open, comparative, three-arm, randomized clinical trial (EudraCT number 2015-000431-32) to compare the efficacy, at one and two years, of autologous human bone marrow-derived expanded mesenchymal stromal cell (hBM-MSC) treatments versus iliac crest autograft (ICA) to enhance bone healing in patients with diaphyseal and/or metaphysodiaphyseal fracture (femur, tibia, and humerus) status of atrophic or oligotrophic nonunion (more than 9 months after the acute fracture, including recalcitrant cases after failed treatments). The primary objective is to determine if the treatment with hBM-MSCs combined with biomaterial is superior to ICA in obtaining bone healing. If confirmed, a secondary objective is set to determine if the dose of 100 × 106 hBM-MSCs is noninferior to that of 200 × 106 hBM-MSCs. The participants (n = 108) will be randomly assigned to either the experimental low dose (n = 36), the experimental high dose (n = 36), or the comparator arm (n = 36) using a central randomization service. The trial will be conducted in 20 clinical centres in Spain, France, Germany, and Italy under the same clinical protocol. The confirmation of superiority for the proposed ATMP in nonunions may foster the future of bone regenerative medicine in this indication. On the contrary, absence of superiority may underline its limitations in clinical use.

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Cutaneous T-cell lymphomas (CTCLs) represent different subtypes of lymphoproliferative disorders with no curative therapies for the advanced forms of the disease (namely mycosis fungoides and the leukemic variant, Sézary syndrome). Molecular events leading to CTCL progression are heterogeneous, however recent DNA and RNA sequencing studies highlighted the importance of NF-κB and β-catenin pathways. We here show that the kinase TAK1, known as essential in B-cell lymphoma, is constitutively activated in CTCL cells, but tempered by the MYPT1/PP1 phosphatase complex. Blocking PP1 activity, both pharmacologically and genetically, resulted in TAK1 hyperphosphorylation at residues T344, S389, T444, and T511, which have functional impact on canonical NF-κB signaling. Inhibition of TAK1 precluded NF-κB and β-catenin signaling and induced apoptosis of CTCL cell lines and primary Sézary syndrome cells both in vitro and in vivo. Detection of phosphorylated TAK1 at T444 and T344 is associated with the presence of lymphoma in a set of 60 primary human samples correlating with NF-κB and β-catenin activation. These results identified TAK1 as a potential biomarker and therapeutic target for CTCL therapy.

4737 Objective: Microscopic examination of peripheral blood cells is an important diagnostic tool. We evaluated the CellaVision DM96 (CellaVision AB, Lund, Sweden), an automated image analysis system for digital peripheral blood cell analysis, comparing the results with direct manual microscopy. The system obtains digital images of the blood cells at high magnification and these images are analyzed using a neural network based on a large database of cells. Material and Methods: We analyzed 234 PB films stained with May-Grünwald-Giemsa from patients of the Hospital Clínic of Barcelona. Leukocyte values were from 1.12 to 282 × 109/L (Advia 2120, Siemens Healthcare Diagnostics SL). 177 of the PB films were from patients with hematological diseases: lymphoid neoplasias: 83, acute leukemias: 52, chronic myeloproliferative diseases: 20, myelodisplastic syndromes: 18, paroxysmal nocturnal hemoglobinuria: 2, hemoglobin S: 1 and thrombotic thrombocytopenic purpura: 1. Manual differentials were performed using standard microscopy. After the microscopic analysis the slides were loaded into the CellaVision DM96 obtaining digital images of preclassified cells, which were verified or corrected when necessary by the hematologist (DM96POST). WBC differentials were abnormal in 120 cases. Statistical analysis was performed using correlation (Pearson) and concordance (Lin) tests. Results: Correlation coefficients between results obtained from the CellaVision DM96 preclassification and by conventional direct microscopy were excellent for segmented neutrophils, lymphocytes, monocytes and blasts (r>0.87<0.94 and p<0.0001) and good for band neutrophils, eosinophils, basophils and plasma cells (r>0.74<0.81 and p<0.0001). Concordance coefficients were higher than 0.7 for all of the white blood cell subtypes preclassified by the DM96. Pearson and Lin coefficients were higher when we compared DM96POST values. After the reclassification of the cells very good concordance coefficients were observed for promyelocytes and myelocytes (> 0.7), intermediates for reactive lymphocytes and erythroblasts (>0.5 and <0,7) and low (<0.5) for metamyelocytes. Whatever the pathology and the number of blasts on the manual review films all 97 patients were positive for blast detection on DM96. Pathological cells such as prolymphocytes, large granular lymphocytes, hairy cells, Sézary cells and other atypical lymphocytes were reclassified by the user. Digital images showed dysplastic features or inclusions in blood cells and morphologic alterations in red cells or platelets were easily identified. Conclusion: Comparison of morphological classification of blood cells by the automated system DM96 shows good correlation and concordance values with respect to manual differentials. Advantages of the Cellavision DM96 over direct microscopy includes that requires less time than manual differentiation, allows the verification of the results by an expert from another location (telehematology), digital images can be stored and therefore available for re-evaluation, is a good tool for educational purposes and can improve the efficiency of a modern Hematology Laboratory. Disclosures: No relevant conflicts of interest to declare.

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