An anti-interleukin-2 receptor drug attenuates thelper 1 lymphocytes-mediated inflammation in an acute model of endotoxin-induced uveitis

The aim of the present study was to evaluate the anti-inflammatory efficacy of Daclizumab, an anti-interleukin-2 receptor drug, in an experimental uveitis model upon a subcutaneous injection of lipopolysaccharide into Lewis rats, a valuable model for ocular acute inflammatory processes. The integrity of the blood-aqueous barrier was assessed 24 h after endotoxin-induced uveitis by evaluating two parameters: cell count and protein concentration in aqueous humors. The histopathology of all the ocular structures (cornea, lens, sclera, choroid, retina, uvea, and anterior and posterior chambers) was also considered. Enzyme-linked immunosorbent assays of the aqueous humor samples were performed to quantify the levels of the different chemokine and cytokine proteins. Similarly, a biochemical analysis of oxidative stress-related markers was also assessed. The inflammation observed in the anterior chamber of the eyes when Daclizumab was administered with endotoxin was largely prevented since the aqueous humor protein concentration substantially lowered concomitantly with a significant reduction in the uveal and vitreous histopathological grading. Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon-c, also significantly reduced with related anti-oxidant systems recovery. Daclizumab treatment in endotoxin-induced uveitis reduced Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon gamma, by about 60–70% and presented a preventive role in endotoxin-induced oxidative stress. This antioxidant protective effect of Daclizumab may be related to several of the observed Daclizumab effects in our study, including IL-6 cytokine regulatory properties and a substantial concomitant drop in INFc. Concurrently, Daclizumab treatment triggered a significant reduction in both the uveal histopathological grading and protein concentration in aqueous humors, but not in cellular infiltration

Design and experimental validation of a magnetic device for stem cell culture

Cell culture of bone and tendon tissues requires mechanical stimulation of the cells in order to mimic their physiological state. In the present work, a device has been conceived and developed to generate a controlled magnetic field with a homogeneous gradient in the working space. The design requirement was to maximize the magnetic flux gradient, assuring a minimum magnetizing value in a 15 mm × 15 mm working area, which highly increases the normal operating range of this sort of devices. The objective is to use the machine for two types of biological tests: magnetic irradiation of biological samples and force generation on paramagnetic particles embedded in scaffolds for cell culture. The device has been manufactured and experimentally validated by evaluating the force exerted on magnetic particles in a viscous fluid. Apart from the magnetic validation, the device has been tested for irradiating biological samples. In this case, viability of human dental pulp stem cells has been studied in vitro after electromagnetic field exposition using the designed device. After three days of irradiation treatment, cellular microtissues showed a 59% increase in the viable cell number. Irradiated cells did not show morphological differences when compared with control cells

A cell-free approach with a supporting biomaterial in the form of dispersed microspheres induces hyaline cartilage formation in a rabbit knee model

[EN] The objective of this study was to test a regenerative medicine strategy for the regeneration of articular cartilage. This approach combines microfracture of the subchondral bone with the implant at the site of the cartilage defect of a supporting biomaterial in the form of microspheres aimed at creating an adequate biomechanical environment for the differentiation of the mesenchymal stem cells that migrate from the bone marrow. The possible inflammatory response to these biomaterials was previously studied by means of the culture of RAW264.7 macrophages. The microspheres were implanted in a 3¿mm-diameter defect in the trochlea of the femoral condyle of New Zealand rabbits, covering them with a poly(l-lactic acid) (PLLA) membrane manufactured by electrospinning. Experimental groups included a group where exclusively PLLA microspheres were implanted, another group where a mixture of 50/50 microspheres of PLLA (hydrophobic and rigid) and others of chitosan (a hydrogel) were used, and a third group used as a control where no material was used and only the membrane was covering the defect. The histological characteristics of the regenerated tissue have been evaluated 3 months after the operation. We found that during the regeneration process the microspheres, and the membrane covering them, are displaced by the neoformed tissue in the regeneration space toward the subchondral bone region, leaving room for the formation of a tissue with the characteristics of hyaline cartilage.Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CICPBA), Universidad Nacional de La Plata, Grant/Award Number: 11/X643; Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional de la Unión Europea, Grant/Award Number: MAT2016-76039-C4-1 2-R; Spanish Ministry of Economy and Competitiveness (MINECO)Zurriaga Carda, J.; Lastra, ML.; Antolinos-Turpin, CM.; Morales-Román, RM.; Sancho-Tello, M.; Perea-Ruiz, S.; Milián, L.... (2020). A cell-free approach with a supporting biomaterial in the form of dispersed microspheres induces hyaline cartilage formation in a rabbit knee model. Journal of Biomedical Materials Research Part B Applied Biomaterials. 108(4):1428-1438. https://doi.org/10.1002/jbm.b.34490S142814381084Allepuz, A., Martínez, O., Tebé, C., Nardi, J., Portabella, F., & Espallargues, M. (2014). Joint Registries as Continuous Surveillance Systems: The Experience of the Catalan Arthroplasty Register (RACat). The Journal of Arthroplasty, 29(3), 484-490. doi:10.1016/j.arth.2013.07.048Almeida, C. R., Serra, T., Oliveira, M. I., Planell, J. A., Barbosa, M. A., & Navarro, M. (2014). Impact of 3-D printed PLA- and chitosan-based scaffolds on human monocyte/macrophage responses: Unraveling the effect of 3-D structures on inflammation. Acta Biomaterialia, 10(2), 613-622. doi:10.1016/j.actbio.2013.10.035Bell, A. D., Hurtig, M. B., Quenneville, E., Rivard, G.-É., & Hoemann, C. D. (2016). Effect of a Rapidly Degrading Presolidified 10 kDa Chitosan/Blood Implant and Subchondral Marrow Stimulation Surgical Approach on Cartilage Resurfacing in a Sheep Model. CARTILAGE, 8(4), 417-431. doi:10.1177/1947603516676872Bitencourt, C. da S., Silva, L. B. da, Pereira, P. A. T., Gelfuso, G. M., & Faccioli, L. H. (2015). Microspheres prepared with different co-polymers of poly(lactic-glycolic acid) (PLGA) or with chitosan cause distinct effects on macrophages. Colloids and Surfaces B: Biointerfaces, 136, 678-686. doi:10.1016/j.colsurfb.2015.10.011Bonasia, D. E., Martin, J. A., Marmotti, A., Kurriger, G. L., Lehman, A. D., Rossi, R., & Amendola, A. (2015). The use of autologous adult, allogenic juvenile, and combined juvenile–adult cartilage fragments for the repair of chondral defects. Knee Surgery, Sports Traumatology, Arthroscopy, 24(12), 3988-3996. doi:10.1007/s00167-015-3536-5Carmona, L. (2001). The burden of musculoskeletal diseases in the general population of Spain: results from a national survey. Annals of the Rheumatic Diseases, 60(11), 1040-1045. doi:10.1136/ard.60.11.1040Chu, J., Zeng, S., Gao, L., Groth, T., Li, Z., Kong, J., … Li, L. (2016). Poly (L-Lactic Acid) Porous Scaffold-Supported Alginate Hydrogel with Improved Mechanical Properties and Biocompatibility. The International Journal of Artificial Organs, 39(8), 435-443. doi:10.5301/ijao.5000516Conoscenti, G., Schneider, T., Stoelzel, K., Carfì Pavia, F., Brucato, V., Goegele, C., … Schulze-Tanzil, G. (2017). PLLA scaffolds produced by thermally induced phase separation (TIPS) allow human chondrocyte growth and extracellular matrix formation dependent on pore size. Materials Science and Engineering: C, 80, 449-459. doi:10.1016/j.msec.2017.06.011Dashtdar, H., Murali, M. R., Abbas, A. A., Suhaeb, A. M., Selvaratnam, L., Tay, L. X., & Kamarul, T. (2013). PVA-chitosan composite hydrogel versus alginate beads as a potential mesenchymal stem cell carrier for the treatment of focal cartilage defects. Knee Surgery, Sports Traumatology, Arthroscopy, 23(5), 1368-1377. doi:10.1007/s00167-013-2723-5Denlinger, L. C., Fisette, P. L., Garis, K. A., Kwon, G., Vazquez-Torres, A., Simon, A. D., … Corbett, J. A. (1996). Regulation of Inducible Nitric Oxide Synthase Expression by Macrophage Purinoreceptors and Calcium. Journal of Biological Chemistry, 271(1), 337-342. doi:10.1074/jbc.271.1.337Fernández, J. M., Cortizo, M. S., & Cortizo, A. M. (2014). Fumarate/Ceramic Composite Based Scaffolds for Tissue Engineering: Evaluation of Hydrophylicity, Degradability, Toxicity and Biocompatibility. Journal of Biomaterials and Tissue Engineering, 4(3), 227-234. doi:10.1166/jbt.2014.1158García Cruz, D. M., Escobar Ivirico, J. L., Gomes, M. M., Gómez Ribelles, J. L., Sánchez, M. S., Reis, R. L., & Mano, J. F. (2008). Chitosan microparticles as injectable scaffolds for tissue engineering. Journal of Tissue Engineering and Regenerative Medicine, 2(6), 378-380. doi:10.1002/term.106Gordon, S. (2007). The macrophage: Past, present and future. European Journal of Immunology, 37(S1), S9-S17. doi:10.1002/eji.200737638Goyal, D., Keyhani, S., Lee, E. H., & Hui, J. H. P. (2013). Evidence-Based Status of Microfracture Technique: A Systematic Review of Level I and II Studies. Arthroscopy: The Journal of Arthroscopic & Related Surgery, 29(9), 1579-1588. doi:10.1016/j.arthro.2013.05.027Hangody, L., Kish, G., Kárpáti, Z., Udvarhelyi, I., Szigeti, I., & Bély, M. (1998). Mosaicplasty for the Treatment of Articular Cartilage Defects: Application in Clinical Practice. Orthopedics, 21(7), 751-756. doi:10.3928/0147-7447-19980701-04Hoemann, C., Kandel, R., Roberts, S., Saris, D. B. F., Creemers, L., Mainil-Varlet, P., … Buschmann, M. D. (2011). International Cartilage Repair Society (ICRS) Recommended Guidelines for Histological Endpoints for Cartilage Repair Studies in Animal Models and Clinical Trials. CARTILAGE, 2(2), 153-172. doi:10.1177/1947603510397535Kumar, M. N. V. R., Muzzarelli, R. A. A., Muzzarelli, C., Sashiwa, H., & Domb, A. J. (2004). Chitosan Chemistry and Pharmaceutical Perspectives. Chemical Reviews, 104(12), 6017-6084. doi:10.1021/cr030441bKuo, T.-F., Lin, M.-F., Lin, Y.-H., Lin, Y.-C., Su, R.-J., Lin, H.-W., & Chan, W. P. (2011). Implantation of platelet-rich fibrin and cartilage granules facilitates cartilage repair in the injured rabbit knee: preliminary report. Clinics, 66(10), 1835-1838. doi:10.1590/s1807-59322011001000026Landis, J. R., & Koch, G. G. (1977). The Measurement of Observer Agreement for Categorical Data. Biometrics, 33(1), 159. doi:10.2307/2529310Lao, L., Tan, H., Wang, Y., & Gao, C. (2008). Chitosan modified poly(l-lactide) microspheres as cell microcarriers for cartilage tissue engineering. Colloids and Surfaces B: Biointerfaces, 66(2), 218-225. doi:10.1016/j.colsurfb.2008.06.014Lastra, M. L., Molinuevo, M. S., Blaszczyk-Lezak, I., Mijangos, C., & Cortizo, M. S. (2017). Nanostructured fumarate copolymer-chitosan crosslinked scaffold: An in vitro osteochondrogenesis regeneration study. Journal of Biomedical Materials Research Part A, 106(2), 570-579. doi:10.1002/jbm.a.36260Lastra, M. L., Molinuevo, M. S., Cortizo, A. M., & Cortizo, M. S. (2016). Fumarate Copolymer-Chitosan Cross-Linked Scaffold Directed to Osteochondrogenic Tissue Engineering. Macromolecular Bioscience, 17(5). doi:10.1002/mabi.201600219Lebourg, M., Martínez-Díaz, S., García-Giralt, N., Torres-Claramunt, R., Ribelles, J. G., Vila-Canet, G., & Monllau, J. (2013). Cell-free cartilage engineering approach using hyaluronic acid–polycaprolactone