Tocilizumab plus dexamethasone versus dexamethasone in patients with moderate-to-severe COVID-19 pneumonia: A randomised clinical trial from the CORIMUNO-19 study group.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche.

Tailoring the multiscale architecture of electrospun membranes to promote 3D cellular infiltration.

Controlling the architecture of engineered scaffolds is of outmost importance to induce a targeted cell response and ultimately achieve successful tissue regeneration upon implantation. Robust, reliable and reproducible methods to control scaffold properties at different levels are timely and highly important. However, the multiscale architectural properties of electrospun membranes are very complex, in particular the role of fiber-to-fiber interactions on mechanical properties, and their effect on cell response remain largely unexplored. The work reported here reveals that the macroscopic membrane stiffness, observed by stress-strain curves, cannot be predicted solely based on the Young's moduli of the constituting fibers but is rather influenced by interactions on the microscale, namely the number of fiber-to-fiber bonds. To specifically control the formation of these bonds, solvent systems of the electrospinning solution were fine-tuned, affecting the membrane properties at every length-scale investigated. In contrast to dichloromethane that is characterized by a high vapor pressure, the use of trifluoroacetic acid, a solvent with a lower vapor pressure, favors the generation of fiber-to-fiber bonds. This ultimately led to an overall increased Young's modulus and yield stress of the membrane despite a lower stiffness of the constituting fibers. With respect to tissue engineering applications, an experimental setup was developed to investigate the effect of architectural parameters on the ability of cells to infiltrate and migrate within the scaffold. The results reveal that differences in fiber-to-fiber bonds significantly affect the infiltration of normal human dermal fibroblasts into the membranes. Membranes of loose fibers with low numbers of fiber-to-fiber bonds, as obtained from spinning solutions using dichloromethane, promote cellular infiltration and are thus promising candidates for the formation of a 3D tissue.

Rapid clearance of storage-induced microerythrocytes alters transfusion recovery.

Permanent availability of red blood cells (RBCs) for transfusion depends on refrigerated storage, during which morphologically altered RBCs accumulate. Among these, a subpopulation of small RBCs, comprising type III echinocytes, spheroechinocytes, and spherocytes and defined as storage-induced microerythrocytes (SMEs), could be rapidly cleared from circulation posttransfusion. We quantified the proportion of SMEs in RBC concentrates from healthy human volunteers and assessed correlation with transfusion recovery, investigated the fate of SMEs upon perfusion through human spleen ex vivo, and explored where and how SMEs are cleared in a mouse model of blood storage and transfusion. In healthy human volunteers, high proportion of SMEs in long-stored RBC concentrates correlated with poor transfusion recovery. When perfused through human spleen, 15% and 61% of long-stored RBCs and SMEs were cleared in 70 minutes, respectively. High initial proportion of SMEs also correlated with high retention of RBCs by perfused human spleen. In the mouse model, SMEs accumulated during storage. Transfusion of long-stored RBCs resulted in reduced posttransfusion recovery, mostly due to SME clearance. After transfusion in mice, long-stored RBCs accumulated predominantly in spleen and were ingested mainly by splenic and hepatic macrophages. In macrophage-depleted mice, splenic accumulation and SME clearance were delayed, and transfusion recovery was improved. In healthy hosts, SMEs were cleared predominantly by macrophages in spleen and liver. When this well-demarcated subpopulation of altered RBCs was abundant in RBC concentrates, transfusion recovery was diminished. SME quantification has the potential to improve blood product quality assessment. This trial was registered at www.clinicaltrials.gov as #NCT02889133.

Predicting the macroscopic response of electrospun membranes based on microstructure and single fibre properties.

In the present paper, the three-dimensional structure and macroscopic mechanical response of electrospun poly(L-lactide) membranes is predicted based only on the geometry and elasto-plastic mechanical properties of single fibres supplemented by measurements of membrane weight and volume, and the resulting computational models are used to study the non-affine micro-kinematics of electrospun networks. To this end, statistical parameters describing the in-plane fibre morphology are extracted from scanning electron micrographs of the membranes, and computational network models are generated by matching the porosity of the real mats. The virtual networks are compared against computed tomography scans in terms of structure, and against uniaxial tension tests with respect to their macroscopic mechanical response. The obtained virtual network structure agrees well with the fibre disposition in real networks, and the rigorous prediction of the mechanical response of two membranes with mean diameters of 1.10µm and 0.70µm captures the experimental behaviour qualitatively. Favourable quantitative agreement, however, is obtained only after lowering the Young's moduli, yield stresses and hardening slopes determined in single fibre tests, and after reducing the density of inter-fibre bonds in the model of the membrane with thinner fibres. The simulations thus demonstrate the validity and merits of the approach to study the multi-scale mechanics of electrospun networks, but also point to potential discrepancies between the properties of electrospun fibres within a network and those produced for single fibre characterisation, and highlight the existing uncertainty on the density and quality of bonds between fibres in electrospun networks.

