Numerical simulation of ice growth on a MS-317 swept wing geometry

An effort to develop a 3-D ice accretion modeling method was initiated. This first step towards creation of a complete aircraft icing simulation code builds on previously developed methods for calculating 3-D flow fields and particle trajectories combined with a 2-D ice accretion calculation along coordinate locations corresponding to streamlines. The types of calculations necessary to predict 3-D ice accretion is demonstrated. Results of calculations using 3-D method for a MS-317 swept wing geometry are projected onto a 2-D plane parallel to the free stream direction and compared to experimental results for the same geometry. It is anticipated that many modifications will be made to this approach, however this effort will lay the groundwork for future modeling efforts. Results indicate that rime ice shapes indicate a difficulty in accurately calculating the ice shape in the runback region

Evaluation of the Sustainability of an Intervention to Increase HIV Testing

BACKGROUND Sustainability—the routinization and institutionalization of processes that improve the quality of healthcare—is difficult to achieve and not often studied. OBJECTIVE To evaluate the sustainability of increased rates of HIV testing after implementation of a multi-component intervention in two Veterans Health Administration healthcare systems. DESIGN Quasi-experimental implementation study in which the effect of transferring responsibility to conduct the provider education component of the intervention from research to operational staff was assessed. PATIENTS Persons receiving healthcare between 2005 and 2006 (intervention year) and 2006 and 2007 (sustainability year). MEASUREMENTS Monthly HIV testing rate, stratified by frequency of clinic visits RESULTS The monthly adjusted testing rate increased from 2% at baseline to 6% at the end intervention year and then declined reaching 4% at the end of the sustainability year. However, the stratified, visit-specific testing rate for persons newly exposed to the intervention (i.e., having their first through third visits during the study period) increased throughout the intervention and sustainability years. Increases in the proportion of visits by patients who remained untested despite multiple, prior exposures to the intervention accounted for the aggregate attenuation of testing during the sustainability year. Overall, the percentage of patients who received an HIV test in the sustainability year was 11.6%, in the intervention year 11.1%, and in the pre-intervention year 5.0% CONCLUSIONS Provider education combined with informatics and organizational support had a sustainable effect on HIV testing rates. The effect was most pronounced during patients' early contacts with the healthcare system.Health Services Research & Development Service (SDP 06–001

Experimental and Theoretical Evidence for Nitrogen-Fluorine Halogen Bonding in Silver-Initiated Radical Fluorinations

We report experimental and computational evidence for nitrogen–fluorine halogen bonding in Ag­(I)-initiated radical C–H fluorinations. Simple pyridines form [N–F–N]+ halogen bonds with Selectfluor to facilitate single-electron reduction by catalytic Ag­(I). Pyridine electronics affect the extent of halogen bonding, leading to significant differences in selectivity between mono- and difluorinated products. Electronic structure calculations show that halogen bonding to various pyridines alters the single-electron reduction potential of Selectfluor, which is consistent with experimental electrochemical analysis. Multinuclear correlation NMR also provides spectroscopic evidence for pyridine halogen bonding to Selectfluor under ambient conditions

Maternally sequestered therapeutic polypeptides – a new approach for the management of preeclampsia

The last several decades have seen intensive research into the molecular mechanisms underlying the symptoms of preeclampsia. While the underlying cause of preeclampsia is believed to be defective placental development and resulting placental ischemia, it is only recently that the links between the ischemic placenta and maternal symptomatic manifestation have been elucidated. Several different pathways have been implicated in the development of the disorder; most notably production of the anti-angiogenic protein sFlt-1, induction of auto-immunity and inflammation, and production of reactive oxygen species. While the molecular mechanisms are becoming clearer, translating that knowledge into effective therapeutics has proven elusive. Here we describe a number of peptide based therapies we have developed to target theses pathways, and which are currently being tested in preclinical models. These therapeutics are based on a synthetic polymeric carrier elastin-like polypeptide (ELP), which can be synthesized in various sequences and sizes to stabilize the therapeutic peptide and avoid crossing the placental interface. This prevents fetal exposure and potential developmental effects. The therapeutics designed will target known pathogenic pathways, and the ELP carrier could prove to be a versatile delivery system for administration of a variety of therapeutics during pregnancy

Evaluation of uncomplicated acute respiratory tract infection management in veterans: A national utilization review.