scaffolds: A study in vivo. Journal of Biomaterials Applications, 28(9), 1304-1315. doi:10.1177/0885328213507298Luzardo-Alvarez, A., Blarer, N., Peter, K., Romero, J. F., Reymond, C., Corradin, G., & Gander, B. (2005). Biodegradable microspheres alone do not stimulate murine macrophages in vitro, but prolong antigen presentation by macrophages in vitro and stimulate a solid immune response in mice. Journal of Controlled Release, 109(1-3), 62-76. doi:10.1016/j.jconrel.2005.09.015Mainil-Varlet, P., Van Damme, B., Nesic, D., Knutsen, G., Kandel, R., & Roberts, S. (2010). A New Histology Scoring System for the Assessment of the Quality of Human Cartilage Repair: ICRS II. The American Journal of Sports Medicine, 38(5), 880-890. doi:10.1177/0363546509359068Martinez-Diaz, S., Garcia-Giralt, N., Lebourg, M., Gómez-Tejedor, J.-A., Vila, G., Caceres, E., … Monllau, J. C. (2010). In Vivo Evaluation of 3-Dimensional Polycaprolactone Scaffolds for Cartilage Repair in Rabbits. The American Journal of Sports Medicine, 38(3), 509-519. doi:10.1177/0363546509352448McCormick, F., Harris, J. D., Abrams, G. D., Frank, R., Gupta, A., Hussey, K., … Cole, B. (2014). Trends in the Surgical Treatment of Articular Cartilage Lesions in the United States: An Analysis of a Large Private-Payer Database Over a Period of 8 Years. Arthroscopy: The Journal of Arthroscopic & Related Surgery, 30(2), 222-226. doi:10.1016/j.arthro.2013.11.001Sancho-Tello, M., Forriol, F., Gastaldi, P., Ruiz-Saurí, A., Martín de Llano, J. J., Novella-Maestre, E., … Carda, C. (2015). Time Evolution of in Vivo Articular Cartilage Repair Induced by Bone Marrow Stimulation and Scaffold Implantation in Rabbits. The International Journal of Artificial Organs, 38(4), 210-223. doi:10.5301/ijao.5000404Sancho-Tello, M., Forriol, F., de Llano, J. J. M., Antolinos-Turpin, C., Gómez-Tejedor, J. A., Ribelles, J. L. G., & Carda, C. (2017). Biostable Scaffolds of Polyacrylate Polymers Implanted in the Articular Cartilage Induce Hyaline-Like Cartilage Regeneration in Rabbits. The International Journal of Artificial Organs, 40(7), 350-357. doi:10.5301/ijao.5000598Steadman, J. R., Rodkey, W. G., Briggs, K. K., & Rodrigo, J. J. (1999). The microfracture technique to treat full thickness articular cartilage defects of the knee. Der Orthopäde, 28(1), 26-32. doi:10.1007/pl00003545Tetè, S., Mastrangelo, F., Carone, L., Nargi, E., Costanzo, G., Vinci, R., … Ciccarelli, R. (2007). Morphostructural Analysis of Human Follicular Stem Cells on Highly Porous Bone Hydroxyapatite Scaffold. International Journal of Immunopathology and Pharmacology, 20(4), 819-826. doi:10.1177/039463200702000418Van den Borne, M. P. J., Raijmakers, N. J. H., Vanlauwe, J., Victor, J., de Jong, S. N., Bellemans, J., & Saris, D. B. F. (2007). International Cartilage Repair Society (ICRS) and Oswestry macroscopic cartilage evaluation scores validated for use in Autologous Chondrocyte Implantation (ACI) and microfracture. Osteoarthritis and Cartilage, 15(12), 1397-1402. doi:10.1016/j.joca.2007.05.005Vikingsson, L., Sancho-Tello, M., Ruiz-Saurí, A., Díaz, S. M., Gómez-Tejedor, J. A., Ferrer, G. G., … Ribelles, J. L. G. (2015). Implantation of a Polycaprolactone Scaffold with Subchondral Bone Anchoring Ameliorates Nodules Formation and Other Tissue Alterations. The International Journal of Artificial Organs, 38(12), 659-666. doi:10.5301/ijao.5000457Zan, Q., Wang, C., Dong, L., Cheng, P., & Tian, J. (2008). Effect of surface roughness of chitosan-based microspheres on cell adhesion. Applied Surface Science, 255(2), 401-403. doi:10.1016/j.apsusc.2008.06.074Zhang, C., Cai, Y., & Lin, X. (2016). One-Step Cartilage Repair Technique as a Next Generation of Cell Therapy for Cartilage Defects: Biological Characteristics, Preclinical Application, Surgical Techniques, and Clinical Developments. Arthroscopy: The Journal of Arthroscopic & Related Surgery, 32(7), 1444-1450. doi:10.1016/j.arthro.2016.01.061Zhu, W., Chen, K., Lu, W., Sun, Q., Peng, L., Fen, W., … Zeng, Y. (2013). In vitro study of nano-HA/PLLA composite scaffold for rabbit BMSC differentiation under TGF-β1 induction. In Vitro Cellular & Developmental Biology - Animal, 50(3), 214-220. doi:10.1007/s11626-013-9699-