Revealing non-crystalline polymer superstructures within electrospun fibers through solvent-induced phase rearrangements.

The design of nanofibers for biomedical applications requires a deep understanding of the fiber formation process and the resulting internal structure. In this regard, non-crystalline, mesomorphic structures play a central role in the processing of many polymers as precursors in the formation of crystalline superstructures (e.g. shish-kebab) and influence strongly the physical properties of polymers with a low degree of crystallinity. Yet, our ability to probe these relevant features is often greatly limited by their low contrast differences with the amorphous phase. We present an approach to reveal the organization of the mesomorphic superstructures within such polymeric materials, on the example of electrospun poly(l-lactide) nanofibers. Based on solvent-induced crystallization, this method employs fine-tuned solvent/non-solvent systems to enhance the contrast of these structural features by selectively triggering and controlling reorganization of the phases. Hereby, the mesomorphic regions are transformed into an α-crystalline phase, while the nanoscale spatial arrangement of the underlying superstructures is preserved. Combined with X-ray analytical techniques and electron microscopy, our approach provides detailed insights into the nanofiber's inner architecture, allowing for its direct visualization. Thereby, the influence of electrospinning parameters on the fiber formation process is explained as well as the impact of the resulting non-crystalline superstructures on single fiber mechanical properties. The method can be applied to comparable polymers for the development of materials with controlled, tailored properties.

Interpersonal Skills Among Fourth- and Fifth-Year Medical Students: Validation of an Assessment Tool.

OBJECTIVE: The aim of this study was to validate a French version of the standardized patient satisfaction questionnaire (SPSQ), an interpersonal skills assessment form, originally published in English, destined to be completed by SPs and used as a validated tool for the evaluation of communication skills of French medical students, during ambulatory care consultations. METHODS: During the academic year, fourth- and fifth-year medical students participated in mock ambulatory care consultations. The French SPSQ was completed by 16 SPs who performed scenarios written by professors of medicine. Validity evidence for test content, response process, internal structure, and relation to other variables was determined by calculating the Cronbach α coefficient, the Loevinger H index (response coherence), intraclass coefficients, the differences between fourth- and fifth-year students and by using item correlations as well as the correlation with an independent validated assessment form. G theory was used to identify the sources of variations in the mean of SPSQ. RESULTS: Four hundred thirty-three students were evaluated for a period of 2 months and participated in a total of 1703 mock consultations. The Cronbach α coefficient (0.94) was superior to that of the English SPSQ. The Loevinger H index was good ranging from 0.65 to 0.70. The reproducibility among external observers (intraclass correlation coefficient = 0.67) and between external observers and the SPs (intraclass correlation coefficient = 0.79 and 0.78, respectively) was satisfactory. Results of the French SPSQ were positively and significantly correlated to the scores obtained via an independent, validated, questionnaire (R = 0.72) and showed a significant difference between fourth- and fifth-year students' scores (P < 0.0001). G coefficients were estimated at 0.64 and 0.52 for year 4 and year 5, respectively. CONCLUSIONS: Validity evidence supports the use of French-version SPSQ scores to screen for students experiencing difficulty with communication.

Long-term outcomes of adults with first-relapsed/refractory systemic anaplastic large-cell lymphoma in the pre-brentuximab vedotin era: A LYSA/SFGM-TC study.

BACKGROUND: Long-term outcomes of adults with first-relapsed/refractory (R/R) systemic anaplastic large-cell lymphoma (ALCL) are not definitively established and should be evaluated. PATIENTS AND METHODS: We previously published the long-term outcomes of adults with ALCL initially treated with polychemotherapy in LYmphoma Study Association (LYSA) prospective clinical trials conducted during the pre-brentuximab vedotin era. Herein, we report the long-term outcomes of those patients after the first-relapsed/refractory (R/R) events. RESULTS: Among the 138 (64 (anaplastic lymphoma kinase (ALK(+)) and 74 ALK(-) ALCL) adults initially treated in clinical trials, 40 (14 ALK(+) and 26 ALK(-)) first-R/R ALCL patients and their long-term outcomes were analysed. Median follow-up from the first-R/R events was 12.5 years. For ALK(+) and ALK(-) patients, respectively, median [range] findings were as follows: age at first-R/R event: 35 [19-76] and 61 [34-81] years; time between inclusion in first-line clinical trials and first-R/R events was 6 [1.5-34] and 11.1 [1-67] months (P = 0.36); with median (95% confidence interval) progression-free survival after the first-R/R events: 3.8 (0.7-14.8) and 5.3 (2.4-8.4) months (P = 0.39); and overall survival: 13.6 (0.7-89) and 8.1 (3.3-25) months (P = 0.96). ALCL was the main cause of death. CONCLUSION: Most adults with first-R/R ALCL have poor outcomes, with no significant differences between patients with ALK(+) or ALK(-) disease. These results could be used as reference for the evaluation of new drugs to treat R/R ALCL.

Spherocytic shift of red blood cells during storage provides a quantitative whole cell-based marker of the storage lesion.

BACKGROUND: Storage lesion may explain the rapid clearance of up to 25% of transfused red blood cells (RBCs) in recipients. Several alterations affect stored RBC but a quantitative, whole cell-based predictor of transfusion yield is lacking. Because RBCs with reduced surface area are retained by the spleen, we quantified changes in RBC dimensions during storage. STUDY DESIGN AND METHODS: Using imaging flow cytometry we observed the dimension and morphology of RBCs upon storage, along with that of conventional biochemical and mechanical markers of storage lesion. We then validated these findings using differential interference contrast (DIC) microscopy and quantified the accumulation of microparticles (MPs). RESULTS: Mean projected surface area of the whole RBC population decreased from 72.4 to 68.4 µm2 , a change resulting from the appearance of a well-demarcated subpopulation of RBCs with reduced mean projected surface (58 µm2 , 15.2%-19.9% reduction). These "small RBCs" accounted for 4.9 and 23.6% of all RBCs on Days 3 and 42 of storage, respectively. DIC microscopy confirmed that small RBCs had shifted upon storage from discocytes to echinocytes III, spheroechinocytes, and spherocytes. Glycophorin A-positive MPs and small RBCs appeared after similar kinetics. CONCLUSION: The reduction in surface area of small RBCs is expected to induce their retention by the spleen. We propose that small RBCs generated by MP-induced membrane loss are preferentially cleared from the circulation shortly after transfusion of long-stored blood. Their operator-independent quantification using imaging flow cytometry may provide a marker of storage lesion potentially predictive of transfusion yield.

Identification of intra-hepatic communicating veins through the arch sign on CT-scan.

PURPOSE: Knowledge of vascular outflow is essential in liver surgery. Communicating veins between the right hepatic vein (RHV) and the middle hepatic vein (MHV) have been described and allowed us to perform new surgical procedures. The aim of this study was to predict the existence of intra-hepatic venous anastomosis by identifying communicating veins on 2D CT-scan imaging. METHODS: We retrospectively analysed data from 32 patients operated on for liver tumours between 2004 and 2013 who underwent a bisegmentectomy VI-VII enlarged to the RHV and/or a bisegmentectomy VII-VIII and/or a left hepatectomy enlarged to the MHV and who had pre and post-operative CT-scans. Patients with cirrhosis were excluded. We first analysed post-operative images and, in patients with a proven collateral vein, looked for evidence of this on pre-operative imaging. We then validated this pre-operative sign against post-operative imaging. RESULTS: Collaterals from both the RHV and the MHV formed an arch visible on pre-operative imaging which predicted the development of intrahepatic venous anastomosis in 20 patients. In 14 patients, a perfect match between the arch sign and development of collaterals was observed (n = 28). Sensitivity, specificity, negative and positive predictive values were 87, 80, 80, and 87%, respectively. Positive and negative likelihood ratio tests were 4.3 and 0.16, respectively. CONCLUSION: Communicating veins between the RHV and the MHV are frequent and can be predicted by the arch sign on 2D CT-scan. Hence the arch sign can be very useful when planning liver surgery.

