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 is 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.

Background: Proton pump inhibitor (PPI) continuous infusions or intermittent boluses are used for the treatment of upper gastrointestinal bleeding (UGIB). Intermittent boluses are easier to give and are of lower cost without affecting clinical outcomes. Objective: To compare the rate of rebleeding between intermittent bolus and continuous infusion PPI therapy. Methods: We performed a retrospective, multicenter review of patients with UGIB receiving either continuous or intermittent PPI therapy. During the study period, due to drug and supply shortages, each institution implemented policies preferring intermittent PPI bolus therapy. We performed bivariate and multivariable comparisons of the 2 treatment strategies, with the primary outcome of interest being incidence of rebleeding. Additional variables of interest included intensive care unit (ICU) and hospital lengths of stay, discharge disposition, and in-hospital mortality. Results: Compared with intermittent bolus dosing (n = 209), patients receiving continuous infusion PPI (n = 237) were associated with a higher rate of rebleeding (33.8% vs 23.0%; P = 0.012); however, no difference was detected in multivariable analysis: adjusted odds ratio, 1.50 (95% confidence interval, 0.91-2.50). There was no difference in median hospital or ICU length of stay, discharge disposition, or in-hospital mortality. Correlatively, patients receiving continuous infusion therapy were more likely to have liver disease (29.1% vs 20.1%; P = 0.028), alcohol use disorder (28.3% vs 16.3.%; P = 0.003), history of lower gastrointestinal bleeding (6.4% vs 1.9%; P = 0.021), variceal bleeding (6.3 vs 2.4%, P = 0.045), and be admitted to the ICU (65.0% vs 32.5%, P = 0.00). Conclusions: Introduction of intermittent PPI bolus UGIB treatment via change in hospital policy was not associated with higher rates of rebleeding. However, continuous PPI therapy may have been perceived as more effective as it was used more commonly in high-risk patients.

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Background Experimental data suggest γ-aminobutyric acid-A receptor preferring general anesthetics (GA) may increase post-operative pain in patients with persistent inflammation (PI). This study was designed to begin to test this prediction. Methods Groups of rats were defined by the presence of inflammation, surgical intervention and/or the type of GA used for a three-hour period of anesthesia. PI was induced with complete Freund's adjuvant. The surgical intervention was a plantar incision. Three mechanistically distinct GAs were used: pentobarbital, ketamine/xylazine and isoflurane. Ongoing pain and hypersensitivity was assessed with guarding behavior analysis and the von Frey test, respectively. Results There was no influence of GA type on the magnitude or time course of recovery from post-operative hypersensitivity in the absence of PI. In the presence of PI, however, recovery from hypersensitivity was significantly slower in the pentobarbital group than in ketamine/xylazine or isoflurane groups. The pentobarbital effect was significant within three 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 hindpaw incision. The time to 50% recovery in 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 γ-aminobutyric acid-A receptor preferring GAs may have deleterious consequences when used in the presence of PI.

Background Non-operative management (NOM) is the current standard of care of hemodynamically stable patients with traumatic blunt solid abdominal organ injuries. Guidelines do not define the optimal timing of initiation of venous thromboembolism (VTE) prophylaxis in this population, and fear of failure of NOM may lead to delayed initiation of prophylaxis specifically in patients with high-grade injuries. Methods This was a single-center, retrospective study of patients with high-grade (AAST grades ≥3) blunt liver and splenic lacerations presenting to our level 1 trauma center between January 2010 and October 2017. Patients were divided into groups based on timing of low-molecular weight heparin (LMWH) initiation for VTE prophylaxis. The primary outcome was rate of failure of NOM, defined as the need for interventional radiology or surgical intervention for management of abdominal organ bleeding. Secondary outcomes included rates of VTE, lengths of ICU and hospital stay, and in-hospital mortality. Results A total of 207 patients with high-grade blunt liver and splenic injuries undergoing an initial attempt at NOM were identified. The distribution of grades 3, 4, and 5 liver and splenic injuries were similar across all groups. Overall, 55.5% of patients received LMWH during their index admission. Early administration of LMWH was not associated with a statistically significant increased risk of failure of NOM ( p = 0.054). Rates of VTE and in-hospital mortality were similar. Conclusions Early initiation of VTE prophylaxis was not associated with an increased rate of failure of NOM in patients with high-grade blunt abdominal organ injuries in patients who survived 24 h post-admission and did not require massive transfusion; however, the study was likely underpowered to detect a difference among groups due to small sample size.