Association of Receiving Multiple, Concurrent Fracture-Associated Drugs With Hip Fracture Risk

Importance: Many prescription drugs increase fracture risk, which raises concern for patients receiving 2 or more such drugs concurrently. Logic suggests that risk will increase with each additional drug, but the risk of taking multiple fracture-associated drugs (FADs) is unknown. Objective: To estimate hip fracture risk associated with concurrent exposure to multiple FADs. Design, Setting, and Participants: This cohort study used a 20% random sample of Medicare fee-for-service administrative data for age-eligible Medicare beneficiaries from 2004 to 2014. Sex-stratified Cox regression models estimated hip fracture risk associated with current receipt of 1, 2, or 3 or more of 21 FADs and, separately, risk associated with each FAD and 2-way FAD combination vs no FADs. Models included sociodemographic characteristics, comorbidities, and use of non-FAD medications. Analyses began in November 2018 and were completed April 2019. Exposure: Receipt of prescription FADs. Main Outcomes and Measures: Hip fracture hospitalization. Results: A total of 11.3 million person-years were observed, reflecting 2,646,255 individuals (mean [SD] age, 77.2 [7.3] years, 1,615,613 [61.1%] women, 2,136,585 [80.7%] white, and 219 579 [8.3%] black). Overall, 2,827,284 person-years (25.1%) involved receipt of 1 FAD; 1,322,296 (11.7%), 2 FADs; and 954,506 (8.5%), 3 or more FADs. In fully adjusted, sex-stratified models, an increase in hip fracture risk among women was associated with the receipt of 1, 2, or 3 or more FADs (1 FAD: hazard ratio [HR], 2.04; 95% CI, 1.99-2.11; P\u3c.001; 2 FADs: HR, 2.86; 95% CI, 2.77-2.95; P\u3c.001; ≥3 FADs: HR, 4.50; 95% CI, 4.36-4.65; P\u3c.001). Relative risks for men were slightly higher (1 FAD: HR, 2.23; 95% CI, 2.11-2.36; P\u3c.001; 2 FADs: HR, 3.40; 95% CI, 3.20-3.61; P\u3c.001; ≥3 FADs: HR, 5.18; 95% CI, 4.87-5.52; P\u3c.001). Among women, 2 individual FADs were associated with HRs greater than 3.00; 80 pairs of FADs exceeded this threshold. Common, risky pairs among women included sedative hypnotics plus opioids (HR, 4.90; 95% CI, 3.98-6.02; P\u3c.001), serotonin reuptake inhibitors plus benzodiazepines (HR, 4.50; 95% CI, 3.76-5.38; P\u3c.001), and proton pump inhibitors plus opioids (HR, 4.00; 95% CI, 3.56-4.49; P\u3c.001). Receipt of 1, 2, or 3 or more non-FADs was associated with a small, significant reduction in fracture risk compared with receipt of no non-FADs among women (1 non-FAD: HR, 0.93; 95% CI, 0.90-0.96; P\u3c.001; 2 non-FADs: HR, 0.84; 95% CI, 0.81-0.87; P\u3c.001; ≥3 non-FADs: HR, 0.74; 95% CI, 0.72-0.77; P\u3c.001). Conclusions and Relevance: Among older adults, FADs are commonly used and commonly combined. In this cohort study, the addition of a second and third FAD was associated with a steep increase in fracture risk. Many risky pairs of FADs included potentially avoidable drugs (eg, sedatives and opioids). If confirmed, these findings suggest that fracture risk could be reduced through tighter adherence to long-established prescribing guidelines and recommendations

Sub-100-nm negative bend resistance ballistic sensors for high spatial resolution magnetic field detection

We report the magnetic field detection properties of ballistic sensors utilizing the negative bend resistance of InSb∕In(1−x)Al(x)Sb quantum well cross junctions as a function of temperature and geometric size. We demonstrate that the maximum responsivity to magnetic field and its linearity increase as the critical device dimension is reduced. This observation deviates from the predictions of the classical billiard ball model unless significant diffuse boundary scattering is included. The smallest device studied has an active sensor area of 35×35 nm(2), with a maximum responsivity of 20 kΩ∕T, and a noise-equivalent field of [Formula: see text] at 100 K

Authentication of the R06E Fruit Bat Cell Line

Fruit bats and insectivorous bats are believed to provide a natural reservoir for a wide variety of infectious diseases. Several lines of evidence, including the successful isolation of infectious viruses, indicate that Marburg virus and Ravn virus have found a major reservoir in colonies of the Egyptian rousette (Rousettus aegyptiacus). To facilitate molecular studies on virus-reservoir host interactions and isolation of viruses from environmental samples, we established cell lines from primary cells of this animal. The cell lines were given to several laboratories until we realized that a contamination with Vero cells in one of the cultures had occurred. Here we describe a general diagnostic procedure for identification of cross-species contamination with the focus on Vero and Rousettus cell lines, and summarize newly discovered properties of the cell lines that may pertain to pathogen discovery

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.Peer reviewe

New World Hantaviruses Activate IFNλ Production in Type I IFN-Deficient Vero E6 Cells

Hantaviruses indigenous to the New World are the etiologic agents of hantavirus cardiopulmonary syndrome (HCPS). These viruses induce a strong interferon-stimulated gene (ISG) response in human endothelial cells. African green monkey-derived Vero E6 cells are used to propagate hantaviruses as well as many other viruses. The utility of the Vero E6 cell line for virus production is thought to owe to their lack of genes encoding type I interferons (IFN), rendering them unable to mount an efficient innate immune response to virus infection. Interferon lambda, a more recently characterized type III IFN, is transcriptionally controlled much like the type I IFNs, and activates the innate immune system in a similar manner.We show that Vero E6 cells respond to hantavirus infection by secreting abundant IFNlambda. Three New World hantaviruses were similarly able to induce IFNlambda expression in this cell line. The IFNlambda contained within virus preparations generated with Vero E6 cells independently activates ISGs when used to infect several non-endothelial cell lines, whereas innate immune responses by endothelial cells are specifically due to viral infection. We show further that Sin Nombre virus replicates to high titer in human hepatoma cells (Huh7) without inducing ISGs.Herein we report that Vero E6 cells respond to viral infection with a highly active antiviral response, including secretion of abundant IFNlambda. This cytokine is biologically active, and when contained within viral preparations and presented to human epithelioid cell lines, results in the robust activation of innate immune responses. We also show that both Huh7 and A549 cell lines do not respond to hantavirus infection, confirming that the cytoplasmic RNA helicase pathways possessed by these cells are not involved in hantavirus recognition. We demonstrate that Vero E6 actively respond to virus infection and inhibiting IFNlambda production in these cells might increase their utility for virus propagation