Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.
To assess the extent of use of data from conference abstracts and presentations in health technology assessments (HTAs) provided as part of the National Institute for Health and Clinical Excellence (NICE) appraisal process. Also to assess the methodological quality of trials from conference abstracts and presentations, the consistency of reporting major outcomes between these sources and subsequent full-length publications, the effect of inclusion or exclusion of data from these sources on the meta-analysis pooled effect estimates, and the timeliness of availability of data from these sources and full articles in relation to the development of technology assessment reviews (TARs). A survey of seven TAR groups. An audit of published TARs: included all NICE TARs published between January 2000 and October 2004. Case studies of selected TARs. Analyses of the results of the survey and audit were presented as a descriptive summary and in a tabular format. Sensitivity analyses were carried out to compare the effect of inclusion of data from abstracts and presentations on the meta-analysis pooled effect estimates by including data from both abstracts/presentations and full papers, and data from only full publications, included in the original TAR. These analyses were then compared with meta-analysis of data from trials that have subsequently been published in full. All seven TAR groups completed and returned the survey. Five out of seven groups reported a general policy that included searching for and including studies available as conference abstracts/presentations. Five groups responded that if they included data from these sources they would carry out methodological quality assessment of studies from these sources using the same assessment tools as for full publications, and manage the data from these sources in the same way as fully published reports. All groups reported that if relevant outcome data were reported in both an abstract/presentation and a full publication, they would only consider the data in the full publication. Conversely, if data were only available in conference abstract/presentation, all but two groups reported that they would extract and use the data from the abstract/presentation. In total, 63 HTA reports for NICE were identified. In 20 of 63 TARs (32%) explicit statements were made with regards to inclusion and assessment of data from abstracts/presentations. Thirty-eight (60%) identified at least one randomised controlled trial (RCT) available as a conference abstract or presentation. Of these, 26 (68%) included trials available as abstracts/presentations. About 80% (20/26) of the 26 TARs that included RCTs in abstract/presentation form carried out an assessment of the methodological quality of such trials. In 16 TARs full reports of these trials were used for quality assessment where both abstracts/presentations and subsequent full publications were available. Twenty-three of 63 TARs (37%) carried out a quantitative analysis of results. Of these, ten (43%) included trials that were available as abstracts/presentations in the review; however, only 60% (6/10) of these included data from abstracts/presentations in the data analysis of results. Thirteen TARs evaluated rapidly evolving technologies and only three of these identified and included trial data from conference abstracts/presentations and carried out a quantitative analysis where abstract/presentation data were used. These three TARs were used as case studies. In all three case studies the overall quality of reporting in abstracts/presentations was generally poor. In all case studies abstracts and presentations failed to describe the method of randomisation or allocation concealment. Overall, there was no mention of blinding in 66% (25/38) of the abstracts and in 26% (7/27) of the presentations included in case studies, and one presentation (4%) explicitly stated use of intention-to-treat analysis. Results from one case study demonstrated discrepancies in data made available in abstracts or online conference presentations. Not only were discrepancies evident between these sources, but also comparison of conference abstracts/presentations with subsequently published full-length articles demonstrates data discrepancies in reporting of results. Sensitivity analyses based on one case study indicated a change in significance of effect in two outcome measures when only full papers published to date were included. There are variations in policy and practice across TAR groups regarding searching for and inclusion of studies available as conference abstracts/presentations. There is also variation in the level of detail reported in TARs regarding the use of abstracts/presentations. Therefore, TAR teams should be encouraged to state explicitly their search strategies for identifying conference abstracts and presentations, their methods for assessing these for inclusion, and where appropriate how the data were used and their effect on the results. Comprehensive searching for trials available as conference abstracts/presentations is time consuming and may be of questionable value. However, there may be a case for searching for and including abstract/presentation data if, for example, other sources of data are limited. If conference abstracts/presentations are to be included, the TAR teams need to allocate additional time for searching and managing data from these sources. Incomplete reporting in conference abstracts and presentations limits the ability of reviewers to assess confidently the methodological quality of trials. Where conference abstracts and presentations are considered for inclusion in the review, the TAR teams should increase their efforts to obtain further study details by contacting trialists. Where abstract/presentation data are included, reviewers should discuss the effect of including data from these sources. Any data discrepancies identified across sources in TARs should be highlighted and their impact discussed in the review. In addition, there is a need to carry out, for example, a sensitivity analysis with and without abstract/presentation data in the analysis. There is a need for research into the development of search strategies specific to identification of studies available as conference abstracts and presentations in TARs. Such strategies may include guidance with regard to identification of relevant electronic databases and appropriate conference sites relevant to certain clinical areas. As there are limited case studies included in this report, analyses should be repeated as more TARs accrue, or include the work of other international HTA groups.


Highly increased levels of IgE antibodies to vaccine components in children with influenza vaccine-associated anaphylaxis.
Influenza vaccines produced in embryonated eggs might pose a risk to patients with egg allergy. However, patients experiencing influenza vaccine-associated anaphylaxis (IVA) do not always have egg allergy. In the 2011-2012 season, an unusually high incidence of IVA was reported in Japan. We sought to identify the cause of the increase in anaphylactic events in 2011-2012 in Japan. We collected blood specimens from patients with IVA from all areas of Japan. We analyzed 19 patients with confirmed IVA and 25 age-matched control subjects, including 10 with egg allergy who had no adverse events after corresponding vaccination. ELISA was used to measure specific IgE levels to the trivalent vaccines of several manufacturers and hemagglutinin proteins derived from both egg and cell cultures. Antigen-induced basophil activation was evaluated by measuring CD203c expression by means of flow cytometry. Vaccine excipients were also examined for effects on CD203c expression. None of the patients with IVA had severe egg allergy. Levels of specific IgE antibodies to influenza vaccine antigens, whole-vaccine products from different manufacturers, and hemagglutinin proteins (A H1, H3, and B) derived from both egg and cell cultures were significantly increased in patients with IVA compared with those in control subjects. Influenza vaccine-induced CD203c expression in basophils was also highly enhanced in patients with IVA but not in control subjects. Because IVA was most frequent in patients who received 2-phenoxyethanol (2-PE)-containing vaccine, the effect of this preservative on basophil activation was examined, and the activation was slightly enhanced by 2-PE but not thimerosal. The 2011-2012 IVA spike in Japan was caused by specific IgE antibodies to influenza vaccine components. Excipients could not be implicated, except for a modest effect of 2-PE.


Distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP.
How lipopolysaccharide (LPS) signals through toll-like receptors (TLRs) to induce nuclear factor (NF)-kappa B inflammatory cytokines in sepsis remains unclear. Major candidates for that process are myeloid differentiation protein 88 (MyD88) and MyD88 adaptor-like/TIR domain-containing adaptor protein (Mal/TIRAP) but their role needs to be further defined. Here, we have examined the role of MyD88 and Mal/TIRAP in primary human cells of nonmyeloid and myeloid origin as physiologically relevant systems. We found that MyD88 and Mal/TIRAP are essential for LPS-induced I kappa B alpha phosphorylation, NF-kappa B activation, and interleukin 6 (IL-6) or IL-8 production in fibroblasts and endothelial cells in a pathway that also requires IKK2. In contrast, in macrophages neither MyD88, Mal/TIRAP, nor I kappa B kinase 2 (IKK2) are required for NF-kappa B activation or tumor necrosis factor alpha (TNF alpha), IL-6, or IL-8 production, although Mal/TIRAP is still involved in the production of interferon beta (IFN beta). Differential usage of TLRs may account for that, as in macrophages but not fibroblasts or endothelial cells, TLR4 is expressed in high levels at the cell surface, and neutralization of TLR4 but not TLR2 blocks LPS signaling. These observations demonstrate for the first time the existence of 2 distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of TLR4, MyD88, Mal/TIRAP, and IKK2, and reveal a layer of complexity not previously expected.


The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function.
Although CLIC5 is a member of the chloride intracellular channel protein family, its association with actin-based cytoskeletal structures suggests that it may play an important role in their assembly or maintenance. Mice homozygous for a new spontaneous recessive mutation of the Clic5 gene, named jitterbug (jbg), exhibit impaired hearing and vestibular dysfunction. The jbg mutation is a 97 bp intragenic deletion that causes skipping of exon 5, which creates a translational frame shift and premature stop codon. Western blot and immunohistochemistry results confirmed the predicted absence of CLIC5 protein in tissues of jbg/jbg mutant mice. Histological analysis of mutant inner ears revealed dysmorphic stereocilia and progressive hair cell degeneration. In wild-type mice, CLIC5-specific immunofluorescence was detected in stereocilia of both cochlear and vestibular hair cells and also along the apical surface of Kolliker's organ during cochlear development. Refined immunolocalization in rat and chicken vestibular hair cells showed that CLIC5 is limited to the basal region of the hair bundle, similar to the known location of radixin. Radixin immunostaining appeared reduced in hair bundles of jbg mutant mice. By mass spectrometry and immunoblotting, CLIC5 was shown to be expressed at high levels in stereocilia of the chicken utricle, in an approximate 1:1 molar ratio with radixin. These results suggest that CLIC5 associates with radixin in hair cell stereocilia and may help form or stabilize connections between the plasma membrane and the filamentous actin core.


Management of aortic aneurysms and dissections with the Zenith TX2 stent graft.
Endovascular repair of thoracic aortic aneurysms offers a less invasive alternative to conventional surgery, similar to its counterpart in the abdominal aorta. Although its long-term durability and outcome remain relatively unknown, published midterm results from clinical trials suggest comparable rates of aneurysm-related mortality and significant reductions in early morbidity compared with open repair. The Zenith TX2 stent graft (Cook Endovascular, Bloomington, IN) is an investigational endovascular device that is designed to treat aneurysms and other degenerative pathologies of the thoracic aorta. At the time of this writing, it is nearing completion of its pivotal trial. Clinical experience with this device is limited to countries outside the United States and to sites participating in the clinical trials. The purpose of this article is to provide a description of the Zenith TX2 device and its application in the repair of thoracic aortic aneurysms and dissections.


Folding induced assembly of polypeptide decorated gold nanoparticles.
Reversible assembly of gold nanoparticles controlled by the homodimerization and folding of an immobilized de novo designed synthetic polypeptide is described. In solution at neutral pH, the polypeptide folds into a helix-loop-helix four-helix bundle in the presence of zinc ions. When immobilized on gold nanoparticles, the addition of zinc ions induces dimerization and folding between peptide monomers located on separate particles, resulting in rapid particle aggregation. The particles can be completely redispersed by removal of the zinc ions from the peptide upon addition of EDTA. Calcium ions, which do not induce folding in solution, have no effect on the stability of the peptide decorated particles. The contribution from folding on particle assembly was further determined utilizing a reference peptide with the same primary sequence but containing both D and L amino acids. Particles functionalized with the reference peptide do not aggregate, as the peptides are unable to fold. The two peptides, linked to the nanoparticle surface via a cysteine residue located in the loop region, form submonolayers on planar gold with comparable properties regarding surface density, orientation, and ability to interact with zinc ions. These results demonstrate that nanoparticle assembly can be induced, controlled, and to some extent tuned, by exploiting specific molecular interactions involved in polypeptide folding.


Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia.
The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo 2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P<0.001) for unmutated IGHV. The association between elevated birth rate and shorter TFS was observed in subjects with either mutated or unmutated IGHVs, and the use of both markers was a better predictor of TFS than either parameter alone. Thus, an increased CLL birth rate in early stage disease is a strong predictor of disease progression and earlier treatment.


Sensitivity of A-549 human lung cancer cells to nanoporous zinc oxide conjugated with Photofrin.
In the present study, we demonstrated the use of nanoporous zinc oxide (ZnO NPs) in photodynamic therapy. The ZnO NPs structure possesses a high surface to volume ratio due to its porosity and ZnO NPs can be used as an efficient photosensitizer carrier system. We were able to grow ZnO NPs on the tip of borosilicate glass capillaries (0.5 μm diameter) and conjugated this with Photofrin for efficient intracellular drug delivery. The ZnO NPs on the capillary tip could be excited intracellularly with 240 nm UV light, and the resultant 625 nm red light emitted in the presence of Photofrin activated a chemical reaction that produced reactive oxygen species (ROS). The procedure was tested in A-549 cells and led to cell death within a few minutes. The morphological changes in necrosed cells were examined by microscopy. The viability of control and treated A-549 cells with the optimum dose of UV/visible light was assessed using the MTT assay, and ROS were detected using a fluorescence microscopy procedure.


Phylogenetic analysis, structural evolution and functional divergence of the 12-oxo-phytodienoate acid reductase gene family in plants.
The 12-oxo-phytodienoic acid reductases (OPRs) are enzymes that catalyze the reduction of double-bonds in alpha, beta-unsaturated aldehydes or ketones and are part of the octadecanoid pathway that converts linolenic acid to jasmonic acid. In plants, OPRs belong to the old yellow enzyme family and form multigene families. Although discoveries about this family in Arabidopsis and other species have been reported in some studies, the evolution and function of multiple OPRs in plants are not clearly understood. A comparative genomic analysis was performed to investigate the phylogenetic relationship, structural evolution and functional divergence among OPR paralogues in plants. In total, 74 OPR genes were identified from 11 species representing the 6 major green plant lineages: green algae, mosses, lycophytes, gymnosperms, monocots and dicots. Phylogenetic analysis showed that seven well-conserved subfamilies exist in plants. All OPR genes from green algae were clustered into a single subfamily, while those from land plants fell into six other subfamilies, suggesting that the events leading to the expansion of the OPR family occurred in land plants. Further analysis revealed that lineage-specific expansion, especially by tandem duplication, contributed to the current OPR subfamilies in land plants after divergence from aquatic plants. Interestingly, exon/intron structure analysis showed that the gene structures of OPR paralogues exhibits diversity in intron number and length, while the intron positions and phase were highly conserved across different lineage species. These observations together with the phylogenetic tree revealed that successive single intron loss, as well as indels within introns, occurred during the process of structural evolution of OPR paralogues. Functional divergence analysis revealed that altered functional constraints have occurred at specific amino acid positions after diversification of the paralogues. Most notably, significant functional divergence was also found in all pairs, except for the II/IV, II/V and V/VI pairs. Strikingly, analysis of the site-specific profiles established by posterior probability revealed that the positive-selection sites and/or critical amino acid residues for functional divergence are mainly distributed in alpha-helices and substrate binding loop (SBL), indicating the functional importance of these regions for this protein family. This study highlights the molecular evolution of the OPR gene family in all plant lineages and indicates critical amino acid residues likely relevant for the distinct functional properties of the paralogues. Further experimental verification of these findings may provide valuable information on the OPRs' biochemical and physiological functions.


Contributions of five secondary metal uptake systems to metal homeostasis of Cupriavidus metallidurans CH34.
Cupriavidus metallidurans is adapted to high concentrations of transition metal cations and is a model system for studying metal homeostasis in difficult environments. The elemental composition of C. metallidurans cells cultivated under various conditions was determined, revealing the ability of the bacterium to shield homeostasis of one essential metal from the toxic action of another. The contribution of metal uptake systems to this ability was studied. C. metallidurans contains three CorA members of the metal inorganic transport (MIT) protein family of putative magnesium uptake systems, ZupT of the ZRT/IRT protein, or ZIP, family, and PitA, which imports metal phosphate complexes. Expression of the genes for all these transporters was regulated by zinc availability, as shown by reporter gene fusions. While expression of zupT was upregulated under conditions of zinc starvation, expression of the other genes was downregulated at high zinc concentrations. Only corA(1) expression was influenced by magnesium starvation. Deletion mutants were constructed to characterize the contribution of each system to transition metal import. This identified ZupT as the main zinc uptake system under conditions of low zinc availability, CorA(1) as the main secondary magnesium uptake system, and CorA(2) and CorA(3) as backup systems for metal cation import. PitA may function as a cation-phosphate uptake system, the main supplier of divalent metal cations and phosphate in phosphate-rich environments. Thus, metal homeostasis in C. metallidurans is achieved by highly redundant metal uptake systems, which have only minimal cation selectivity and are in combination with efflux systems that "worry later" about surplus cations.


Nucleotide sequence and transcriptional startpoint of the glpT gene of Escherichia coli: extensive sequence homology of the glycerol-3-phosphate transport protein with components of the hexose-6-phosphate transport system.
The nucleotide sequences of the glpT gene of Escherichia coli and its regulatory region have been elucidated and the primary structure of the glycerol-3-phosphate transport protein deduced. Extensive amino acid sequence homology was found with two other cytoplasmic membrane proteins: the functionally related hexose-6-phosphate transport protein, and the UHPC protein involved in regulating hexose-6-phosphate uptake. Although no significant amino acid sequence homology was found with other transport proteins, such as the arabinose, citrate, glucose, melibiose, lactose or xylose transporters, all of these proteins share a common secondary structure arrangement with the GLP T protein as they apparently contain twelve membrane-spanning alpha-helical segments. The promoter for glpT was located by transcript mapping and shown to overlap a site to which catabolite activator protein binds in vitro. These findings indicate how catabolite repression may be mediated but do not explain its physiological significance in glycerol metabolism.


Monocyte chemotactic protein 3 is a homing factor for circulating angiogenic cells.
Circulating angiogenic cells (CAC) participate in cardiac repair. CAC recruitment to the ischaemic heart is mainly induced by the chemokine (C-X-C motif) receptor 4 (CXCR4)/stromal-cell derived factor-1α axis. However, CAC mobilization is only partly prevented by CXCR4 blockade, indicating that other mechanisms are involved. Since the expression of monocyte chemotactic protein 3 (MCP3) is increased in ischaemic hearts, we hypothesized that it may participate in CAC mobilization. CAC were obtained from peripheral blood mononuclear cells of healthy volunteers. In vitro migration of CAC was concentration-dependently increased by recombinant MCP3 (one-fold increase, P= 0.001), and this effect was inhibited by antibodies neutralizing the chemokine (C-C motif) receptor 1 (CCR1). CCR1 expression at the surface of CAC was confirmed by flow cytometry. Conditioned medium from heparan sulfate-activated macrophages, which contained MCP3, induced the migration of CAC (one-fold increase, P= 0.01). This increase was partly inhibited by CCR1 antibodies. The migration of CAC was also stimulated by macrophage inflammatory protein 3β. This effect was blocked by CCR7 antibodies and was of lower magnitude than that of MCP3. MCP3 induced the formation of blood vessels in Matrigel plugs implanted in mice (1.5-fold increase, P< 0.001). This effect was abrogated by anti-CCR1 antibodies. This study shows that MCP3 stimulates the migration of CAC and angiogenesis, suggesting that MCP3 may be useful to improve cardiac repair.


Adverse Outcomes after Non-Chest Surgeries in Patients with Pulmonary Tuberculosis: A Nationwide Study.
The association between pulmonary tuberculosis (TB) and postoperative outcomes remains unknown. This study investigated outcomes following non-chest surgeries in patients with previous pulmonary TB. Using Taiwan's National Health Insurance Research Database, we analyzed 6911 patients (aged ≥ 20 years) with preoperative diagnosis of pulmonary TB and 6911 propensity score-matched controls receiving non-chest surgeries in 2008-2010. Postoperative outcomes were compared between patients with or without pulmonary TB by calculating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) in the multivariate logistic regressions. Surgical patients with pulmonary TB had a significantly higher postoperative complication rates than controls, including septicemia, pneumonia, acute renal failure, deep wound infection, overall complications, and 30-day postoperative mortality (OR 1.41; 95% CI 1.07-1.86). The ORs of patients with low-income status were as high as 2.27 (95% CI 1.03-5.03). Preoperative use of TB drugs and TB-related medical expenditure also associated with higher postoperative mortality among surgical patients with pulmonary TB. Surgical patients with pulmonary TB have significantly increased risks of postoperative complications and mortality after non-chest surgeries. This study suggests the need to improve postoperative care for surgical patients with pulmonary TB.


Selection and structural characterization of anti-TREM2 scFvs that reduce levels of shed ectodomain.
Mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration, including Alzheimer's disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signaling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterized. Here, we present phage display generated antibody single-chain variable fragments (scFvs) to human TREM2 immunoglobulin-like domain. Co-crystal structures revealed the binding of two scFvs to an epitope on the TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species, which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterization of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research.


Artificial intelligence for teleophthalmology-based diabetic retinopathy screening in a national programme: an economic analysis modelling study.
Deep learning is a novel machine learning technique that has been shown to be as effective as human graders in detecting diabetic retinopathy from fundus photographs. We used a cost-minimisation analysis to evaluate the potential savings of two deep learning approaches as compared with the current human assessment: a semi-automated deep learning model as a triage filter before secondary human assessment; and a fully automated deep learning model without human assessment. In this economic analysis modelling study, using 39 006 consecutive patients with diabetes in a national diabetic retinopathy screening programme in Singapore in 2015, we used a decision tree model and TreeAge Pro to compare the actual cost of screening this cohort with human graders against the simulated cost for semi-automated and fully automated screening models. Model parameters included diabetic retinopathy prevalence rates, diabetic retinopathy screening costs under each screening model, cost of medical consultation, and diagnostic performance (ie, sensitivity and specificity). The primary outcome was total cost for each screening model. Deterministic sensitivity analyses were done to gauge the sensitivity of the results to key model assumptions. From the health system perspective, the semi-automated screening model was the least expensive of the three models, at US$62 per patient per year. The fully automated model was $66 per patient per year, and the human assessment model was $77 per patient per year. The savings to the Singapore health system associated with switching to the semi-automated model are estimated to be $489 000, which is roughly 20% of the current annual screening cost. By 2050, Singapore is projected to have 1 million people with diabetes; at this time, the estimated annual savings would be $15 million. This study provides a strong economic rationale for using deep learning systems as an assistive tool to screen for diabetic retinopathy. Ministry of Health, Singapore.


A low-fat vegan diet improves glycemic control and cardiovascular risk factors in a randomized clinical trial in individuals with type 2 diabetes.
We sought to investigate whether a low-fat vegan diet improves glycemic control and cardiovascular risk factors in individuals with type 2 diabetes. Individuals with type 2 diabetes (n = 99) were randomly assigned to a low-fat vegan diet (n = 49) or a diet following the American Diabetes Association (ADA) guidelines (n = 50). Participants were evaluated at baseline and 22 weeks. Forty-three percent (21 of 49) of the vegan group and 26% (13 of 50) of the ADA group participants reduced diabetes medications. Including all participants, HbA(1c) (A1C) decreased 0.96 percentage points in the vegan group and 0.56 points in the ADA group (P = 0.089). Excluding those who changed medications, A1C fell 1.23 points in the vegan group compared with 0.38 points in the ADA group (P = 0.01). Body weight decreased 6.5 kg in the vegan group and 3.1 kg in the ADA group (P < 0.001). Body weight change correlated with A1C change (r = 0.51, n = 57, P < 0.0001). Among those who did not change lipid-lowering medications, LDL cholesterol fell 21.2% in the vegan group and 10.7% in the ADA group (P = 0.02). After adjustment for baseline values, urinary albumin reductions were greater in the vegan group (15.9 mg/24 h) than in the ADA group (10.9 mg/24 h) (P = 0.013). Both a low-fat vegan diet and a diet based on ADA guidelines improved glycemic and lipid control in type 2 diabetic patients. These improvements were greater with a low-fat vegan diet.


Four-sample lactose hydrogen breath test for diagnosis of lactose malabsorption in irritable bowel syndrome patients with diarrhea.
To validate 4-sample lactose hydrogen breath testing (4SLHBT) compared to standard 13-sample LHBT in the clinical setting. Irritable bowel syndrome patients with diarrhea (IBS-D) and healthy volunteers (HVs) were enrolled and received a 10 g, 20 g, or 40 g dose lactose hydrogen breath test (LHBT) in a randomized, double-blinded, controlled trial. The lactase gene promoter region was sequenced. Breath samples and symptoms were acquired at baseline and every 15 min for 3 h (13 measurements). The detection rates of lactose malabsorption (LM) and lactose intolerance (LI) for a 4SLHBT that acquired four measurements at 0, 90, 120, and 180 min from the same data set were compared with the results of standard LHBT. Sixty IBS-D patients and 60 HVs were studied. The genotype in all participants was C/C-13910. LM and LI detection rates increased with lactose dose from 10 g, 20 g to 40 g in both groups (P < 0.001). 4SLHBT showed excellent diagnostic concordance with standard LHBT (97%-100%, Kappa 0.815-0.942) with high sensitivity (90%-100%) and specificity (100%) at all three lactose doses in both groups. Reducing the number of measurements from 13 to 4 samples did not significantly impact on the accuracy of LHBT in health and IBS-D. 4SLHBT is a valid test for assessment of LM and LI in clinical practice.


Nutrition-responsive gene expression and the developmental evolution of insect polyphenism.
Nutrition-responsive development is a ubiquitous and highly diversified example of phenotypic plasticity, yet its underlying molecular and developmental mechanisms and modes of evolutionary diversification remain poorly understood. We measured genome-wide transcription in three closely related species of horned beetles exhibiting strikingly diverse degrees of nutrition responsiveness in the development of male weaponry. We show that (1) counts of differentially expressed genes between low- and high-nutritional backgrounds mirror species-specific degrees of morphological nutrition responsiveness; (2) evolutionary exaggeration of morphological responsiveness is underlain by both amplification of ancestral nutrition-responsive gene expression and recruitment of formerly low nutritionally responsive genes; and (3) secondary loss of morphological responsiveness to nutrition coincides with a dramatic reduction in gene expression plasticity. Our results further implicate genetic accommodation of ancestrally high variability of gene expression plasticity in both exaggeration and loss of nutritional plasticity, yet reject a major role of taxon-restricted genes in the developmental regulation and evolution of nutritional plasticity.


Novelty and Inductive Generalization in Human Reinforcement Learning.
In reinforcement learning (RL), a decision maker searching for the most rewarding option is often faced with the question: What is the value of an option that has never been tried before? One way to frame this question is as an inductive problem: How can I generalize my previous experience with one set of options to a novel option? We show how hierarchical Bayesian inference can be used to solve this problem, and we describe an equivalence between the Bayesian model and temporal difference learning algorithms that have been proposed as models of RL in humans and animals. According to our view, the search for the best option is guided by abstract knowledge about the relationships between different options in an environment, resulting in greater search efficiency compared to traditional RL algorithms previously applied to human cognition. In two behavioral experiments, we test several predictions of our model, providing evidence that humans learn and exploit structured inductive knowledge to make predictions about novel options. In light of this model, we suggest a new interpretation of dopaminergic responses to novelty.


SU-E-T-594: Dosimetric Evaluation of Different Treatment Techniques for Prostate Cancer.
To evaluate the Volumetric Modulated Arc Therapy (VMAT, RapidArc) and IMRT plan quality for prostate deliveries conducted by two different treatment planning systems: Oncentra Masterplan (Nucletron inc.) and Eclipse (Varian inc.). We investigated ten prostate treatment delivery plans. For a given case studied we created a RapidArc plan (Eclipse), a VMAT and an IMRT plan (Oncentra) by using both treatment planning systems. The rotational therapy plans consisted of 2 to 3 arcs and the IMRT fields consisted of 7 to 9 fields. The prescription dose was 200 cGy X 40 fx using a Varian Trilogy with 10 MV beams. The treatment parameters were used to evaluate the plan quality: the minimal, mean and maximal doses to the target (PTV) and the volumes received 65Gy and 40 Gy, respectively, for the rectum and bladder, V65 and V40. In addition, we calculated the conformity index (CI) and the heterogeneity index (HI) for each delivery type. No significant difference was found between RapidArc, VMAT and IMRT, regarding the minimal and average PTV dose value. The rectum and bladder constraints showed no significant variation as well. The PTV hot spot was significantly higher for the VMAT plan compared to the RapidArc plan (p=0.007). The target CI for VMAT (0.55±0.05) and IMRT (0.71±0.08) was found to be smaller than the RapidArc (0.82±0.04) and the difference is statistically significant (p=0). The HI, value was found to have no significant difference between RapidArc, VMAT and IMRT plan deliveries. Two TPS are capable of producing high-quality treatment plans for prostate cancer. The quality is associated with the degree of intensity modulation and the number of incident angles. Overall, the RapidArc plans with 2-3 arcs showed better dosimetric qualities than the VMAT and IMRT plans.


The availability of electronic cigarettes in U.S. retail outlets, 2012: results of two national studies.
Since their introduction in 2007, electronic cigarette ('e-cigarette') awareness and use has grown rapidly. Little is known about variation in e-cigarette availability across areas with different levels of tobacco taxes and smoke-free air policies. This paper looks at US retail availability of e-cigarettes and factors at the store, neighbourhood and policy levels associated with it. In-person store audit data collected in 2012 came from two national samples of tobacco retailers in the contiguous US. Study 1 collected data from a nationally representative sample of tobacco retailers (n=2165). Study 2 collected data from tobacco retailers located in school enrolment zones for nationally representative samples of 8th, 10th and 12th grade public school students (n=2526). In 2012, e-cigarette retail availability was 34% in study 1 and 31% in study 2. Tobacco, pharmacy and gas/convenience stores were more likely to sell e-cigarettes than beer/wine/liquor stores. Retail availability of e-cigarettes was more likely in neighbourhoods with higher median household income (study 1), and lower percent of African-American (studies 1 and 2) and Hispanic residents (study 2). Price of traditional cigarettes was inversely related to e-cigarette availability. Stores in states with an American Lung Association Smoke-Free Air grade of F (study 1) or D (study 2) compared with A had increased likelihood of having e-cigarettes. Currently, e-cigarette availability appears more likely in areas with weak tax and smoke-free air policies. Given the substantial availability of e-cigarettes at tobacco retailers nationwide, states and localities should monitor the sales and marketing of e-cigarettes at point of sale (POS).


The E117K mutation in β-tropomyosin disturbs concerted conformational changes of actomyosin in muscle fibers.
The effect of the skeletal myopathy-causing E117K mutation in human β-tropomyosin on actomyosin structure during the ATPase cycle was studied using fluorescent probes bound to actin subdomain 1 and the myosin head. Multistep changes in flexural rigidity of actin filament and in spatial arrangement of actin subdomain 1 and myosin SH1 helix in troponin-free ghost muscle fibers were revealed. During the ATPase cycle E117K tropomyosin inhibited the rotation of subdomain 1 by 46% and the tilt of the SH1 helix by 49% compared with wild-type. At strong-binding stages the proportion of strong binding sub-states in the actomyosin population is decreased by the mutation. At weak-binding stages abnormally high numbers of switched-on actin monomers were observed, thus indicating a disturbance in concerted conformational changes of actomyosin. These structural alterations are likely to underlie the contractile deficit observed with this mutation.


Encoding of temporal probabilities in the human brain.
Anticipating the timing of future events is a necessary precursor to preparing actions and allocating resources to sensory processing. This requires elapsed time to be represented in the brain and used to predict the temporal probability of upcoming events. While neuropsychological, imaging, magnetic stimulation studies, and single-unit recordings implicate the role of higher parietal and motor-related areas in temporal estimation, the role of earlier, purely sensory structures remains more controversial. Here we demonstrate that the temporal probability of expected visual events is encoded not by a single area but by a wide network that importantly includes neuronal populations at the very earliest cortical stages of visual processing. Moreover, we show that activity in those areas changes dynamically in a manner that closely accords with temporal expectations.


Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function.
Inhalation of iloprost, a stable prostacyclin (PGI(2)) analog, is a well-accepted and safe treatment for pulmonary arterial hypertension. Although iloprost mainly acts as a vasodilator by binding to the I prostanoid (IP) receptor, recent evidence suggests that signaling via this receptor also has antiinflammatory effects through unclear mechanisms. Here we show in a murine model of asthma that iloprost inhalation suppressed the cardinal features of asthma when given during the priming or challenge phase. As a mechanism of action, iloprost interfered with the function of lung myeloid DCs, critical antigen-presenting cells of the airways. Iloprost treatment inhibited the maturation and migration of lung DCs to the mediastinal LNs, thereby abolishing the induction of an allergen-specific Th2 response in these nodes. The effect of iloprost was DC autonomous, as iloprost-treated DCs no longer induced Th2 differentiation from naive T cells or boosted effector cytokine production in primed Th2 cells. These data should pave the way for a clinical effectiveness study using inhaled iloprost for the treatment of asthma.


Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism.
Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are often highly reactive and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cytochromes P450 oxidize acetaminophen to N-acetyl-p-benzoquinone imine, which is electrophilically reactive and covalently binds to nucleophilic sites within proteins. This reactive quinone metabolite elicits a toxic immune response when acetaminophen exceeds a safe dose. Using a deep learning approach, this study reports the first published method for predicting quinone formation: the formation of a quinone species by metabolic oxidation. We model both one- and two-step quinone formation, enabling accurate quinone formation predictions in nonobvious cases. We predict atom pairs that form quinones with an AUC accuracy of 97.6%, and we identify molecules that form quinones with 88.2% AUC. By modeling the formation of quinones, one of the most common types of reactive metabolites, our method provides a rapid screening tool for a key drug toxicity risk. The XenoSite quinone formation model is available at http://swami.wustl.edu/xenosite/p/quinone .


rQuant.web: a tool for RNA-Seq-based transcript quantitation.
We provide a novel web service, called rQuant.web, allowing convenient access to tools for quantitative analysis of RNA sequencing data. The underlying quantitation technique rQuant is based on quadratic programming and estimates different biases induced by library preparation, sequencing and read mapping. It can tackle multiple transcripts per gene locus and is therefore particularly well suited to quantify alternative transcripts. rQuant.web is available as a tool in a Galaxy installation at http://galaxy.fml.mpg.de. Using rQuant.web is free of charge, it is open to all users, and there is no login requirement.


Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in cattle.
The availability of dense genotypes and whole-genome sequence variants from various sources offers the opportunity to compile large datasets consisting of tens of thousands of individuals with genotypes at millions of polymorphic sites that may enhance the power of genomic analyses. The imputation of missing genotypes ensures that all individuals have genotypes for a shared set of variants. We evaluated the accuracy of imputation from dense genotypes to whole-genome sequence variants in 249 Fleckvieh and 450 Holstein cattle using Minimac and FImpute. The sequence variants of a subset of the animals were reduced to the variants that were included on the Illumina BovineHD genotyping array and subsequently inferred in silico using either within- or multi-breed reference populations. The accuracy of imputation varied considerably across chromosomes and dropped at regions where the bovine genome contains segmental duplications. Depending on the imputation strategy, the correlation between imputed and true genotypes ranged from 0.898 to 0.952. The accuracy of imputation was higher with Minimac than FImpute particularly for variants with a low minor allele frequency. Using a multi-breed reference population increased the accuracy of imputation, particularly when FImpute was used to infer genotypes. When the sequence variants were imputed using Minimac, the true genotypes were more correlated to predicted allele dosages than best-guess genotypes. The computing costs to impute 23,256,743 sequence variants in 6958 animals were ten-fold higher with Minimac than FImpute. Association studies with imputed sequence variants revealed seven quantitative trait loci (QTL) for milk fat percentage. Two causal mutations in the DGAT1 and GHR genes were the most significantly associated variants at two QTL on chromosomes 14 and 20 when Minimac was used to infer genotypes. The population-based imputation of millions of sequence variants in large cohorts is computationally feasible and provides accurate genotypes. However, the accuracy of imputation is low in regions where the genome contains large segmental duplications or the coverage with array-derived single nucleotide polymorphisms is poor. Using a reference population that includes individuals from many breeds increases the accuracy of imputation particularly at low-frequency variants. Considering allele dosages rather than best-guess genotypes as explanatory variables is advantageous to detect causal mutations in association studies with imputed sequence variants.


Race, disadvantage and faculty experiences in academic medicine.
Despite compelling reasons to draw on the contributions of under-represented minority (URM) faculty members, US medical schools lack these faculty, particularly in leadership and senior roles. The study's purpose was to document URM faculty perceptions and experience of the culture of academic medicine in the US and to raise awareness of obstacles to achieving the goal of having people of color in positions of leadership in academic medicine. The authors conducted a qualitative interview study in 2006-2007 of faculty in five US medical schools chosen for their diverse regional and organizational attributes. Using purposeful sampling of medical faculty, 96 faculty were interviewed from four different career stages (early, plateaued, leaders and left academic medicine) and diverse specialties with an oversampling of URM faculty. We identified patterns and themes emergent in the coded data. Analysis was inductive and data driven. Predominant themes underscored during analyses regarding the experience of URM faculty were: difficulty of cross-cultural relationships; isolation and feeling invisible; lack of mentoring, role models and social capital; disrespect, overt and covert bias/discrimination; different performance expectations related to race/ethnicity; devaluing of research on community health care and health disparities; the unfair burden of being identified with affirmative action and responsibility for diversity efforts; leadership's role in diversity goals; and financial hardship. Achieving an inclusive culture for diverse medical school faculty would help meet the mission of academic medicine to train a physician and research workforce that meets the disparate needs of our multicultural society. Medical school leaders need to value the inclusion of URM faculty. Failure to fully engage the skills and insights of URM faculty impairs our ability to provide the best science, education or medical care.


Target-independent prediction of drug synergies using only drug lipophilicity.
Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descriptors for a set of antifungal compounds ("drugs") previously examined for interaction. Analyzing the relationship between molecular weight, lipophilicity, H-bond donor, and H-bond acceptor values for drugs and their propensity to show pairwise antifungal drug synergy, we found that combinations of two lipophilic drugs had a greater tendency to show drug synergy. We developed a more refined decision tree model that successfully predicted drug synergy in stringent cross-validation tests based on only lipophilicity of drugs. Our predictions achieved a precision of 63% and allowed successful prediction for 58% of synergistic drug pairs, suggesting that this phenomenon can extend our understanding for a substantial fraction of synergistic drug interactions. We also generated and analyzed a large-scale synergistic human toxicity network, in which we observed that combinations of lipophilic compounds show a tendency for increased toxicity. Thus, lipophilicity, a simple and easily determined molecular descriptor, is a powerful predictor of drug synergy. It is well established that lipophilic compounds (i) are promiscuous, having many targets in the cell, and (ii) often penetrate into the cell via the cellular membrane by passive diffusion. We discuss the positive relationship between drug lipophilicity and drug synergy in the context of potential drug synergy mechanisms.


15-keto-prostaglandin E2 activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promote Cryptococcus neoformans growth during infection.
Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.


Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1.
Plasma levels of high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are inversely correlated with the risk of cardiovascular disease. One major atheroprotective mechanism of HDL and apoA-I is their role in reverse cholesterol transport, i.e., the transport of excess cholesterol from foam cells to the liver for secretion. The ATP-binding cassette transporters ABCA1 and ABCG1 play a pivotal role in this process by effluxing lipids from foam cells to apoA-I and HDL, respectively. In the liver, ABCA1 activity is one rate-limiting step in the formation of HDL. In macrophages, ABCA1 and ABCG1 prevent the excessive accumulation of lipids and thereby protect the arteries from developing atherosclerotic lesions. However, the mechanisms by which ABCA1 and ABCG1 mediate lipid removal are still unclear. Particularly, three questions remain controversial and are discussed in this review: (1) Do apoA-I and HDL directly interact with ABCA1 and ABCG1, respectively? (2) Does cholesterol efflux involve retroendocytosis of apoA-I or HDL? (3) Which lipids are directly transported by ABCA1 and ABCG1?


Split-bolus dual-energy CT urography: protocol optimization and diagnostic performance for the detection of urinary stones.
Prospective protocol optimization, determination of image quality and diagnostic performance of virtual non-enhanced images (VNEI) derived from split-bolus dual-energy computed tomography (DECT) urography in patients with urinary stones. IRB-approved, prospective study of 100 patients who, after written informed consent, underwent single-energy, non-enhanced CT and split-bolus, contrast-enhanced DECT (30 + 50 mL of contrast media; combined nephro-urographic acquisition). DECT was performed using setting A (80/140 kVp) in the first 20, and setting B (100/140 kVp) in the second 20 patients. Tin filtration was used in all patients. After a pre-analysis of VNEI quality, 60 additional patients were examined using setting B. Two readers qualitatively and quantitatively determined image quality of all weighted-average DECT images regarding urinary tract opacification (n = 100), and all VNEI regarding quality of iodine subtraction and urinary stone detection (n = 80). True nonenhanced (TNEI) images were the standard of reference for statistical analysis (inter-reader variability and diagnostic performance characteristics). The urinary tract was completely opacified in 94% (94/100) of patients. Iodine subtraction was improved (p < 0.01) and image noise of VNEI was lower (p < 0.05) in DECT setting B. On VNEI, 83% (86/104) of urinary stones were correctly identified and 17% (18/104) were missed. Stones missed (2.5 mm, 1-4) were significantly smaller than stones correctly identified (5 mm, 2-27; p < 0.001). Diagnostic accuracy was 98% on a per-renal-unit basis and 96% on a per-patient basis. Inter-reader agreements were excellent (κ = 0.91-1.00; ICC = 0.86-0.99). Split-bolus DECT urography was technically feasible and quality of VNEI was improved with the 100/140 kVp setting. Detection of urinary stones <4 mm on VNEI was limited.


Automated segmentation of prostate zonal anatomy on T2-weighted (T2W) and apparent diffusion coefficient (ADC) map MR images using U-Nets.
Accurate regional segmentation of the prostate boundaries on magnetic resonance (MR) images is a fundamental requirement before automated prostate cancer diagnosis can be achieved. In this paper, we describe a novel methodology to segment prostate whole gland (WG), central gland (CG), and peripheral zone (PZ), where PZ + CG = WG, from T2W and apparent diffusion coefficient (ADC) map prostate MR images. We designed two similar models each made up of two U-Nets to delineate the WG, CG, and PZ from T2W and ADC map MR images, separately. The U-Net, which is a modified version of a fully convolutional neural network, includes contracting and expanding paths with convolutional, pooling, and upsampling layers. Pooling and upsampling layers help to capture and localize image features with a high spatial consistency. We used a dataset consisting of 225 patients (combining 153 and 72 patients with and without clinically significant prostate cancer) imaged with multiparametric MRI at 3 Tesla. Our proposed model for prostate zonal segmentation from T2W was trained and tested using 1154 and 1587 slices of 100 and 125 patients, respectively. Median of Dice similarity coefficient (DSC) on test dataset for prostate WG, CG, and PZ were 95.33 ± 7.77%, 93.75 ± 8.91%, and 86.78 ± 3.72%, respectively. Designed model for regional prostate delineation from ADC map images was trained and validated using 812 and 917 slices from 100 and 125 patients. This model yielded a median DSC of 92.09 ± 8.89%, 89.89 ± 10.69%, and 86.1 ± 9.56% for prostate WG, CG, and PZ on test samples, respectively. Further investigation indicated that the proposed algorithm reported high DSC for prostate WG segmentation from both T2W and ADC map MR images irrespective of WG size. In addition, segmentation accuracy in terms of DSC does not significantly vary among patients with or without significant tumors. We describe a method for automated prostate zonal segmentation using T2W and ADC map MR images independent of prostate size and the presence or absence of tumor. Our results are important in terms of clinical perspective as fully automated methods for ADC map images, which are considered as one of the most important sequences for prostate cancer detection in the PZ and CG, have not been reported previously.


Triple valve repair for rheumatic heart disease.
The onset of the clinical expression of rheumatic heart disease (RHD) is variable. Exercise or other states that necessitate increased cardiac output often precipitate symptoms. Mitral stenosis (MS) is present in 25% of patients with RHD, and 40% of patients have concomitant MS and mitral regurgitation. About two third of patients with MS have concurrent aortic insufficiency. Pulmonary and tricuspid insufficiency may occur from rheumatic involvement of these valves, or secondary to dilatation of valve annuli from pulmonary hypertension secondary to mitral and/or aortic valve disease. Pregnancy is associated with many hemodynamic changes including expanded intravascular volume, tachycardia, increased intracardiac dimensions, and valvular regurgitation. We report a case of a young female who developed flash pulmonary edema during parturition and was found to have abnormal rheumatic involvement of her aortic, mitral, and tricuspid valves. Successful triple valve repair was performed in a single operation. A review of rheumatic valvular abnormalities, and literature supporting multivalvular repair for rheumatic heart disease is provided.


Nitrous Oxide and Serious Long-term Morbidity and Mortality in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II Trial.
The Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial randomly assigned 7,112 noncardiac surgery patients at risk of perioperative cardiovascular events to 70% N2O or 70% N2 groups. The aim of this follow-up study was to determine the effect of nitrous oxide on a composite primary outcome of death and major cardiovascular events at 1 yr after surgery. One-year follow-up was conducted via a medical record review and telephone interview. Disability was defined as a Katz index of independence in activities of daily living score less than 8. Adjusted odds ratios and hazard ratios were calculated as appropriate for primary and secondary outcomes. Among 5,844 patients evaluated at 1 yr, 435 (7.4%) had died, 206 (3.5%) had disability, 514 (8.8%) had a fatal or nonfatal myocardial infarction, and 111 (1.9%) had a fatal or nonfatal stroke during the 1-yr follow-up period. Exposure to nitrous oxide did not increase the risk of the primary outcome (odds ratio, 1.08; 95% CI, 0.94 to 1.25; P = 0.27), disability or death (odds ratio, 1.07; 95% CI, 0.90 to 1.27; P = 0.44), death (hazard ratio, 1.17; 95% CI, 0.97 to 1.43; P = 0.10), myocardial infarction (odds ratio, 0.97; 95% CI, 0.81 to 1.17; P = 0.78), or stroke (odds ratio, 1.08; 95% CI, 0.74 to 1.58; P = 0.70). These results support the long-term safety of nitrous oxide administration in noncardiac surgical patients with known or suspected cardiovascular disease.


Preliminary investigation of flexibility in learning color-reward associations in gibbons (Hylobatidae).
Previous studies in learning set formation have shown that most animal species can learn to learn with subsequent novel presentations being solved in fewer presentations than when they first encounter a task. Gibbons (Hylobatidae) have generally struggled with these tasks and do not show the learning to learn pattern found in other species. This is surprising given their phylogenetic position and level of cortical development. However, there have been conflicting results with some studies demonstrating higher level learning abilities in these small apes. This study attempts to clarify whether gibbons can in fact use knowledge gained during one learning task to facilitate performance on a similar, but novel problem that would be a precursor to development of a learning set. We tested 16 captive gibbons' ability to associate color cues with provisioned food items in two experiments where they experienced a period of learning followed by experimental trials during which they could potentially use knowledge gained in their first learning experience to facilitate solution I subsequent novel tasks. Our results are similar to most previous studies in that there was no evidence of gibbons being able to use previously acquired knowledge to solve a novel task. However, once the learning association was made, the gibbons performed well above chance. We found no differences across color associations, indicating learning was not affected by the particular color / reward association. However, there were variations in learning performance with regard to genera. The hoolock (Hoolock leuconedys) and siamang (Symphalangus syndactylus) learned the fastest and the lar group (Hylobates sp.) learned the slowest. We caution these results could be due to the small sample size and because of the captive environment in which these gibbons were raised. However, it is likely that environmental variability in the native habitats of the subjects tested could facilitate the evolution of flexible learning in some genera. Further comparative study is necessary in order to incorporate realistic cognitive variables into foraging models.


Functional identification of the Plasmodium centromere and generation of a Plasmodium artificial chromosome.
The artificial chromosome represents a useful tool for gene transfer, both as cloning vectors and in chromosome biology research. To generate a Plasmodium artificial chromosome (PAC), we had to first functionally identify and characterize the parasite's centromere. A putative centromere (pbcen5) was cloned from chromosome 5 of the rodent parasite P. berghei based on a Plasmodium gene-synteny map. Plasmids containing pbcen5 were stably maintained in parasites during a blood-stage infection with high segregation efficiency, without drug pressure. pbcen5-containing plasmids were also stably maintained during parasite meiosis and mitosis in the mosquito. A linear PAC (L-PAC) was generated by integrating pbcen5 and telomere into a plasmid. The L-PAC segregated with a high efficiency and was stably maintained throughout the parasite's life cycle, as either one or two copies. These results suggest that L-PAC behaves like a Plasmodium chromosome, which can be exploited as an experimental research tool.