Bevacizumab Diminishes Inflammation in an Acute Endotoxin-Induced Uveitis Model

Introduction: Uveitis is an eye disease characterized by inflammation of the uvea and an early and exhaustive diagnosis is essential for its treatment. The aim of our study is to assess the potential toxicity and anti-inflammatory efficacy of Bevacizumab in an experimental uveitis model by subcutaneously injecting lipopolysaccharide into Lewis rats and to clarify its mechanism.Material and Methods: Blood–aqueous barrier integrity was assessed 24 h after endotoxin-induced uveitis (EIU) by analyzing two parameters: cell count and protein concentration in aqueous humors. Histopathology of all eye structures was also studied. Enzyme-linked immunosorbent analyses of the aqueous humor samples were performed in order to calculate the diverse chemokine and cytokine protein levels and oxidative stress-related markers were also evaluated.Results: The aqueous humor’s cellular content significantly increased in the group treated with only Bevacizumab, but it had no effect on retina histopathological grading. Nevertheless, the inflammation noted in ocular structures when administering Bevacizumab with endotoxin was mostly prevented since aqueous humor cell content considerably lowered, and concomitantly with a sharp drop in uveal, vitreous, and retina histopathological grading. The values of the multi-faceted cytokine IL-2 also significantly decreased (p < 0.05 vs. endotoxin group), and the protective IL-6 and IL-10 cytokines values rose with related anti-oxidant system recovery (p < 0.05 vs. endotoxin group). Concurrently, some related M1 macrophage chemokines substantially increased, e.g., GRO/KC, a chemokine that also displays any kind of protective role.Conclusion: All these results revealed that 24 h after being administered, Bevacizumab treatment in EIU significantly prevented inflammation in various eye structures and correct results in efficacy vs. toxicity balance were obtained

Seroprevalence of SARS-CoV-2 in a Cohort of Patients with Multiple Sclerosis under Disease-Modifying Therapies

Background: Disease-modifying therapies (DMTs) used to treat multiple sclerosis (MS) alter the immune system and therefore increase the risk of infection. There is growing concern about the impact of COVID-19 on patients with MS (pwMS), especially those treated with DMTs. Methods: This is a single-center prospective observational study based on data from the Esclerosis Múltiple y COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data and SARS-CoV-2 serology, and symptoms of COVID-19 in pwMS treated with any DTM were extracted. The relationship among demographics, MS status, DMT, and COVID-19 was evaluated. Results: A total of 259 pwMS were included. The administration of interferon was significantly associated with the presence of SARS-CoV-2 antibodies (26.4% vs. 10.7%, p = 0.006). Although patients taking interferon were significantly older (49.1 vs. 43.5, p = 0.003), the association of interferon with the presence of SARS-CoV-2 antibodies was still significant in the multivariate analysis (OR 2.99 (1.38; 6.36), p = 0.006). Conclusions: According to our data, pwMS present a higher risk of COVID-19 infection compared with results obtained from the general population. There is no evidence of a worse COVID-19 outcome in pwMS. DMTs did not significantly change the frequency of COVID-19, except for interferon; however, these findings must be interpreted with caution given the small sample of pwMS taking each DMT

Influence of Dll4 via HIF-1α-VEGF Signaling on the Angiogenesis of Choroidal Neovascularization under Hypoxic Conditions

Choroidal neovascularization (CNV) is the common pathological basis of irreversible visual impairment encountered in a variety of chorioretinal diseases; the pathogenesis of its development is complicated and still imperfectly understood. Recent studies indicated that delta-like ligand 4 (Dll4), one of the Notch family ligands might participate in the HIF-1α-VEGF pathway to regulate CNV angiogenesis. But little is known about the influence and potential mechanism of Dll4/Notch signals on CNV angiogenesis. Real-time RT-PCR, Western blotting were used to analyze the expression alteration of Dll4, VEGF and HIF-1α in hypoxic RF/6A cells. Immunofluorescence staining, a laser-induced rat CNV model and intravitreal injection techniques were used to confirm the relationships among these molecules in vitro and in vivo. RPE-RF/6A cell co-culture systems were used to investigate the effects of Dll4/Notch signals on CNV angiogenesis. We found that the Dll4 was involved in hypoxia signaling in CNV angiogenesis. Results from the co-culture system showed that the enhancement of Dll4 expression in RF/6A cells led to the significantly faster proliferation and stronger tube forming ability, but inhibited cells migration and invasion across a monolayer of RPE cells in hypoxic environment, while siRNA-mediated Dll4 silencing caused the opposite effects. Pharmacological disruption of Notch signaling using gamma-secretase inhibitor (GSI) produced similar, but not identical effects, to that caused by the Dll4 siRNA. In addition, the expression of several key molecules involved in the angiogenesis of CNV was altered in RF/6A cells showing constitutively active Dll4 expression. These results suggest that Dll4 play an important role in CNV angiogenesis, which appears to be regulated by HIF-1α and VEGF during the progression of CNV under hypoxic conditions. Targeting Dll4/Notch signaling may facilitate further understanding of the mechanisms that underlie CNV angiogenesis

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure

Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs. Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups. LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted