Impact of Iron Supplementation on Hospital Length of Stay for Pneumonia or Skin and Skin Structure Infections: A Retrospective Cohort Study.

Objectives: Pathogenic organisms utilize iron to survive and replicate and have evolved many processes to extract iron from human hosts. The goal of this study was to elucidate the impact of iron supplementation given in the setting of acute infection. Methods: This was a retrospective cohort study of Veterans Affairs patients who received intravenous antibiotics for pneumonia or skin and skin structure infections. Five-thousand subjects were included in each of the 2 cohorts: iron-receiving and non-iron-receiving. Data was analyzed using Fischer's Exact test if categorical and independent t-tests if continuous. Primary and secondary objectives analyzed with Cox proportional hazard regression and outcome rates estimated utilizing Kaplan-Meier method. Results: Five-thousand patients were included in each cohort. The iron cohort was significantly older (Mean-years: Iron = 71.6, No-iron = 68.9; mean-difference = 2.7, P < .0001) with reduced renal function (Mean-eGFR[mL/min/1.73 m²]: Iron = 67.2, No-iron = 77.4; mean-difference = 10.2, P < .0001). For the primary outcome, the iron cohort had a significantly longer mean length of hospital stay (10.4 days) compared to the no-iron cohort (8.7 days) (mean difference 1.7 days, P < .0001). Secondary outcome analysis showed the iron cohort received intravenous antibiotics for longer (Iron = 8.2 days, No-iron = 7.1 days; mean-difference = 1.1 days, P < .0001) with a higher proportion of 30-day readmissions (Iron = 15.6%, No-iron = 12.8%; proportion difference = 2.8%, P < .0001). No significant difference was found between cohort proportions for 30-day mortality (Iron = 12.7%, No-iron = 11.3%, proportion difference = 1.4%, P = .052). Conclusions: Baseline characteristic differences between cohorts is representative of patients who would be expected to require iron replacement therapy. Given the magnitude of primary and secondary-outcomes, further studies controlling for these factors would be warranted.

In silico prediction of ARB resistance: A first step in creating personalized ARB therapy.

Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are among the most prescribed drugs. However, ARB effectiveness varies widely, which may be due to non-synonymous single nucleotide polymorphisms (nsSNPs) within the AT1R gene. The AT1R coding sequence contains over 100 nsSNPs; therefore, this study embarked on determining which nsSNPs may abrogate the binding of selective ARBs. The crystal structure of olmesartan-bound human AT1R (PDB:4ZUD) served as a template to create an inactive apo-AT1R via molecular dynamics simulation (n = 3). All simulations resulted in a water accessible ligand-binding pocket that lacked sodium ions. The model remained inactive displaying little movement in the receptor core; however, helix 8 showed considerable flexibility. A single frame representing the average stable AT1R was used as a template to dock Olmesartan via AutoDock 4.2, MOE, and AutoDock Vina to obtain predicted binding poses and mean Boltzmann weighted average affinity. The docking results did not match the known pose and affinity of Olmesartan. Thus, an optimization protocol was initiated using AutoDock 4.2 that provided more accurate poses and affinity for Olmesartan (n = 6). Atomic models of 103 of the known human AT1R polymorphisms were constructed using the molecular dynamics equilibrated apo-AT1R. Each of the eight ARBs was then docked, using ARB-optimized parameters, to each polymorphic AT1R (n = 6). Although each nsSNP has a negligible effect on the global AT1R structure, most nsSNPs drastically alter a sub-set of ARBs affinity to the AT1R. Alterations within N298 -L314 strongly effected predicted ARB affinity, which aligns with early mutagenesis studies. The current study demonstrates the potential of utilizing in silico approaches towards personalized ARB therapy. The results presented here will guide further biochemical studies and refinement of the model to increase the accuracy of the prediction of ARB resistance in order to increase overall ARB effectiveness.

Distinctive cellular response to aluminum based adjuvants.

Aluminum-based adjuvants (ABAs) are used in human vaccines to enhance the magnitude of protective immune responses elicited against specific pathogens. One hypothesis is that stress signals released by aluminum-exposed necrotic cells play a role in modulating an immune response that contributes to the adjuvant's effectiveness. We hypothesized that aluminum adjuvant-induced necrosis would be similar irrespective of cellular origin or composition of the adjuvant. To test this hypothesis, human macrophages derived from peripheral monocytic cell line (THP-1) and cells derived from the human brain (primary astrocytes) were evaluated. Three commercially available formulations of ABAs (Alhydrogel, Imject alum, and Adju-Phos) were examined. Alum was also used as a reference. Cell viability, reactive oxygen species formation, and production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were quantified. Cells were exposed to different concentrations (10-100 µg/mL) of the adjuvants for 24 h or 72 h. The two FDA approved adjuvants (Alhydrogel and Adju-Phos) decreased cell viability in both cell types. At the 72 h time point, the decrease in viability was accompanied with increased ROS formation. The size of the aluminum agglomerates was not relatable to the changes observed. After exposure to ABAs, astrocytes and macrophages presented a distinct profile of cytokine secretion which may relate to the function and unique characteristics of each cell type. These variations indicate that aluminum adjuvants may have differing capability of activating cells of different origin and thus their utility in specific vaccine design should be carefully assessed for optimum efficacy.