BackgroundAntibiotics are overprescribed for acute respiratory tract infections (ARIs). Guidelines provide criteria to determine which patients should receive antibiotics. We assessed congruence between documentation of ARI diagnostic and treatment practices with guideline recommendations, treatment appropriateness, and outcomes.MethodsA multicenter quality improvement evaluation was conducted in 28 Veterans Affairs facilities. We included visits for pharyngitis, rhinosinusitis, bronchitis, and upper respiratory tract infections (URI-NOS) that occurred during the 2015-2016 winter season. A manual record review identified complicated cases, which were excluded. Data were extracted for visits meeting criteria, followed by analysis of practice patterns, guideline congruence, and outcomes.ResultsOf 5,740 visits, 4,305 met our inclusion criteria: pharyngitis (n = 558), rhinosinusitis (n = 715), bronchitis (n = 1,155), URI-NOS (n = 1,475), or mixed diagnoses (>1 ARI diagnosis) (n = 402). Antibiotics were prescribed in 68% of visits: pharyngitis (69%), rhinosinusitis (89%), bronchitis (86%), URI-NOS (37%), and mixed diagnosis (86%). Streptococcal diagnostic testing was performed in 33% of pharyngitis visits; group A Streptococcus was identified in 3% of visits. Streptococcal tests were ordered less frequently for patients who received antibiotics (28%) than those who did not receive antibiotics 44%; P < .01). Although 68% of visits for rhinosinusitis had documentation of symptoms, only 32% met diagnostic criteria for antibiotics. Overall, 39% of patients with uncomplicated ARIs received appropriate antibiotic management. The proportion of 30-day return visits for ARI care was similar for appropriate (11%) or inappropriate (10%) antibiotic management (P = .22).ConclusionsAntibiotics were prescribed in most uncomplicated ARI visits, indicating substantial overuse. Practice was frequently discordant with guideline diagnostic and treatment recommendations

Growth factor purification and delivery systems (PADS) for therapeutic angiogenesis

BACKGROUND: Therapeutic angiogenesis with vascular endothelial growth factor (VEGF), delivered either via recombinant protein infusion or via gene therapy, has shown promise in preclinical models of various diseases including myocardial infarction, renovascular disease, preeclampsia, and neurodegenerative disorders. However, dosing, duration of expression, and tissue specificity are challenges to VEGF gene therapy, and recombinant VEGF delivery suffers from extremely rapid plasma clearance, necessitating continuous infusion and/or direct injection at the site of interest. METHODS: Here we describe a novel growth factor purification and delivery system (PADS) generated by fusion of VEGF(121) to a protein polymer based on Elastin-like Polypeptide (ELP). ELP is a thermally responsive biopolymer derived from a five amino acid repeat sequence found in human tropoelastin. (VEGF)PADS were constructed by fusion of the ELP coding sequence in-frame with the VEGF(121) coding sequence connected by a flexible di-glycine linker. In vitro activity of (VEGF)PADS was determined using cell proliferation, tube formation, and migration assays with vascular endothelial cells. Pharmacokinetics and biodistribution of (VEGF)PADS in vivo were compared to free VEGF in mice using quantitative fluorescence techniques. RESULTS: ELP fusion allowed for recombinant expression and simple, non-chromatographic purification of the ELP-VEGF(121) chimera in yields as high as 90 mg/L of culture and at very high purity. ELP fusion had no effect on the VEGF activity, as the (VEGF)PADS were equally potent as free VEGF(121) in stimulating HUVEC proliferation, tube formation, and migration. Additionally, the (VEGF)PADS had a molecular weight five-fold larger than free VEGF(121), which lead to slower plasma clearance and an altered biodistribution after systemic delivery in vivo. CONCLUSION: PADS represent a new method of both purification and in vivo stabilization of recombinant growth factors. The use of this system could permit recombinant growth factors to become viable options for therapeutic angiogenesis in a number of disease models. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13221-014-0026-3) contains supplementary material, which is available to authorized users

Megakaryocytes Enhance Mesenchymal Stromal Cells Proliferation and Inhibit Differentiation

Megakaryocytes (MKs) can induce proliferation of calvarial osteoblasts [Ciovacco et al., 2009], but this same phenomenon has not been reported for bone marrow stromal populations from long bones. Bone marrow contains several types of progenitor cells which can be induced to differentiate into multiple cell types. Herein, we examined mesenchymal stromal cell proliferation and osteoblastic differentiation when rabbit or mouse MK were cultured with i) rabbit bone marrow stromal cells, ii) rabbit dental pulp stromal cells, or iii) mouse bone marrow stromal cells. Our results demonstrated that rabbit and mouse stromal cells co-cultured with rabbit MK or mouse MK, have significant increases in proliferation on day 7 by 52%, 46%, and 24%, respectively, compared to cultures without MK. Conversely, alkaline phosphatase (ALP) activity was lower at various time points in these cells when cultures contain MK. Similarly, calcium deposition observed at day 14 rabbit bone marrow and dental pulp stromal cells and day 21 mouse bone marrow stromal cells was 63%, 69%, and 30% lower respectively, when co-cultured with MK. Gene expression studies reveal transcriptional changes broadly consistent with increased proliferation and decreased differentiation. Transcript levels of c-fos (associated with cell proliferation) trended higher after 3, 7, and 14 days in culture. Also, expression of alkaline phosphatase, osteonectin, osterix, and osteopontin, which are markers for osteoblast differentiation, showed MK-induced decreases in a cell type and time dependent manner. Taken together, these data suggest that MK play a role in stromal cell proliferation and differentiation, from multiple sites/locations in multiple species

Decreases in Antimicrobial Use Associated With Multihospital Implementation of Electronic Antimicrobial Stewardship Tools.

BackgroundAntimicrobial stewards may benefit from comparative data to inform interventions that promote optimal inpatient antimicrobial use.MethodsAntimicrobial stewards from 8 geographically dispersed Veterans Affairs (VA) inpatient facilities participated in the development of antimicrobial use visualization tools that allowed for comparison to facilities of similar complexity. The visualization tools consisted of an interactive web-based antimicrobial dashboard and, later, a standardized antimicrobial usage report updated at user-selected intervals. Stewards participated in monthly learning collaboratives. The percent change in average monthly antimicrobial use (all antimicrobial agents, anti-methicillin-resistant Staphylococcus aureus [anti-MRSA] agents, and antipseudomonal agents) was analyzed using a pre-post (January 2014-January 2016 vs July 2016-January 2018) design with segmented regression and external comparison with uninvolved control facilities (n = 118).ResultsIntervention sites demonstrated a 2.1% decrease (95% confidence interval [CI], -5.7% to 1.6%) in total antimicrobial use pre-post intervention vs a 2.5% increase (95% CI, 0.8% to 4.1%) in nonintervention sites (absolute difference, 4.6%; P = .025). Anti-MRSA antimicrobial use decreased 11.3% (95% CI, -16.0% to -6.3%) at intervention sites vs a 6.6% decrease (95% CI, -9.1% to -3.9%) at nonintervention sites (absolute difference, 4.7%; P = .092). Antipseudomonal antimicrobial use decreased 3.4% (95% CI, -8.2% to 1.7%) at intervention sites vs a 3.6% increase (95% CI, 0.8% to 6.5%) at nonintervention sites (absolute difference, 7.0%; P = .018).ConclusionsComparative data visualization tool use by stewards at 8 VA facilities was associated with significant reductions in overall antimicrobial and antipseudomonal use relative to uninvolved facilities

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor Nuclear Matrix Protein 4 (Nmp4, Zfp384, Ciz, ZNF384) respond to several classes of osteoporosis drugs with enhanced bone formation compared to wild type (WT) animals. Nmp4-/- mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyper-anabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and Nmp4-/- MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that Nmp4 has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that Nmp4-/- MSPCs exhibited an enhanced capacity for glycolytic conversion- a key step in bone anabolism. Nmp4-/- cells showed elevated collagen translation and secretion. Expression of matrix genes that contribute to bone material-level mechanical properties were elevated in Nmp4-/- cells, an observation that was supported by biomechanical testing of bone samples from Nmp4-/- and WT mice. We conclude that loss of Nmp4 increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality