Predictors of thrombosis during VV ECMO: an analysis of 9809 patients from the ELSO registry.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving therapy for critically ill patients, but it carries an increased risk of thrombosis due to blood interacting with non-physiological surfaces. While the relationship between clinical variables and thrombosis remains unclear, our study aimed to identify which factors are most predictive of thrombosis. The Extracorporeal Life Support Organization Registry was queried to obtain a cohort of VV-ECMO patients aged 18 years and older from 2015 to 2019. Patients who were over 80-years-old, at the extremes of weight, who received less than 24 h of ECMO, multiple rounds of ECMO, or had missing data were excluded. Multivariate logistic regression modeling was used to assess predictors of thrombosis and mortality. A total of 9809 patients were included in the analysis, with a mean age of 47.1 ± 15.1 years and an average ECMO run time of 305 ± 353 h. Thrombosis occurred in 19.9% of the cohort, with circuit thrombosis (8.6%) and membrane lung failure (6.1%) being the most common. Multivariate analysis showed that ECMO runs over 14 days (OR: 2.62, P < 0.001) and pregnancy-related complications (OR: 1.79, P = 0.004) were associated with an increased risk of thrombosis. Risk factors for circuit thrombosis included incremental unit increases in the pump flow rate at 24 h (OR: 1.07 [1.00-1.14], P = 0.044) and specific cannulation sites. Increased body weight (OR: 1.02 [1.00-1.04], P = 0.026) and increased duration on ECMO (OR: 3.82 [3.12-4.71], P < 0.001) were predictive of membrane lung failure. Additionally, patients with thrombosis were at increased likelihood of in-hospital mortality (OR: 1.52, P < 0.001). This study identified multiple thrombotic risk factors in VV-ECMO, suggesting that future studies investigating the impact of pregnancy associated complications and ECMO flow rate on hemostasis would be illuminating.

Synthesis and structure-activity analysis of diphenylpyrazolodiazene inhibitors of the HIV-1 Nef virulence factor.

HIV-1 Nef is a critical AIDS progression factor yet underexplored target for antiretroviral drug discovery. A recent high-throughput screen for pharmacological inhibitors of Nef-dependent Src-family kinase activation identified a diphenylpyrazolodiazene hit compound with submicromolar potency in HIV-1 replication assays against a broad range of primary Nef variants. This compound, known as 'B9', binds directly to Nef and inhibits its dimerization in cells as a possible mechanism of action. Here were synthesized a diverse set of B9 analogs and identified structural features essential to antiretroviral activity. Chemical modifications to each of the three rings present in the parent compound were identified that did not compromise antiviral action. These analogs will guide the development of next-generation compounds with appropriate pharmacological profiles for assessment of antiretroviral activity in vivo.

Deleterious impact of a γ-aminobutyric acid type A receptor preferring general anesthetic when used in the presence of persistent inflammation.

BACKGROUND: Experimental data suggest general anesthetics preferring γ-aminobutyric acid receptor type A may increase postoperative pain in patients with persistent inflammation. The current study was designed to begin to test this hypothesis. METHODS: Groups of rats were defined by the presence of inflammation, surgical intervention, and/or the type of general anesthetic used for a 3-h period of anesthesia. Persistent inflammation was induced with complete Freund adjuvant. The surgical intervention was a plantar incision. Three mechanistically distinct general anesthetics were used: pentobarbital, ketamine/xylazine, and isoflurane. Ongoing pain and hypersensitivity were assessed with guarding behavior analysis and the von Frey test, respectively. RESULTS: There was no influence of general anesthetic type on the magnitude or time course of recovery from postoperative hypersensitivity in the absence of persistent inflammation. However, in the presence of persistent inflammation, recovery from hypersensitivity was significantly slower in the pentobarbital group than in the ketamine/xylazine or isoflurane groups. The pentobarbital effect was significant within 3 days of surgery and persisted through the remainder of the testing period. A comparable delay in recovery was observed in pentobarbital-anesthetized inflamed rats not subjected to hind paw incision. The time to 50% recovery in the pentobarbital-treated inflamed groups was almost double that in the other groups. No differences were observed between ketamine/xylazine and isoflurane. Pentobarbital exposure did not increase guarding scores. CONCLUSIONS: These results suggest that general anesthetics preferring γ-aminobutyric acid receptor type A may have deleterious consequences when used in the presence of persistent inflammation.