RESUMO
The use of allogeneic blood products to restore hemostasis during pediatric cardiac surgery is associated with major risks. Consequently, there has been a growing interest in new patient blood management strategies, such as those based on the use of fibrinogen concentrate (FC). Accumulating evidence has shown FC supplementation to be safe and effective. Nevertheless, no guidelines are available on using FC in the pediatric setting, and few objective evaluations have been provided in clinical practice. The endpoint of this monocenter retrospective study was the hemostatic effect of additional FC in infants undergoing complex cardiac surgery with cardiopulmonary bypass to manage persistent clinically relevant bleeding. After weaning from cardiopulmonary bypass and after protamine administration, patients were transfused with conventional allogeneic products such as packed red blood cells, fresh frozen plasma (FFP), and platelets. In the case of redo surgery, according to the institutional protocol, patients also received tranexamic acid. In case of clinically persistent relevant bleeding, according to the anesthesiologist's judgment and thromboelastography, patients received FC supplementation (group with FC) or further FFP transfusions without receiving FC supplementation (group without FC). The primary endpoint was the hemostatic effects of FC. Secondary endpoints were the functional hypofibrinogenemia threshold value (expressed as maximum amplitude fibrinogen, MA-Fib) and postoperative MA-Fib, fibrinogenemia, intraoperative transfusions, and adverse events (AEs). In total, 139 patients who underwent cardiac surgery with CPB and aged less than 2 years were enrolled: 70 patients received allogeneic blood products and FC supplementation (group FC); 69 patients received allogeneic products without FC supplementation (group without FC). Patients that received FC supplementation were characterized by a significantly longer time of extracorporeal circulation (p < 0.001) and aortic cross-clamping (p < 0.001), a significantly lower minimum temperature (p = 0.011), increased use of concentrated prothrombin complex (p = 0.016) and tranexamic acid (p = 0.010), and a significantly higher amount of packed red blood cells, platelets (p < 0.001) and fresh frozen plasma (p = 0.03). Postoperative bleeding and severe bleeding were not statistically different between patients treated with FC and those not treated with FC supplementation (p = 0.786 and p = 0.695, respectively); after adjustment, a trend toward reduced bleeding can be observed with FC (p = 0.064). Overall, 88% of patients with severe bleeding had MA-Fib < 10 mm; a moderate association between severe bleeding and MA-Fib (odds ratio 1.7, 95% CI 0.5-6.5, p = 0.425) was found. Increased MA-Fib and postoperative fibrinogen were higher in the FC group (p = 0.003 and p < 0.001, respectively) than in FFP. AEs in the FC group were comparable to those observed in less complicated surgeries. Our results suggest a potential role of FC in complex surgery in maintaining postoperative bleeding at a level comparable to less complicated surgical procedures and favoring the increase in postoperative MA-Fib and fibrinogen.
RESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is still missing effective therapeutic strategies. Although manipulation of neuronal excitability has been tested in murine and human ALS models, it is still under debate whether neuronal activity might represent a valid target for efficient therapies. In this study, we exploited a combination of transcriptomics, proteomics, optogenetics and pharmacological approaches to investigate the activity-related pathological features of iPSC-derived C9orf72-mutant motoneurons (MN). We found that human ALSC9orf72 MN are characterized by accumulation of aberrant aggresomes, reduced expression of synaptic genes, loss of synaptic contacts and a dynamic "malactivation" of the transcription factor CREB. A similar phenotype was also found in TBK1-mutant MN and upon overexpression of poly(GA) aggregates in primary neurons, indicating a strong convergence of pathological phenotypes on synaptic dysregulation. Notably, these alterations, along with neuronal survival, could be rescued by treating ALS-related neurons with the K+ channel blockers Apamin and XE991, which, respectively, target the SK and the Kv7 channels. Thus, our study shows that restoring the activity-dependent transcriptional programme and synaptic composition exerts a neuroprotective effect on ALS disease progression.
