FDA collaboration to improve safe use of fluoroquinolone antibiotics: an ex post facto matched control study of targeted short-form messaging and online education served to high prescribers

OBJECTIVE: This ex post facto matched control study was conducted to evaluate the effect of targeted short-form messages or continuing medical education (CME) on fluoroquinolone prescribing among high prescribers. METHODS: A total of 11,774 Medscape healthcare provider (HCP) members prescribing high volumes of fluoroquinolones were randomized into three segments to receive one of three unique targeted short-form messages, each delivered via email, web alerts, and mobile alerts. Some HCPs receiving targeted short-form messages also participated in CME on fluoroquinolone prescribing. A fourth segment of HCPs participated in CME only. Test HCPs were matched to third-party-provider prescriber data to identify control HCPs. We used prescriber data to determine new prescription volume; percentage (%) of HCPs with reduced prescribing; new prescription volume for acute bacterial sinusitis (ABS), uncomplicated urinary tract infection (uUTI), and acute bacterial exacerbations of chronic bronchitis in those with chronic obstructive pulmonary disease (ABECB-COPD). Open rates for emailed targeted short-form messages were also measured. RESULTS: Targeted short-form messages and CME each resulted in significant new prescription volume reduction versus control. Combining targeted short-form messages with CME yielded the greatest percentage of test HCPs with reduced prescribing (80.1%) versus controls (76.2%; p < 0.0001). New prescription volume decreased significantly for uUTI and ABS following exposure to targeted short-form messages, CME, or both. Targeted short-form messages containing comparative prescribing information with or without clinical context were opened at slightly higher rates (10.8% and 10.6%, respectively) than targeted short-form messages containing clinical context alone (9.1%). CONCLUSIONS: Targeted short-form messages and CME, alone and in combination, are associated with reduced oral fluoroquinolone prescribing among high prescribers

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FDA collaboration to improve safe use of fluoroquinolone antibiotics: an ex post facto matched control study of targeted short-form messaging and online education served to high prescribers.

OBJECTIVE: This ex post facto matched control study was conducted to evaluate the effect of targeted short-form messages or continuing medical education (CME) on fluoroquinolone prescribing among high prescribers. METHODS: A total of 11,774 Medscape healthcare provider (HCP) members prescribing high volumes of fluoroquinolones were randomized into three segments to receive one of three unique targeted short-form messages, each delivered via email, web alerts, and mobile alerts. Some HCPs receiving targeted short-form messages also participated in CME on fluoroquinolone prescribing. A fourth segment of HCPs participated in CME only. Test HCPs were matched to third-party-provider prescriber data to identify control HCPs. We used prescriber data to determine new prescription volume; percentage (%) of HCPs with reduced prescribing; new prescription volume for acute bacterial sinusitis (ABS), uncomplicated urinary tract infection (uUTI), and acute bacterial exacerbations of chronic bronchitis in those with chronic obstructive pulmonary disease (ABECB-COPD). Open rates for emailed targeted short-form messages were also measured. RESULTS: Targeted short-form messages and CME each resulted in significant new prescription volume reduction versus control. Combining targeted short-form messages with CME yielded the greatest percentage of test HCPs with reduced prescribing (80.1%) versus controls (76.2%; p<0.0001). New prescription volume decreased significantly for uUTI and ABS following exposure to targeted short-form messages, CME, or both. Targeted short-form messages containing comparative prescribing information with or without clinical context were opened at slightly higher rates (10.8% and 10.6%, respectively) than targeted short-form messages containing clinical context alone (9.1%). CONCLUSIONS: Targeted short-form messages and CME, alone and in combination, are associated with reduced oral fluoroquinolone prescribing among high prescribers.

Interleukin-12 elicits a non-canonical response in B16 melanoma cells to enhance survival.