Comparison of F-18 FDG-PET/CT and Tc-99m MIBI in the preoperative evaluation of cold thyroid nodules in the same patient group.
Recent studies have reported that standardized uptake values of FDG-PET imaging might predict malignant thyroid nodules and can be used in the preoperative evaluation of thyroid lesions. The aim of our study was to evaluate FDG-PET imaging in patients with cold thyroid nodules and to compare the imaging findings with Tc-99m MIBI scans and with post-op histopathology results. Twenty-three patients (18F, 5M) with 24 nodules that were suspicious in ultrasound and cold in Tc-99m pertechnetate scan, were included in the study. Each nodule underwent sonographically guided fine-needle aspiration biopsy. FDG-PET and MIBI scans were performed with an interval of 3-5 days. All patients underwent thyroidectomy and their FDG-PET, and MIBI thyroid scan results were compared with post-thyroidectomy pathology results. Post-op histopathology results found 7 malignant and 17 benign nodules. Six of the seven malignant nodules had increased uptake, which were positive for malignancy in both PET and MIBI scans. Each imaging method used different radiopharmaceuticals but showed one false-negative result in two different patients. FDG-PET produced false positives in eight nodules and MIBI scans found false positives in four nodules. FDG-PET imaging and MIBI scan showed the same sensitivity in malignant nodule evaluation, but their specificity differed. As a result, we suggest that FDG-PET imaging is not superior to MIBI scanning in differentiating malignant from benign thyroid nodules. MIBI imaging should be the first choice in the preoperative evaluation of patients with cold thyroid nodules as an adjunct procedure to FNAB because of its low cost and availability. This imaging technique can be used routinely in patients who are reluctant to undergo FNAB.


Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice.
Several studies have illustrated that transcutaneous vagus nerve stimulation (tVNS) can elicit therapeutic effects that are similar to those produced by its invasive counterpart, vagus nerve stimulation (VNS). VNS is an FDA-approved therapy for the treatment of both depression and epilepsy, but it is limited to the management of more severe, intervention-resistant cases as a second or third-line treatment option due to perioperative risks involved with device implantation. In contrast, tVNS is a non-invasive technique that involves the application of electrical currents through surface electrodes at select locations, most commonly targeting the auricular branch of the vagus nerve (ABVN) and the cervical branch of the vagus nerve in the neck. Although it has been shown that tVNS elicits hypo- and hyperactivation in various regions of the brain associated with anxiety and mood regulation, the mechanism of action and influence of stimulation parameters on clinical outcomes remains predominantly hypothetical. Suppositions are largely based on correlations between the neurobiology of the vagus nerve and its effects on neural activity. However, tVNS has also been investigated for several other disorders, including tinnitus, migraine and pain, by targeting the vagus nerve at sites in both the ear and the neck. As most of the described methods differ in the parameters and protocols applied, there is currently no firm evidence on the optimal location for tVNS or the stimulation parameters that provide the greatest therapeutic effects for a specific condition. This review presents the current status of tVNS with a focus on stimulation parameters, stimulation sites, and available devices. For tVNS to reach its full potential as a non-invasive and clinically relevant therapy, it is imperative that systematic studies be undertaken to reveal the mechanism of action and optimal stimulation modalities.


Gray space and green space proximity associated with higher anxiety in youth with autism.
This study used ZIP code level data on children's health (National Survey of Children's Health, 2012) and land cover (National Land Cover Database, 2011) from across the United States to investigate connections between proximity to green space (tree canopy), gray space (impervious surfaces), and expression of a critical co-morbid condition, anxiety, in three groups of youth: children diagnosed with autism spectrum disorder (ASD, n = 1501), non-ASD children with special healthcare needs (CSHCN, n = 15,776), and typically developing children (n = 53,650). Both impervious surface coverage and tree canopy coverage increased the risk of severe anxiety in youth with autism, but not CSHCN or typical children. Children with ASD might experience the stress-reducing benefits of nature differently than their typically developing peers. More research using objective diagnostic metrics at finer spatial scales would help to illuminate complex relationships between green space, anxiety, and other co-morbid conditions in youth with ASD.


[Perception of prenatal care among clients of the Brazilian National Health System (SUS): a comparative study].
This was a comparative cross-sectional study among public prenatal care users in conventional outpatient health services and family health services, aimed at assessing perception and quality differences between the two models of health services organization according to Ministry of Health guidelines. A total of 203 pregnant women from 22 municipalities in five regions of the country were interviewed while waiting for prenatal consultation. Besides soliciting the women's opinions, we checked for possible advantages in innovative family care services in issues like access and commitment. Data revealed approval by users for key aspects related to care and consultation in both types of public facilities and suggest consistent primary care policies. Low coverage in dentistry (18.9%), gynecological preventive tests (39.6%), and HIV tests (52.6%) indicates policy obstacles. Comparatively, family health services received significantly greater approval by women on issues like quality of the last visit (p = 0.0432), maternity hospital access (p = 0.0106), vaccination schedules (p = 0.0023), drug delivery (p = 0.0053), blood glucose tests (p = 0.0309), nursing visit (p = 0.0469), and home visits (p < 0.0001).


Effect of electroconvulsive therapy on neural response to affective pictures: A randomized, sham-controlled fMRI study.
Electroconvulsive therapy (ECT) is the most effective treatment for severe depression but its neurocognitive mechanisms are unclear. This randomized, sham-controlled functional magnetic resonance imaging (fMRI) study explored the effects of a single ECT on neural response to affective pictures. Twenty-seven patients with major depressive disorder were randomized to a single active ECT (N = 15) or sham (N = 12) session in a double-blind, parallel-group design. On the following day, patients underwent fMRI during which they viewed pleasant, unpleasant and neutral pictures and performed a free recall test after the scan. Mood symptoms were assessed before ECT/sham and at the time of fMRI. Subsequently, all patients continued active ECT as usual. Mood symptoms were reassessed after six active ECT sessions. A single ECT vs. sham session reduced neural response to unpleasant vs. pleasant pictures in the medial prefrontal cortex, a region showing greater response in the more depressed patients. This effect occurred in the absence of between-group differences in picture recall, mood symptoms or concomitant medication. In conclusion, modulation of medial prefrontal hyper-activity during encoding of negative affective information may be a common mechanism of distinct biological depression treatments.


Behavioral couples therapy for alcoholism and drug abuse.
Behavioral couples therapy (BCT) sees the substance-abusing patient with the spouse to arrange a daily "sobriety contract" in which the patient states his or her intent not to drink or use drugs and the spouse expresses support for the patient's efforts to stay abstinent. BCT also teaches communication and increases positive activities. Research supports three conclusions. First, BCT for both alcoholism and drug abuse produces more abstinence and fewer substance-related problems, happier relationships, fewer couple separations and lower risk of divorce than does individual-based treatment. Second, domestic violence is substantially reduced after BCT for both alcoholism and drug abuse. Third, cost outcomes after BCT are very favorable for both alcoholism and drug abuse, and are superior to individual-based treatment for drug abuse. The Institute of Medicine (1998) documented a large gap between research and practice in substance abuse treatment. BCT is one example of this gap. BCT has relatively strong research support, but it has not yet become widely used.


Identification of a novel cell type-specific intronic enhancer of macrophage migration inhibitory factor (MIF) and its regulation by mithramycin.
The aim of this study was to determine the genetic regulation of macrophage migration inhibitory factor (MIF). DNase I hypersensitivity was used to identify potential hypersensitive sites (HS) across the MIF gene locus. Reporter gene assays were performed in different human cell lines with constructs containing the native or mutated HS element. Following phylogenetic and transcription factor binding profiling, electrophoretic mobility shift assay (EMSA) and RNA interference were performed and the effects of incubation with mithramycin, an antibiotic that binds GC boxes, were also studied. An HS centred on the first intron of MIF was identified. The HS acted as an enhancer in human T lymphoblasts (CEMC7A), human embryonic kidney cells (HEK293T) and human monocytic cells (THP-1), but not in a fibroblast-like synoviocyte (FLS) cell line (SW982) or cultured FLS derived from rheumatoid arthritis (RA) patients. Two cis-elements within the first intron were found to be responsible for the enhancer activity. Mutation of the consensus Sp1 GC box on each cis-element abrogated enhancer activity and EMSA indicated Sp1 binding to one of the cis-elements contained in the intron. SiRNA knock-down of Sp1 alone or Sp1 and Sp3 together was incomplete and did not alter the enhancer activity. Mithramycin inhibited expression of MIF in CEMC7A cells. This effect was specific to the intronic enhancer and was not seen on the MIF promoter. These results identify a novel, cell type-specific enhancer of MIF. The enhancer appears to be driven by Sp1 or related Sp family members and is highly sensitive to inhibition via mithramycin.


Improving the policy application of footprint indicators to support Europe's transition to a one planet economy: the development of the EUREAPA tool.
Environmentally extended multi-regional input-output (EE-MRIO) models provide us with a wealth of data relating to consumption-based environmental impacts at a national level. The results can identify the categories of consumption and sectors of production that contribute most to environmental impact allowing policy makers to prioritise intervention into particular areas. However, these data are not readily accessible to policy makers and civil society, making it difficult to extract and communicate the important messages it contains. The web-based tool - EUREAPA - was created as a usable, task-oriented interface to improve access to environmental and economic data held within a complex EE-MRIO model and make it more relevant to policy makers and civil society. The project team of scientists and IT specialists used an iterative, agile and participatory approach to engage potential end-users in the specification and testing of the tool. The engagement process identified two principal functions that were essential for the EUREAPA tool: viewing data and creating scenarios. The viewing data function allows users to analyse the wealth of data held within the model and present results from a range of perspectives. This helps to understand the causes of environmental pressure and identify priorities for policy intervention. The scenario function helps to communicate how changes in consumption and production might affect the future environmental impact of citizens of the EU, and facilitates long-term planning. Through this dialogue process the project has been able to ensure EUREAPA is relevant, user-friendly and fit-for-purpose. It is intended that EUREAPA will be adopted by policy makers and civil society as an important policy planning and assessment aid in the complex field of sustainable consumption and production.


Superiority of Serum Cystatin C Over Creatinine in Prediction of Long-Term Prognosis at Discharge From ICU.
Renal outcomes after critical illness are seldom assessed despite strong correlation between chronic kidney disease and survival. Outside hospital, renal dysfunction is more strongly associated with mortality when assessed by serum cystatin C than by creatinine. The relationship between creatinine and longer term mortality might be particularly weak in survivors of critical illness. Retrospective observational cohort study. In 3,077 adult ICU survivors, we compared ICU discharge cystatin C and creatinine and their association with 1-year mortality. Exclusions were death within 72 hours of ICU discharge, ICU stay less than 24 hours, and end-stage renal disease. None. During ICU admission, serum cystatin C and creatinine diverged, so that by ICU discharge, almost twice as many patients had glomerular filtration rate less than 60 mL/min/1.73 m when estimated from cystatin C compared with glomerular filtration rate estimated from creatinine, 44% versus 26%. In 743 patients without acute kidney injury, where ICU discharge renal function should reflect ongoing baseline, discharge glomerular filtration rate estimated from creatinine consistently overestimated follow-up glomerular filtration rate estimated from creatinine, whereas ICU discharge glomerular filtration rate estimated from cystatin C well matched follow-up chronic kidney disease status. By 1 year, 535 (17.4%) had died. In survival analysis adjusted for age, sex, and comorbidity, cystatin C was near-linearly associated with increased mortality, hazard ratio equals to 1.78 (95% CI, 1.46-2.18), 75th versus 25th centile. Conversely, creatinine demonstrated a J-shaped relationship with mortality, so that in the majority of patients, there was no significant association with survival, hazard ratio equals to 1.03 (0.87-1.2), 75th versus 25th centile. After adjustment for both creatinine and cystatin C levels, higher discharge creatinine was then associated with lower long-term mortality. In contrast to creatinine, cystatin C consistently associated with long-term mortality, identifying patients at both high and low risk, and better correlated with follow-up renal function. Conversely, lower creatinine relative to cystatin C appeared to confer adverse prognosis, confounding creatinine interpretation in isolation. Cystatin C warrants further investigation as a more meaningful measure of renal function after critical illness.


Sex differences in African-Americans regarding sensitivity to insulin's glucoregulatory and antilipolytic actions.
The purpose of this study was to determine if there are sex differences in African-Americans regarding the effect of obesity on sensitivity to insulin as a glucoregulatory and antilipolytic hormone. Data from study participants, 127 nondiabetic African-Americans (mean age 32 +/- 4 years), included anthropometric measurements, an oral glucose tolerance test (OGTT), a 2-h euglycemic-hyperinsulinemic clamp, and a fasting triglyceride level. Sensitivity to insulin as a glucoregulatory hormone was determined by M/FFM, where M is the mean glucose infusion rate during the second hour of the clamp and FFM is fat-free mass. Sensitivity to insulin's antilipolytic action was assessed during the OGTT by the percent suppression of free fatty acid (FFA) concentrations between 0 and 120 min. The higher the suppression of FFAs, the greater the sensitivity to insulin's antilipolytic action. The participants were classified by BMI into three groups: nonobese (31 men, 24 women), obese (17 men, 14 women), and severely obese (12 men, 29 women). The women had higher percentages of body fat (P < 0.001), and the men had greater FFM (P < 0.001). The M/FFM values for men versus women in each BMI group were nonobese, 8.8 +/- 2.8 vs. 10.8 +/- 4.4; obese, 7.2 +/- 3.4 vs. 8.5 +/- 3.4; and severely obese, 4.7 +/- 2.1 vs. 6.1 +/- 2.2. The difference between the BMI groups was significant (P < 0.001), as was the difference between men and women (P < 0.01). In addition, there was a significant sex difference in percent suppression of FFAS (P < 0.001). The men and women had similar fasting insulin and FFA concentrations; however, in the men only, the percent suppression of FFA declined with increasing obesity (nonobese, 83 +/- 15%; obese, 73 +/- 18%; and severely obese, 69 +/- 19%; P = 0.02). The women in all three BMI groups had lower FFA levels of 86-88%. Obese African-American men and women are resistant to insulin as a glucoregulatory hormone, but only obese men are resistant to insulin's antilipolytic action; obese African-American women are sensitive to insulin's antilipolytic action. The combined presence of sensitivity to insulin's antilipolytic action with resistance to insulin's glucoregulatory action in obese African-American women may contribute to their high prevalence of obesity and type 2 diabetes.


Chitobiose utilization in Borrelia burgdorferi is dually regulated by RpoD and RpoS.
Borrelia burgdorferi has limited biosynthetic capabilities and must scavenge N-acetylglucosamine (GlcNAc), an essential component of the microbial cell wall, from the surrounding environment. Spirochetes cultured in the absence of free GlcNAc exhibit biphasic growth; however, addition of chitobiose (a dimer of GlcNAc) substitutes for free GlcNAc resulting in a single exponential phase. We evaluated the effect of RpoS and RpoN, the only alternative sigma factors in B. burgdorferi, on biphasic growth and chitobiose utilization in the absence of free GlcNAc. In addition, we investigated the source of GlcNAc in the second exponential phase. By comparing the growth of wild-type cells to insertional mutants for rpoS and rpoN we determined that RpoS, but not RpoN, partially regulates both biphasic growth and chitobiose utilization. The rpoS mutant, cultured in the absence of free GlcNAc, exhibited a significant delay in the ability to initiate a second exponential phase compared to the wild type and rpoS complemented mutant. Expression analysis of chbC, which encodes the membrane-spanning protein of the chitobiose phosphotransferase system, suggests the delay is due to the inability of the rpoS mutant to up regulate chbC. Furthermore, supplementing GlcNAc starved cultures with high concentrations (75 or 150 microM) of chitobiose resulted in biphasic growth of the rpoS mutant compared to a single exponential phase for the wild type and rpoS complemented mutant. In contrast, growth of the rpoN mutant under all conditions was similar to the wild type. 5' Rapid amplification of cDNA ends (5' RACE) revealed the transcriptional start site for chbC to be 42 bp upstream of the translational start site. Analysis of the chbC promoter region revealed homology to previously described RpoD and RpoS B. burgdorferi promoters. We also determined that yeastolate, a component of the growth medium (BSK-II), is not essential for second exponential phase growth. Together these results suggest that RpoD and RpoS, but not RpoN, regulate biphasic growth and chitobiose utilization in B. burgdorferi by regulating the expression of the chitobiose transporter (chbC). The data also demonstrate that the second exponential phase observed in wild-type cells in the absence of free GlcNAc is not due to free chitobiose or GlcNAc oligomers present in the medium.


Utility of early MRI in the diagnosis and management of acute spontaneous intracerebral hemorrhage.
The optimal diagnostic evaluation for spontaneous intracerebral hemorrhage (ICH) remains controversial. In this retrospective study, we assessed the utility of early magnetic resonance imaging (MRI) in ICH diagnosis and management. Eighty-nine (72%) of 123 patients with spontaneous ICH underwent a brain CT and MRI within 30 days of ICH onset. Seventy patients with a mean age of 62 ± 15 years were included. A stroke neurologist and a general neurologist, each blinded to the final diagnosis, independently reviewed the admission data and the initial head CT and then assigned a presumed ICH cause under 1 of 9 categories. ICH cause was potentially modified after subsequent MRI review. The final 'gold standard' ICH etiology was determined after review of the complete medical record by an independent investigator. Change in diagnostic category and confidence and the potential impact on patient management were systematically recorded. Mean time to MRI was 3 ± 5 days. Final ICH diagnosis was hypertension or cerebral amyloid angiopathy (CAA) in 50% of patients. After MRI review the stroke neurologist changed diagnostic category in 14%, diagnostic confidence in an additional 23% and management in 20%, and the general neurologist did so in 19, 21 and 21% of patients, respectively. MRI yield was highest in ICH secondary to ischemic stroke, CAA, vascular malformations and neoplasms, and did not differ by age, history of hypertension, hematoma location or the presence of intraventricular hemorrhage. The results of this study suggest potential additive clinical benefit of early MRI in patients with spontaneous ICH.


Estimated liver weight is directly related to hepatic very low-density lipoprotein-triglyceride secretion rate in men.
Animal studies suggest that liver weight is directly related to hepatic very low-density lipoprotein-triglyceride (VLDL-TG) secretion, independently of body size. This relationship has never been examined in humans. We measured VLDL-TG secretion rate by using stable isotope-labelled tracers in 21 healthy, non-obese men (age: 25 +/- 3 years; body mass index: 24.8 +/- 1.6 kg m(-2)), and evaluated the relationship between VLDL-TG secretion and indices of total and regional adiposity (body mass index, total body fat, trunk fat), metabolic parameters (free fatty acid, glucose, and insulin concentrations, homeostasis model assessment index of insulin resistance, resting energy expenditure), and estimated liver weight. Correlation analysis showed that estimated liver weight was positively associated with total VLDL-TG secretion rate (r = 0.722, P < 0.001), VLDL-TG secretion rate per liter of plasma (r = 0.562, P = 0.008), VLDL-TG secretion rate per kilogram of body weight (r = 0.555, P = 0.009), and VLDL-TG secretion rate per kilogram of liver weight (r = 0.620, P = 0.003). In multiple regression analysis, estimated liver weight was the only significant predictor of VLDL-TG secretion rate regardless of units of expression, explaining 31-52% of total variance; none of the metabolic parameters and indices of body fatness entered the regression models. We conclude that estimated liver weight is directly related to hepatic VLDL-TG secretion rate in healthy non-obese men; this relationship is likely not mediated by interindividual variation in body size.


Non-targeted screening for contaminants in paper and board food-contact materials using effect-directed analysis and accurate mass spectrometry.
Due to large knowledge gaps in chemical composition and toxicological data for substances involved, paper and board food-contact materials (P&B FCM) have been emerging as a FCM type of particular concern for consumer safety. This study describes the development of a step-by-step strategy, including extraction, high-performance liquid chromatography (HPLC) fractionation, tentative identification of relevant substances and in vitro testing of selected tentatively identified substances. As a case study, we used two fractions from a recycled pizza box sample which exhibited aryl hydrocarbon receptor (AhR) activity. These fractions were analysed by gas chromatography (GC) and ultra-HPLC (UHPLC) coupled to quadrupole time-of-flight mass spectrometers (QTOF MS) in order tentatively to identify substances. The elemental composition was determined for peaks above a threshold, and compared with entries in a commercial mass spectral library for GC-MS (GC-EI-QTOF MS) analysis and an in-house built library of accurate masses for substances known to be used in P&B packaging for UHPLC-QTOF analysis. Of 75 tentatively identified substances, 15 were initially selected for further testing in vitro; however, only seven were commercially available and subsequently tested in vitro and quantified. Of these seven, the identities of three pigments found in printing inks were confirmed by UHPLC tandem mass spectrometry (QqQ MS/MS). Two pigments had entries in the database, meaning that a material relevant accurate mass database can provide a fast tentative identification. Pure standards of the seven tentatively identified substances were tested in vitro but could not explain a significant proportion of the AhR-response in the extract. Targeted analyses of dioxins and PCBs, both well-known AhR agonists, was performed. However, the dioxins could explain approximately 3% of the activity observed in the pizza box extract indicating that some very AhR active substance(s) still remain to be identified in recycled low quality P&B.


Formal dementia care among first nations in southwestern Ontario.
This article explores how dementia care is provided to First Nations communities in southwestern Ontario. Data were collected through in-depth interviews with health care providers and analysed using a constructivist grounded-theory methodology. Two interrelated frameworks for understanding dementia care were identified: a care delivery framework and a knowledge framework. The care delivery framework identified care goals, care elements being provided, care barriers, and strategies and solutions to deliver care and overcome barriers. The knowledge framework defined four groups of knowledge stakeholders: persons with dementia, informal care providers, formal care providers, and the First Nations community. It identified the knowledge each stakeholder held or needed and processes of sharing - or failing to share - knowledge in dementia care. Several barriers, many created by a lack of knowledge, negatively impacted dementia care. However, health care professionals had effective strategies for providing care, designed to overcome barriers and which encompassed elements of knowledge sharing.


Derivation of Breast Cancer Cell Lines Under Physiological (5%) Oxygen Concentrations.
Background: Most human breast cancer cell lines currently in use were developed and are cultured under ambient (21%) oxygen conditions. While this is convenient in practical terms, higher ambient oxygen could increase oxygen radical production, potentially modulating signaling pathways. We have derived and grown a series of four human breast cancer cell lines under 5% oxygen, and have compared their properties to those of established breast cancer lines growing under ambient oxygen. Methods: Cell lines were characterized in terms of appearance, cellular DNA content, mutation spectrum, hormone receptor status, pathway utilization and drug sensitivity. Results: Three of the four lines (NZBR1, NZBR2, and NZBR4) were triple negative (ER-, PR-, HER2-), with NZBR1 also over-expressing EGFR. NZBR3 was HER2+ and ER+ and also over-expressed EGFR. Cell lines grown in 5% oxygen showed increased expression of the hypoxia-inducible factor 1 (HIF-1) target gene carbonic anhydrase 9 (CA9) and decreased levels of ROS. As determined by protein phosphorylation, NZBR1 showed low AKT pathway utilization while NZBR2 and NZBR4 showed low p70S6K and rpS6 pathway utilization. The lines were characterized for sensitivity to 7-hydroxytamoxifen, doxorubicin, paclitaxel, the PI3K inhibitor BEZ235 and the HER inhibitors lapatinib, afatinib, dacomitinib, and ARRY-380. In some cases they were compared to established breast cancer lines. Of particular note was the high sensitivity of NZBR3 to HER inhibitors. The spectrum of mutations in the NZBR lines was generally similar to that found in commonly used breast cancer cell lines but TP53 mutations were absent and mutations in EVI2B, LRP1B, and PMS2, which have not been reported in other breast cancer lines, were detected. The results suggest that the properties of cell lines developed under low oxygen conditions (5% O2) are similar to those of commonly used breast cancer cell lines. Although reduced ROS production and increased HIF-1 activity under 5% oxygen can potentially influence experimental outcomes, no difference in sensitivity to estrogen or doxorubicin was observed between cell lines cultured in 5 vs. 21% oxygen.


Structuring payment to medical homes after the affordable care act.
The Patient-Centered Medical Home (PCMH) is a leading model of primary care reform, a critical element of which is payment reform for primary care services. With the passage of the Affordable Care Act, the Accountable Care Organization (ACO) has emerged as a model of delivery system reform, and while there is theoretical alignment between the PCMH and ACOs, the discussion of physician payment within each model has remained distinct. Here we compare payment for medical homes with that for accountable care organizations, consider opportunities for integration, and discuss implications for policy makers and payers considering ACO models. The PCMH and ACO are complementary approaches to reformed care delivery: the PCMH ultimately requires strong integration with specialists and hospitals as seen under ACOs, and ACOs likely will require a high functioning primary care system as embodied by the PCMH. Aligning payment incentives within the ACO will be critical to achieving this integration and enhancing the care coordination role of primary care in these settings.


Photon-phonon Interaction in a Microfiber Induced by Optical and Electrostrictive Forces.
Stimulated Brillouin scattering (SBS) via electrostrictive force is a fundamental interaction between light and sound which limits the power in conventional optical fibers. The emergence of optical microfibers with subwavelength diameter, ultralight mass and an intense light field, provides a new platform for photon-phonon coupling, resulting in the radiation pressure mediated contribution of SBS. This study examines the optomechanical system in cylindrical coordinates, reveals the theoretically radiation pressure induced analogous, and demonstrates contrary effect compared with electrostrictive force in solid or hollow silica microfibers. The finding shows that the photon-phonon coupling, which is related to SBS, can be suppressed in a solid microfiber, and even be completely cancelled in a hollow microfiber.


Topical dexamethasone-cyclodextrin nanoparticle eye drops for non-infectious Uveitic macular oedema and vitritis - a pilot study.
To evaluate the safety and efficacy of 1.5% dexamethasone nanoparticle (DexNP) drops in eyes with non-infectious uveitic macular oedema and vitritis. In a prospective pilot study, DexNP drops were administered four times a day for 4 weeks followed by drops tapering over a period of another 4 weeks. Follow-up time was 12 weeks. Five eyes with macular oedema and three eyes with vitritis were included in the study. Best corrected visual acuity (BCVA) significantly improved from a median of 0.2 logMAR to a median of 0.15 logMAR at 4 weeks' time (p < 0.05). Median BCVA was 0.175 logMAR and 0.2 logMAR, at week 8 and 12, respectively (p > 0.05). Macular oedema significantly improved at all time-points as compared to baseline (p < 0.05) and resolved in all eyes during follow-up. One eye had macular oedema relapse at week 12. Vitritis improved in all eyes and resolved completely in two eyes. One eye had intraocular pressure (IOP) elevation which was well controlled with topical antihypertensive treatment, and one eye had cataract progression. This short pilot study demonstrates favourable effect of 1.5% DexNP eye drops on eyes with non-infectious uveitic macular oedema and vitritis. Further comparative long-term studies are warranted to assess this effect.


Endovascular stent-graft repair of penetrating descending thoracic aortic ulcer.
This article presents a case in which covered stent-graft cuffs were used to treat a penetrating ulcer of the descending thoracic aorta. An 80-year-old woman presented with penetrating ulcer in the descending thoracic aorta. Two endovascular stent graft cuffs were used for total exclusion of the penetrating ulcer, because the patient had a high operative risk. Her postoperative course was uneventful, and follow-up computed tomographic angiography showed complete coverage of the ulcer without evidence of leak. This case demonstrates that endoluminal stent-graft repair of penetrating descending thoracic aortic ulcers is a safe, less-invasive treatment, especially for elderly, high-risk patients.


All-atomic simulations on human telomeric G-quadruplex DNA binding with thioflavin T.
Ligand-stabilized human telomeric G-quadruplex DNA is believed to be an anticancer agent, as it can impede the continuous elongation of telomeres by telomerase in cancer cells. In this study, five well-established human telomeric G-quadruplex DNA models were probed on their binding behaviors with thioflavin T (ThT) via both conventional molecular dynamics (MD) and well-tempered metadynamics (WT-MetaD) simulations. Novel dynamics and characteristic binding patterns were disclosed by the MD simulations. It was observed that the K(+) promoted parallel and hybridized human telomeric G-quadruplex conformations pose higher binding affinities to ThT than the Na(+) and K(+) promoted basket conformations. It is the end, sandwich, and base stacking driven by π-π interactions that are identified as the major binding mechanisms. As the most energy favorable binding mode, the sandwich stacking observed in (3 + 1) hybridized form 1 G-quadruplex conformation is triggered by reversible conformational change of the G-quadruplex. To further examine the free energy landscapes, WT-MetaD simulations were utilized on G-quadruplex-ThT systems. It is found that all of the major binding modes predicted by the MD simulations are confirmed by the WT-MetaD simulations. The results in this work not only accord with existing experimental findings, but also reinforce our understanding on the dynamics of G-quadruplexes and aid future drug developments for G-quadruplex stabilization ligands.