Gag p24 is a Marker of HIV Expression in Tissues and Correlates with Immune Response

We demonstrate that HIV gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T-cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma sCD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.

Pharmacokinetics of Anti-Infective Agents During CytoSorb Hemoadsorption: An Experimental Study

Background: Cytokine hemoadsorption might be effective in patients with sepsis. However, its effect on anti-infective agents' pharmacokinetics remains largely unknown. We sought to determine the influence of hemoadsorption on the pharmacokinetics of common anti-infective agents. Methods: This is an interventional experimental study, conducted in 24 healthy pigs. Animals were randomly allocated to either hemoadsorption (cases) or sham procedure (controls) and to a drug combination (3 cases and 3 controls for each combination). Hemoadsorption was performed with CytoSorb® (CytoSorbents Corporation, USA). We evaluated 17 drugs (clindamycin, fluconazole, linezolid, meropenem, piperacillin, anidulafungin, ganciclovir, clarithromycin, posaconazole, teicoplanin, tobramycin, ceftriaxone, ciprofloxacin, metronidazole, liposomal amphotericin B, flucloxacillin and cefepime). Repeated blood sampling from the extracorporeal circulation (adsorber inlet/outlet, sham circulation) were performed within six hours of administration. Total clearance and adsorber-specific clearances were computed at each time point.Results: Hemoadsorption was associated with increased clearance of all study drugs, except for ganciclovir. Its impact on total body clearance was major for fluconazole (+282%), linezolid (+115%) and amphotericin B (+75%). It was minor for posaconazole (+32%), teicoplanin (+31%), anidulafungin (+23%), piperacillin (+19%), flucloxacillin (+16%), metronidazole (+16%) and ciprofloxacin (+15%) and insignificant (<10%) for all other drugs. Hemoadsorber clearance declined over time with even delayed desorption for beta-lactams. It was moderately correlated with drug's lipophilicity (p=0.01; r2=0.43). Conclusions: Hemoadsorption with CytoSorb® has limited effect on the pharmacokinetics of most tested anti-infective drugs but appears to increase fluconazole, linezolid and liposomal amphotericin B clearance. Studies in humans with sepsis are required to confirm these findings.

Abstract P015: Factors Altering Luminal Succinate Effect Blood Pressure

Luminal succinate (Suc) has been reported to activate its receptor Sucnr1, stimulate renin release and increase BP in certain contexts. NaDC1 (Na + dicarboxylate cotransporter), located only on apical membrane in the proximal tubule of the kidney, reabsorbs filtered citrate and Suc, and is upregulated in acidosis. NaDC1 regulation is key in preventing stones and in maintaining acid-base homeostasis; but its role in BP regulation is not known. We postulate that luminal Suc alters BP. Our purpose was to examine the role of NaDC1, luminal Suc, and acidosis in BP regulation. To address these issues, we used NaDC1 KO (knock out) and WT (wild type) mice on normal diet or 72 hr acid diet (AD). Acidosis should lower luminal Suc due to upregulation of NaDC1 in WT mice. AD was associated with statistically significant BP decreases in both male and female WT but not in NaDC1 KO. Clearance studies compared Suc infused (SI) with non-infused NaDC1 KO and WT. ANOVA showed borderline increases between some groups: WT males on AD, BP increased from 71.48 ± 2.30 to 81.63 ± 2.16 with SI; and NaDC1 KO females on normal diet BP increased from 86.20 ± 3.98 to 96.48 ± 3.39 with SI. KO was only associated with increased BP in males on AD (p=0.05). Recently Khamaysi et al (JASN 2019) found only activity-dependent BP was altered by Suc. So, in additional studies we used telemetry (BP/T) for 24/7 monitoring of NaDC1 KO vs WT. On normal diets, mean arterial pressure (MAP) was significantly higher in KO than in WT. MAP at 9 pm: KO 122.44 ± 1.85 vs WT 110.40 ± 2.59, p <0.002, 5 am: KO 118.81 ± 2.64 vs WT 103.18 ± 4.00, p <0.01 and 8 am: KO 106.86 ± 1.28 vs 99.22 ± 2.64, p <0.02. Acidosis appeared to lessen these BP/T differences. Thus, increased luminal delivery of succinate due to KO of NaDC1 yields significant MAP increases during active periods. We examined levels of Sucnr1 in kidney cortex using droplet digital PCR (data are expressed as copy numbers of target gene in 1 ng PCR reaction). Sucnr1 expression was higher in NaDC1 KO (1343.6 ± 51) vs WT (1052.8 ± 50, p< 0.007) mice on normal diet. When fed acid diet Sucnr1 expression in KO fell (1039.6 ± 33) but increased in WT (1148 ± 50, p <0.006). In sum luminal Suc predominantly via NaDC1 reabsorption, does influence BP but this is modified by a variety of factors such as acidosis and activity.

Solving Homicides: The Influence of Neighborhood Characteristics and Investigator Caseload

The primary theoretical perspectives through which homicide clearance is analyzed do not give explicit attention to the neighborhood context in which people are victimized. Indeed, few clearance studies incorporate neighborhood effects. This study investigates whether neighborhood context influences the odds of homicide clearance in Rochester, NY, net of theoretically relevant victim and incident characteristics. The study also incorporates a direct measure of investigator caseload to assess the influence of organizational characteristics on clearance rates. Findings indicate that homicides, particularly of Black victims, were significantly more likely to be cleared in disadvantaged neighborhoods even as witnesses were less likely to cooperate with police in those neighborhoods. However, the odds of clearance decrease as the number of open cases each investigator is carrying increases. Case incident characteristics and the quality of evidence collected remain salient solvability factors regardless of location. Equally important is maintaining adequate staffing and keeping investigator caseloads at manageable levels. Heavy caseloads impose a significant constraint on the time that can be devoted to otherwise solvable cases and as such are analogous to the constraints imposed on prosecutors and courts by their typically heavy caseloads.