Molecular Aspects of Conifer Zygotic and Somatic Embryo Development: A Review of Genome-Wide Approaches and Recent Insights.

Genome-wide profiling (transcriptomics, proteomics, metabolomics) is providing unprecedented opportunities to unravel the complexity of coordinated gene expression during embryo development in trees, especially conifer species harboring "giga-genome." This knowledge should be critical for the efficient delivery of improved varieties through seeds and/or somatic embryos in fluctuating markets and to cope with climate change. We reviewed "omics" as well as targeted gene expression studies during both somatic and zygotic embryo development in conifers and tentatively puzzled over the critical processes and genes involved at the specific developmental and transition stages. Current limitations to the interpretation of these large datasets are going to be lifted through the ongoing development of comprehensive genome resources in conifers. Nevertheless omics already confirmed that master regulators (e.g., transcription and epigenetic factors) play central roles. As in model angiosperms, the molecular regulation from early to late embryogenesis may mainly arise from spatiotemporal modulation of auxin-, gibberellin-, and abscisic acid-mediated responses. Omics also showed the potential for the development of tools to assess the progress of embryo development or to build genotype-independent, predictive models of embryogenesis-specific characteristics.

Cotyledonary somatic embryos of Pinus pinaster Ait. most closely resemble fresh, maturing cotyledonary zygotic embryos: biological, carbohydrate and proteomic analyses.

Cotyledonary somatic embryos (SEs) of maritime pine are routinely matured for 12 weeks before being germinated and converted to plantlets. Although regeneration success is highly dependent on SEs quality, the date of harvesting is currently determined mainly on the basis of morphological features. This empirical method does not provide any accurate information about embryo quality with respect to storage compounds (proteins, carbohydrates). We first analyzed SEs matured for 10, 12 and 14 weeks by carrying out biological (dry weight, water content) and biochemical measurements (total protein and carbohydrate contents). No difference could be found between collection dates, suggesting that harvesting SEs after 12 weeks is appropriate. Cotyledonary SEs were then compared to various stages, from fresh to fully desiccated, in the development of cotyledonary zygotic embryos (ZEs). We identified profiles that were similar using hierarchical ascendant cluster analysis (HCA). Fresh and dehydrated ZEs could be distinguished, and SEs clustered with fresh ZEs. Both types of embryo exhibited similar carbohydrate and protein contents and signatures. This high level of similarity (94.5 %) was further supported by proteome profiling. Highly expressed proteins included storage, stress-related, late embryogenesis abundant and energy metabolism proteins. By comparing overexpressed proteins in developing and cotyledonary SEs or ZEs, some (23 proteins) could be identified as candidate biomarkers for the late, cotyledonary stage. This is the first report of useful generic protein markers for monitoring embryo development in maritime pine. Our results also suggest that improvements of SEs quality may be achieved if the current maturation conditions are refined.

Early molecular events involved in Pinus pinaster Ait. somatic embryo development under reduced water availability: transcriptomic and proteomic analyses.

Maritime pine somatic embryos (SEs) require a reduction in water availability (high gellan gum concentration in the maturation medium) to reach the cotyledonary stage. This key switch, reported specifically for pine species, is not yet well understood. To facilitate the use of somatic embryogenesis for mass propagation of conifers, we need a better understanding of embryo development. Comparison of both transcriptome (Illumina RNA sequencing) and proteome [two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis with mass spectrometry (MS) identification] of immature SEs, cultured on either high (9G) or low (4G) gellan gum concentration, was performed, together with analysis of water content, fresh and dry mass, endogenous abscisic acid (ABA; gas chromatography-MS), soluble sugars (high-pressure liquid chromatography), starch and confocal laser microscope observations. This multiscale, integrated analysis was used to unravel early molecular and physiological events involved in SE development. Under unfavorable conditions (4G), the glycolytic pathway was enhanced, possibly in relation to cell proliferation that may be antagonistic to SE development. Under favorable conditions (9G), SEs adapted to culture constraint by activating specific protective pathways, and ABA-mediated molecular and physiological responses promoting embryo development. Our results suggest that on 9G, germin-like protein and ubiquitin-protein ligase could be used as predictive markers of SE development, whereas protein phosphatase 2C could be a biomarker for culture adaptive responses. This is the first characterization of early molecular mechanisms involved in the development of pine SEs following an increase in gellan gum concentration in the maturation medium, and it is also the first report on somatic embryogenesis in conifers combining transcriptomic and proteomic datasets.