BACKGROUND: Oncogenesis rewires signaling networks to confer a fitness advantage to malignant cells. For instance, the B16F0 melanoma cell model creates a cytokine sink for Interleukin-12 (IL-12) to deprive neighboring cells of this important anti-tumor immune signal. While a cytokine sink provides an indirect fitness advantage, does IL-12 provide an intrinsic advantage to B16F0 cells? METHODS: Acute in vitro viability assays were used to compare the cytotoxic effect of imatinib on a melanoma cell line of spontaneous origin (B16F0) with a normal melanocyte cell line (Melan-A) in the presence of IL-12. The results were analyzed using a mathematical model coupled with a Markov Chain Monte Carlo approach to obtain a posterior distribution in the parameters that quantified the biological effect of imatinib and IL-12. Intracellular signaling responses to IL-12 were compared using flow cytometry in 2D6 cells, a cell model for canonical signaling, and B16F0 cells, where potential non-canonical signaling occurs. Bayes Factors were used to select among competing signaling mechanisms that were formulated as mathematical models. Analysis of single cell RNAseq data from human melanoma patients was used to explore generalizability. RESULTS: Functionally, IL-12 enhanced the survival of B16F0 cells but not normal Melan-A melanocytes that were challenged with a cytotoxic agent. Interestingly, the ratio of IL-12 receptor components (IL12RB2:IL12RB1) was increased in B16F0 cells. A similar pattern was observed in human melanoma. To identify a mechanism, we assayed the phosphorylation of proteins involved in canonical IL-12 signaling, STAT4, and cell survival, Akt. In contrast to T cells that exhibited a canonical response to IL-12 by phosphorylating STAT4, IL-12 stimulation of B16F0 cells predominantly phosphorylated Akt. Mechanistically, the differential response in B16F0 cells is explained by both ligand-dependent and ligand-independent aspects to initiate PI3K-AKT signaling upon IL12RB2 homodimerization. Namely, IL-12 promotes IL12RB2 homodimerization with low affinity and IL12RB2 overexpression promotes homodimerization via molecular crowding on the plasma membrane. CONCLUSIONS: The data suggest that B16F0 cells shifted the intracellular response to IL-12 from engaging immune surveillance to favoring cell survival. Identifying how signaling networks are rewired in model systems of spontaneous origin can inspire therapeutic strategies in humans. Interleukin-12 is a key cytokine that promotes anti-tumor immunity, as it is secreted by antigen presenting cells to activate Natural Killer cells and T cells present within the tumor microenvironment. Thinking of cancer as an evolutionary process implies that an immunosuppressive tumor microenvironment could arise during oncogenesis by interfering with endogenous anti-tumor immune signals, like IL-12. Previously, we found that B16F0 cells, a cell line derived from a spontaneous melanoma, interrupts this secreted heterocellular signal by sequestering IL-12, which provides an indirect fitness advantage. Normally, IL-12 signals via a receptor comprised of two components, IL12RB1 and IL12RB2, that are expressed in a 1:1 ratio and activates STAT4 as a downstream effector. Here, we report that B16F0 cells gain an intrinsic advantage by rewiring the canonical response to IL-12 to instead initiate PI3K-AKT signaling, which promotes cell survival. The data suggest a model where overexpressing one component of the IL-12 receptor, IL12RB2, enables melanoma cells to shift the functional response via both IL-12-mediated and molecular crowding-based IL12RB2 homodimerization. To explore the generalizability of these results, we also found that the expression of IL12RB2:IL12RB1 is similarly skewed in human melanoma based on transcriptional profiles of melanoma cells and tumor-infiltrating lymphocytes. Additional file 6: Video abstract. (MP4 600 kb).

Exosomes derived from B16F0 melanoma cells alter the transcriptome of cytotoxic T cells that impacts mitochondrial respiration.

While recent clinical studies demonstrate the promise of cancer immunotherapy, a barrier for broadening the clinical benefit is identifying how tumors locally suppress cytotoxic immunity. As an emerging mode of intercellular communication, exosomes secreted by malignant cells can deliver a complex payload of coding and noncoding RNA to cells within the tumor microenvironment. Here, we quantified the RNA payload within tumor-derived exosomes and the resulting dynamic transcriptomic response to cytotoxic T cells upon exosome delivery to better understand how tumor-derived exosomes can alter immune cell function. Exosomes derived from B16F0 melanoma cells were enriched for a subset of coding and noncoding RNAs that did not reflect the abundance in the parental cell. Upon exosome delivery, RNAseq revealed the dynamic changes in the transcriptome of CTLL2 cytotoxic T cells. In analyzing transiently coexpressed gene clusters, pathway enrichment suggested that the B16F0 exosomal payload altered mitochondrial respiration, which was confirmed independently, and upregulated genes associated with the Notch signaling pathway. Interestingly, exosomal miRNA appeared to have no systematic effect on downregulating target mRNA levels. DATABASES: Gene expression data are available in the GEO database under the accession SuperSeries number GSE102951.

Single-Crystal Time-of-Flight Neutron Diffraction and Magic-Angle-Spinning NMR Spectroscopy Resolve the Structure and 1H and 7Li Dynamics of the Uranyl Peroxide Nanocluster U60.

Single-crystal time-of-flight neutron diffraction has provided atomic resolution of H atoms of H2O molecules and hydroxyl groups, as well as Li cations in the uranyl peroxide nanocluster U60. Solid-state magic-angle-spinning nuclear magnetic resonance (MAS NMR) spectroscopy was used to confirm the dynamics of these constituents, revealing the transportation of Li atoms and H2O through cluster walls. H atoms of hydroxyl units that are located on the cluster surface are involved in the transfer of H2O and Li cations from inside to outside and vice versa. This exchange occurs as a concerted motion and happens rapidly even in the solid state. As a consequence of its large size and open hexagonal pores, U60 exchanges Li cations more rapidly compared to other uranyl nanoclusters.

Determinants of adherence to diabetes treatment.

BACKGROUND: Understanding and improving medication adherence is crucial in diabetes management. Adherence to a diabetes regimen can improve glucose control and limit the development of complications. The aim of the present study was to evaluate the extent to which a variety of factors influence diabetes medication adherence. METHODS: A medication adherence survey was made available on WebMD, a medical information website for patients and/or consumers. Respondents were residents of the US, ≥18 years old, and diagnosed with either type 1 or type 2 diabetes mellitus (self-reported). RESULTS: Behavioral adherence (self-reported doses missed per week) correlated with perceived adherence (patients' self-report of their overall impression of medication adherence, ranked 0-5; P < 0.001). Adherent patients (very few [0%-10%] issues with adherence) were more likely to report having received information from their physician. Mostly adherent patients (few [11%-26%] issues with adherence) were less likely to obtain information from their physician, but reported more medication self-titration. Somewhat non-adherent patients (some [27%-46%] adherence issues) reported more "self-consciousness factors" and hypoglycemia. Non-adherent patients (many [47%-88%] adherence issues) were more likely to report worries about medication side effects. CONCLUSIONS: Receiving information from a healthcare provider is associated with greater diabetes medication adherence, suggesting the importance of clinicians making time to provide patient education.

Relationships between electron density and magnetic properties in water-bridged dimetal complexes.

The electron densities in two analogous dimetallic transition metal compounds, namely, [M2(µ-OH2)((t)BuCOO)4((t)BuCOOH)2(C5H5N)2] (M = Co(1), Ni(2)), were determined from combined X-ray and neutron single-crystal diffraction at 100 K. Excellent correspondence between the thermal parameters from X- and N-derived atomic displacement parameters is found, indicating high-quality X-ray data and a successful separation of thermal and electronic effects. Topological analysis of electron densities derived from high-resolution X-ray diffraction, as well as density functional theory calculations, shows no direct metal-metal bonding in either compound, while the total energy density at the bond critical points suggests stronger metal-oxygen interactions for the Ni system, in correspondence with its shorter bond distances. The analysis also allows for estimation of the relative strength of binding of terminal and bridging ligands to the metals, showing that the bridging water molecule is more strongly bound than terminal carboxylic acid, but less so than bridging carboxylates. Recently, modeling of magnetic and spectroscopic data in both of these systems has shown weak ferromagnetic interactions between the metal atoms. Factors related to large zero-field splitting effects complicate the magnetic analysis in both compounds, albeit to a much greater degree in 1. The current results support the conclusion drawn from previous magnetic and spectroscopic measurements that there is no appreciable direct communication between metal centers.

Inferring alterations in cell-to-cell communication in HER2+ breast cancer using secretome profiling of three cell models.

Challenges in demonstrating durable clinical responses to molecular-targeted therapies have sparked a re-emergence in viewing cancer as an evolutionary process. In somatic evolution, cellular variants are introduced through a random process of somatic mutation and are selected for improved fitness through a competition for survival. In contrast to Darwinian evolution, cellular variants that are retained may directly alter the fitness competition. If cell-to-cell communication is important for selection, the biochemical cues secreted by malignant cells that emerge should be altered to bias this fitness competition. To test this hypothesis, we compared the proteins secreted in vitro by two human HER2+ breast cancer cell lines (BT474 and SKBR3) relative to a normal human mammary epithelial cell line (184A1) using a proteomics workflow that leveraged two-dimensional gel electrophoresis (2DE) and MALDI-TOF mass spectrometry. Supported by the 2DE secretome maps and identified proteins, the two breast cancer cell lines exhibited secretome profiles that were similar to each other and, yet, were distinct from the 184A1 secretome. Using protein-protein interaction and pathway inference tools for functional annotation, the results suggest that all three cell lines secrete exosomes, as confirmed by scanning electron microscopy. Interestingly, the HER2+ breast cancer cell line exosomes are enriched in proteins involved in antigen-processing and presentation and glycolytic metabolism. These pathways are associated with two of the emerging hallmarks of cancer: evasion of tumor immunosurveillance and deregulating cellular energetics.

High-resolution neutron crystallographic studies of the hydration of the coenzyme cob(II)alamin.

The hydration of the coenzyme cob(II)alamin has been studied using high-resolution monochromatic neutron crystallographic data collected at room temperature to a resolution of 0.92 Å on the original D19 diffractometer with a prototype 4° × 64° detector at the high-flux reactor neutron source run by the Institute Laue-Langevin. The resulting structure provides hydrogen-bonding parameters for the hydration of biomacromolecules to unprecedented accuracy. These experimental parameters will be used to define more accurate force fields for biomacromolecular structure refinement. The presence of a hydrophobic bowl motif surrounded by flexible side chains with terminal functional groups may be significant for the efficient scavenging of ligands. The feasibility of extending the resolution of this structure to ultrahigh resolution was investigated by collecting time-of-flight neutron crystallographic data during commissioning of the TOPAZ diffractometer with a prototype array of 14 modular 2° × 21° detectors at the Spallation Neutron Source run by Oak Ridge National Laboratory.