Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial)

Introduction: Several observational studies suggest that statins modulate the pathophysiology of sepsis and may prevent its progression. The aim of this study was to determine if the acute administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis. Methods: A single centre phase II randomized double-blind placebo-controlled trial. Patients with sepsis were randomized to atorvastatin 40 mg daily or placebo for the duration of their hospital stay up to a maximum of 28-days. The primary end-point was the rate of sepsis progressing to severe sepsis during hospitalization. Results: 100 patients were randomized, 49 to the treatment with atorvastatin and 51 to placebo. Patients in the atorvastatin group had a significantly lower conversion rate to severe sepsis compared to placebo (4% vs. 24% p = 0.007.), with a number needed to treat of 5. No significant difference in length of hospital stay, critical care unit admissions, 28-day and 12-month readmissions or mortality was observed. Plasma cholesterol and albumin creatinine ratios were significantly lower at day 4 in the atorvastatin group (p < 0.0001 and p = 0.049 respectively). No difference in adverse events between the two groups was observed (p = 0.238). Conclusions: Acute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings. Trial Registration: International Standard Randomized Control Trial Registry ISRCTN64637517

FcγRI-Deficient Mice Show Multiple Alterations to Inflammatory and Immune Responses

AbstractThe inactivation of the mouse high-affinity IgG Fc receptor FcγRI resulted in a wide range of defects in antibody Fc-dependent functions. These studies showed the primary importance of FcγRI in endocytosis of monomeric IgG, kinetics, and extent of phagocytosis of immune complexes, in macrophage-based ADCC, and in immune complex-dependent antigen presentation to primed T cells. In the absence of FcγRI, antibody responses were elevated, implying the removal of a control point by the deletion of FcγRI. In addition, FcR-γ chain-deficient mice were found to express partially functional FcγRI. Thus, FcγRI is an early participant in Fc-dependent cell activation and in the development of immune responses

The treewidth of smart contracts

Smart contracts are programs that are stored and executed on the Blockchain and can receive, manage and transfer money (cryptocurrency units). Two important problems regarding smart contracts are formal analysis and compiler optimization. Formal analysis is extremely important, because smart contracts hold funds worth billions of dollars and their code is immutable after deployment. Hence, an undetected bug can cause significant financial losses. Compiler optimization is also crucial, because every action of a smart contract has to be executed by every node in the Blockchain network. Therefore, optimizations in compiling smart contracts can lead to significant savings in computation, time and energy. Two classical approaches in program analysis and compiler optimization are intraprocedural and interprocedural analysis. In intraprocedural analysis, each function is analyzed separately, while interprocedural analysis considers the entire program. In both cases, the analyses are usually reduced to graph problems over the control flow graph (CFG) of the program. These graph problems are often computationally expensive. Hence, there has been ample research on exploiting structural properties of CFGs for efficient algorithms. One such well-studied property is the treewidth, which is a measure of tree-likeness of graphs. It is known that intraprocedural CFGs of structured programs have treewidth at most 6, whereas the interprocedural treewidth cannot be bounded. This result has been used as a basis for many efficient intraprocedural analyses. In this paper, we explore the idea of exploiting the treewidth of smart contracts for formal analysis and compiler optimization. First, similar to classical programs, we show that the intraprocedural treewidth of structured Solidity and Vyper smart contracts is at most 9. Second, for global analysis, we prove that the interprocedural treewidth of structured smart contracts is bounded by 10 and, in sharp contrast with classical programs, treewidth-based algorithms can be easily applied for interprocedural analysis. Finally, we supplement our theoretical results with experiments using a tool we implemented for computing treewidth of smart contracts and show that the treewidth is much lower in practice. We use 36,764 real-world Ethereum smart contracts as benchmarks and find that they have an average treewidth of at most 3.35 for the intraprocedural case and 3.65 for the interprocedural case

Local Dexamethasone Administration Delays Allogeneic Islet Graft Rejection in the Anterior Chamber of the Eye of Non-Human Primates

Pancreatic islet transplantation into the anterior chamber of the eye (ACE) has been shown to improve glycemic control and metabolic parameters of diabetes in both murine and primate models. This novel transplantation site also allows the delivery of therapeutic agents, such as immunosuppressive drugs, locally to prevent islet graft rejection and circumvent unwanted systemic side effects. Local intravitreal administration of micronized dexamethasone implant was performed prior to allogeneic islet transplantation into the ACEs of non-human primates. Two study groups were observed namely allogeneic graft without immunosuppression (n = 4 eyes) and allogeneic graft with local immunosuppression (n = 8 eyes). Survival of islet grafts and dexamethasone concentration in the ACE were assessed in parallel for 24 weeks. Allogeneic islet grafts with local dexamethasone treatment showed significantly better survival than those with no immunosuppression (median survival time- 15 weeks vs 3 weeks, log-rank test p<0.0001). Around 73% of the grafts still survived at week 10 with a single local dexamethasone implant, where the control group showed no graft survival. Dexamethasone treated islet grafts revealed a good functional response to high glucose stimulation despite there was a transient suppression of insulin secretion from week 8 to 12. Our findings show a significant improvement of allografts survival in the ACE with local dexamethasone treatment. These results highlight the feasibility of local administration of pharmacological compounds in the ACE to improve islet graft survival and function. By eliminating the need for systemic immunosuppression, these findings may impact clinical islet transplantation in the treatment of diabetes, and the ACE may serve as a novel therapeutic islet transplantation site with high potential for local pharmacological intervention