De novo assembly of maritime pine transcriptome: implications for forest breeding and biotechnology.

Maritime pine (Pinus pinasterAit.) is a widely distributed conifer species in Southwestern Europe and one of the most advanced models for conifer research. In the current work, comprehensive characterization of the maritime pine transcriptome was performed using a combination of two different next-generation sequencing platforms, 454 and Illumina. De novo assembly of the transcriptome provided a catalogue of 26 020 unique transcripts in maritime pine trees and a collection of 9641 full-length cDNAs. Quality of the transcriptome assembly was validated by RT-PCR amplification of selected transcripts for structural and regulatory genes. Transcription factors and enzyme-encoding transcripts were annotated. Furthermore, the available sequencing data permitted the identification of polymorphisms and the establishment of robust single nucleotide polymorphism (SNP) and simple-sequence repeat (SSR) databases for genotyping applications and integration of translational genomics in maritime pine breeding programmes. All our data are freely available at SustainpineDB, the P. pinaster expressional database. Results reported here on the maritime pine transcriptome represent a valuable resource for future basic and applied studies on this ecological and economically important pine species.

Microbial desalination cells packed with ion-exchange resin to enhance water desalination rate.

A novel configuration of microbial desalination cell (MDC) packed with ion-exchange resin (R-MDC) was proposed to enhance water desalination rate. Compared with classic MDC (C-MDC), an obvious increase in desalination rate (DR) was obtained by R-MDC. With relatively low concentration (10-2 g/L NaCl) influents, the DR values of R-MDC were about 1.5-8 times those of C-MDC. Ion-exchange resins packed in the desalination chamber worked as conductor and thus counteracted the increase in ohmic resistance during treatment of low concentration salt water. Ohmic resistances of R-MDC stabilized at 3.0-4.7 Ω. By contrast, the ohmic resistances of C-MDC ranged from 5.5 to 12.7 Ω, which were 55-272% higher than those of R-MDC. Remarkable improvement in desalination rate helped improve charge efficiency for desalination in R-MDC. The results first showed the potential of R-MDC in the desalination of water with low salinity.

Current developments in the practice of individual psychoanalytic psychodrama in France.

The authors present the history of individual psychoanalytic psychodrama and its current developments as practised in France. They put forward the technique, objectives and rules, along with the indications, limits and risks that ensue from the specific nature of this therapeutic approach. Through its technical adjustments, individual psychoanalytic psychodrama provides a therapeutic option that is appropriate to the defences prevalent in many patients that cause classical psychotherapies to fail: massive inhibition, operative functioning far removed from affects or in false self mode; phobias, disavowal or splitting of the internal psychic life and emotions; prevalence of short discharge circuits in acted-out behaviours and bodily or visceral complaints and expressions. Psychodrama utilizes these defences not in order to eliminate them but to 'subvert' them so that they can continue to carry out their protective role, in particular ensuring narcissistic continuity. At the same time, psychodrama relaxes these defences and facilitates a possible filtering through of the repressed material. Through the number of actors and the diffraction of transference that this allows, psychodrama provides a possibility of adjusting the potentially traumatic effect of the encounter with the object and the instigation of the transference in the regressive dimension induced by any psychotherapeutic process.

Long-term response and postsurgical complete remissions after treatment with sunitinib malate, an oral multitargeted receptor tyrosine kinase inhibitor, in patients with metastatic renal cell carcinoma.

Receptor tyrosine kinase (RTK) inhibitors have revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and significantly extended survival in these patients. Sunitinib is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs-1, -2, and -3), platelet-derived growth factor receptors (PDGFRs-α and -ß), stem-cell factor receptor (KIT), FMS-like tyrosine kinase 3 (FLT3), colony-stimulating factor 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (REarranged during Transfection; RET). Sunitinib is approved multinationally for the treatment of advanced RCC, and is considered the reference standard of care for first-line treatment. In clinical trials, sunitinib has been associated with a consistent, distinct profile of adverse events. Here we describe three cases that show that it is possible to manage adverse events occurring during sunitinib therapy, and thus allow patients with mRCC to receive an effective dose of sunitinib in order to achieve long-term disease control. These cases also show that surgical resection, performed whenever possible, can help to improve control of metastatic disease and so avoid the unnecessary toxicity and high costs of prolonged antiangiogenic therapy.