Acute Respiratory Infection Incidence and Outpatient Antibiotic Prescription Patterns in People With or Without Human Immunodeficiency Virus Infection: A Virtual Cohort Study.

Background: Inappropriate antibiotic use in acute respiratory infections (ARIs) is a major public health concern; however, data for people with human immunodeficiency virus (PWH) are limited. Methods: The HIV Virtual Cohort Study is a retrospective cohort of adult Department of Defense beneficiaries. Male PWH cases (n = 2413) were matched 1:2 to controls without HIV (n = 4826) by age, gender, race/ethnicity, and beneficiary status. Acute respiratory infection encounters between 2016 and 2020 and corresponding antibiotic prescriptions were characterized as always, sometimes, or never appropriate based on International Classification of Diseases, Tenth Revision coding. Incidence of ARI encounters and antibiotic appropriateness were compared between PWH and controls. Subgroup analyses were assessed by CD4 count and viral load suppression on antiretroviral therapy. Results: Mean rates of ARI encounters were similar for PWH (1066 per 1000 person-years) and controls (1010 per 1000 person-years); however, the rate was double among PWH without viral load (VL) suppression (2018 per 1000 person-years). Antibiotics were prescribed in 26% of encounters among PWH compared to 34% for controls (P ≤ .01); antibiotic use was "never" appropriate in 38% of encounters with PWH and 36% in controls. Compared to controls, PWH received more sulfonamides (5.5% vs 2.7%; P = .001), and variation existed among HIV subgroups in the prescription of sulfonamides, fluoroquinolones, and ß-lactams. Discussion: Acute respiratory infection encounters were similar for PWH and those without HIV; however, PWH with lower CD4 counts and/or nonsuppressed VL had more frequent ARI visits. Inappropriate antibiotic use for ARIs was high in both populations, and focused interventions to improve antibiotic appropriateness for prescribers caring for PWH should be pursued.

Functional importance of platelet-derived growth factor (PDGF) receptor extracellular immunoglobulin-like domains. Identification of PDGF binding site and neutralizing monoclonal antibodies.

The biological effects of platelet-derived growth factor (PDGF) are mediated by alpha- and beta-PDGF receptors (PDGFR), which have an intracellular tyrosine kinase domain and an extracellular region comprising five immunoglobulin-like domains (D1-D5). Using deletion mutagenesis we mapped the PDGF binding site in each PDGFR to the D2-D3 region. In the case of alpha-PDGFR, 125I-PDGF AA and 125I-PDGF BB bound to the full-length extracellular domain, D1-D5, and D2-D3 with equal affinity (Kd = 0.21-0.42 nM). Identical results were obtained for 125I-PDGF BB binding to beta-PDGFR mutants D1-D5 and D2-D3, establishing that D1, D4, and D5 do not contribute to PDGF binding. Monoclonal antibodies (mAb) directed against individual PDGFR Ig-like domains were used to extend these observations. The anti-D1 mAb 1E10E2 and anti-D5 mAb 2D4G10 had no effect on alpha- or beta-PDGFR function, respectively. In contrast, mAb 2H7C5 and 2A1E2 directed against D2 of the alpha- and beta-receptor, respectively, blocked PDGF binding, receptor autophosphorylation and mitogenic signaling with IC50 values of 0.1-3.0 nM. An anti-D4 mAb 1C7D5 blocked beta-receptor autophosphorylation and signaling without inhibiting PDGF binding consistent with the observation that D4 is essential for PDGFR dimerization (Omura, T., Heldin, C.-H., and Ostman, A. (1997) J. Biol. Chem. 272, 12676-12682). mAbs identified here act as potent PDGFR antagonists that can be used as research tools and potentially as therapeutic agents for the treatment of diseases involving unwanted PDGFR signaling.

The cellular mechanism of glucocorticoid acceleration of fetal lung maturation. Fibroblast-pneumonocyte factor stimulates choline-phosphate cytidylyltransferase activity.

The cellular mechanism by which glucocorticoids stimulate phosphatidylcholine biosynthesis has been studied in the fetal rat lung in vivo and in cultured fetal rat lung cells of varying levels of complexity. Administration of dexamethasone to pregnant rats at 18 days gestation resulted in a significant increase in saturated phosphatidylcholine content in fetal lung 24 h after injection. Dexamethasone administration increased the activity of fetal lung choline-phosphate cytidylyltransferase by 34%. It had no effect on the activities of fetal lung choline kinase and choline phosphotransferase. Exposure of fetal lung type II cells in organotypic cultures (which contain both type II cells and fibroblasts) to cortisol resulted in a 1.6-fold increase in the incorporation of [Me-3H]choline into saturated phosphatidylcholine. The activities of the enzymes in the choline pathway for the de novo biosynthesis of phosphatidylcholine were not significantly altered except for a 105% increase in choline-phosphate cytidylyltransferase activity. Treatment of monolayer cultures of fetal type II cells with cortisol-conditioned medium from fetal lung fibroblasts resulted in a 1.5-fold increase in saturated phosphatidylcholine production. This effect correlated with a doubling of choline-phosphate cytidylyltransferase activity. Additional evidence that this stimulatory action is mediated by fibroblast-pneumonocyte factor, produced by fetal lung fibroblasts in response to cortisol, was obtained. The factor was partially purified from cortisol-conditioned medium of fetal lung fibroblasts by gel filtration and affinity chromatography. Based on biological activity, a 3000-fold purification was obtained. Stimulation of saturated phosphatidylcholine synthesis in type II cells by fibroblast-pneumonocyte factor was maximal within 60 min of incubation. Pulse-chase experiments indicated that the stimulatory effect was correlated with an increased conversion of choline phosphate into CDP choline. Moreover, the enhanced phosphatidylcholine formation by fetal type II cells in response to fibroblast-pneumonocyte factor was accompanied by decreased levels of cellular choline phosphate. These findings further support the concept that glucocorticoid action on surfactant-associated phosphatidylcholine synthesis occurs ultimately at the level of the alveolar type II cell and involves fibroblast-pneumonocyte factor which stimulates the activity of choline-phosphate cytidylyltransferase.