Secretome analysis of human oligodendrocytes derived from neural stem cells.
In this study, we investigated the secretome of human oligodendrocytes (F3.Olig2 cells) generated from human neural stem cells by transduction with the gene encoding the Olig2 transcription factor. Using mRNA sequencing and protein cytokine arrays, we identified a number of biologically important secretory proteins whose expression has not been previously reported in oligodendrocytes. We found that F3.Olig2 cells secrete IL-6, PDGF-AA, GRO, GM-CSF, and M-CSF, and showed prominent expression of their corresponding receptors. Co-expression of ligands and receptors suggests that autocrine signaling loops may play important roles in both differentiation and maintenance of oligodendrocytes. We also found that F3.Olig2 cells secrete matrix metalloproteinases and matrix metalloproteinase-associated proteins associated with functional competence of oligodendrocytes. The results of our secretome analysis provide insights into the functional and molecular details of human oligodendrocytes. To the best of our knowledge, this is the first systematic analysis of the secretome of oligodendrocytes.


The bovine alveolar macrophage DNA methylome is resilient to infection with Mycobacterium bovis.
DNA methylation is pivotal in orchestrating gene expression patterns in various mammalian biological processes. Perturbation of the bovine alveolar macrophage (bAM) transcriptome, due to Mycobacterium bovis (M. bovis) infection, has been well documented; however, the impact of this intracellular pathogen on the bAM epigenome has not been determined. Here, whole genome bisulfite sequencing (WGBS) was used to assess the effect of M. bovis infection on the bAM DNA methylome. The methylomes of bAM infected with M. bovis were compared to those of non-infected bAM 24 hours post-infection (hpi). No differences in DNA methylation (CpG or non-CpG) were observed. Analysis of DNA methylation at proximal promoter regions uncovered >250 genes harbouring intermediately methylated (IM) promoters (average methylation of 33-66%). Gene ontology analysis, focusing on genes with low, intermediate or highly methylated promoters, revealed that genes with IM promoters were enriched for immune-related GO categories; this enrichment was not observed for genes in the high or low methylation groups. Targeted analysis of genes in the IM category confirmed the WGBS observation. This study is the first in cattle examining genome-wide DNA methylation at single nucleotide resolution in an important bovine cellular host-pathogen interaction model, providing evidence for IM promoter methylation in bAM.


Food groups and the risk of colorectal cancer: results from a Jordanian case-control study.
The role of diet in colorectal cancer (CRC) in Jordan has not been studied previously. This study aimed at examining the association between food groups (including grains, fruits, vegetables, milk, and meat and legumes) and CRC risk in Jordan. We compared intakes of the different food groups among CRC patients (n=167) and matched controls (n=240) by age, sex, occupation, and marital status. A validated food frequency questionnaire was used to collect dietary data. Logistic regression was used to evaluate the association of quartiles of intakes of the different food groups with CRC risk. In addition, the association of selected food items with CRC risk was examined. Odds ratios (ORs) for the fourth versus the first quartile of intake were 2.92 [95% confidence interval (CI): 1.40-6.08] for grains, 1.66 (95% CI: 0.81-3.40) for vegetables, 0.55 (95% CI: 0.26-1.16) for fruits, 0.96 (95% CI: 0.46-1.97) for milk, and 1.43 (95% CI: 0.68-2.98) for meat and legumes. In a comparison of the highest with the lowest weekly frequency of consumption, there was a direct association between the risk of CRC and the frequency of consumption of chicken (OR=2.52, 95% CI: 1.33-4.77). An increase in risk was observed with increased consumption of white bread (OR=3.13, 95% CI: 1.18-9.25), whereas consumption of whole bread was associated with a decreased risk for CRC (OR=0.32, 95% CI: 0.12-0.84). Our results support a role of diet in CRC. Direct associations were found for grains, white bread, and chicken, whereas an inverse relation was reported for whole bread.


Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus.
In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.


Long term repeated fire disturbance alters soil bacterial diversity but not the abundance in an Australian wet sclerophyll forest.
Effects of fire on biogeochemical cycling in terrestrial ecosystem are widely acknowledged, while few studies have focused on the bacterial community under the disturbance of long-term frequent prescribed fire. In this study, three treatments (burning every two years (B2), burning every four years (B4) and no burning (B0)) were applied for 38 years in an Australian wet sclerophyll forest. Results showed that bacterial alpha diversity (i.e. bacterial OTU) in the top soil (0-10 cm) was significantly higher in the B2 treatment compared with the B0 and B4 treatments. Non-metric multidimensional analysis (NMDS) of bacterial community showed clear separation of the soil bacterial community structure among different fire frequency regimes and between the depths. Different frequency fire did not have a substantial effect on bacterial composition at phylum level or bacterial 16S rRNA gene abundance. Soil pH and C:N ratio were the major drivers for bacterial community structure in the most frequent fire treatment (B2), while other factors (EC, DOC, DON, MBC, NH4(+), TC and TN) were significant in the less frequent burning and no burning treatments (B4 and B0). This study suggested that burning had a dramatic impact on bacterial diversity but not abundance with more frequent fire.


Insights into one-body density matrices using deep learning.
The one-body reduced density matrix (1-RDM) of a many-body system at zero temperature gives direct access to many observables, such as the charge density, kinetic energy and occupation numbers. It would be desirable to express it as a simple functional of the density or of other local observables, but to date satisfactory approximations have not yet been found. Deep learning is the state of the art approach to performing high dimensional regressions and classification tasks, and is becoming widely used in the condensed matter community to develop increasingly accurate density functionals. Autoencoders are deep learning models that perform efficient dimensionality reduction, allowing the distillation of data to the fundamental features needed to represent it. By training autoencoders on a large data-set of 1-RDMs from exactly solvable real-space model systems, and performing principal component analysis, the machine learns to what extent the data can be compressed and hence how it is constrained. We gain insight into these machine learned constraints and employ them to inform approximations to the 1-RDM as a functional of the charge density. We exploit known physical properties of the 1-RDM in the simplest possible cases to perform feature engineering, where we inform the structure of the models from known mathematical relations, allowing us to integrate existing understanding into the machine learning methods. By comparing various deep learning approaches we gain insight into what physical features of the density matrix are most amenable to machine learning, utilising both known and learned characteristics.


Synergistic lipid-lowering effects of Zingiber mioga and Hippophae rhamnoides extracts.
The effects of a mixture of Hippophae rhamnoides (HR) and Zingiber mioga (ZM) extract (ZH) on intracellular lipid accumulation were investigated in vitro and the anti-obesity effects of ZH evaluated in mice with high-fat diet-induced obesity. The results revealed that ZH inhibited lipid accumulation in 3T3-L1 adipocytes and Huh-7 cells by suppressing adipogenic and lipogenic gene and protein expression. To evaluate the anti-obesity effects of ZH, mice fed a high-fat diet were orally administered low and high doses of ZH (low, ZM 400 mg/kg + HR 100 mg/kg; high, ZM 800 mg/kg + HR 200 mg/kg) for 9 weeks. ZH significantly reduced body weight gain and adipose tissue accumulation with no reduction in food intake when compared to control treatment. Furthermore, ZH reduced hepatic triglyceride and total cholesterol levels, as well as adipose cell size, in the liver and epididymal fat pads, respectively, through inhibition of adipogenesis and lipogenesis-related gene expression. These results suggested that ZH inhibits lipid accumulation, thereby indicating its potential for use as a new therapeutic strategy for obesity.


Fibroblasts Derived From Vestibular Schwannoma Express Protumorogenic Markers.
Vestibular schwannomas (VSs), despite being histologically benign, cause significant morbidity because of their challenging intracranial location and the propensity for growth. The role of the stroma and particularly fibroblasts, in the progression of VS, is not completely understood. This study examines the profile of fibroblasts in VS. Seventeen patients undergoing surgical excision of VS were recruited into the study. Reverse transcription with quantitative polymerase chain reaction (RT-qPCR) was performed on VS tissue samples and fibroblast-associated molecules examined. Immunofluorescence and immunohistochemistry in VS tissue were used to study the expression of fibroblast markers CD90 and podoplanin in situ. Fibroblast cultures were established from VS, and RT-qPCR analysis was performed on a panel of fibroblast markers on VS and control tissue fibroblasts. Several fibroblast-associated molecules including members of galectin family and matrix metalloproteinases were found to be expressed in VS tissue on RT-qPCR analysis. In situ, expression of CD90 and podoplanin was observed in VS tissue both on immunohistochemistry and immunofluorescence. RT-qPCR analysis of fibroblasts from VS and control vestibular neuroepithelium (NE) showed a higher expression of several molecules of the galectin and matrix metalloproteinases family on VS fibroblasts compared with NE fibroblasts. This work examines fibroblasts from VS and shows qualitative differences from NE fibroblasts on RT-qPCR. Further understanding of the fibroblast function in the progression of VS will potentially unveil new targets to manage VS growth.


SAP155-mediated splicing of FUSE-binding protein-interacting repressor serves as a molecular switch for c-myc gene expression.
The Far UpStream Element (FUSE)-binding protein-interacting repressor (FIR), a c-myc transcriptional suppressor, is alternatively spliced removing the transcriptional repression domain within exon 2 (FIRΔexon2) in colorectal cancers. SAP155 is a subunit of the essential splicing factor 3b (SF3b) subcomplex in the spliceosome. This study aims to study the significance of the FIR-SAP155 interaction for the coordination of c-myc transcription, pre-mRNA splicing, and c-Myc protein modification, as well as to interrogate FIRΔexon2 for other functions relating to altered FIR pre-mRNA splicing. Knockdown of SAP155 or FIR was used to investigate their reciprocal influence on each other and on c-myc transcription, pre-mRNA splicing, and protein expression. Pull down from HeLa cell nuclear extracts revealed the association of FIR, FIRΔexon2, and SF3b subunits. FIR and FIRΔexon2 were coimmunoprecipitated with SAP155. FIR and FIRΔexon2 adenovirus vector (Ad-FIR and Ad-FIRΔexon2, respectively) were prepared to test for their influence on c-myc expression. FIR, SAP155, SAP130, and c-myc were coordinately upregulated in human colorectal cancer. These results reveal that SAP155 and FIR/FIRΔexon2 form a complex and are mutually upregulating. Ad-FIRΔexon2 antagonized Ad-FIR transcriptional repression of c-myc in HeLa cells. Because FIRΔexon2 still carries RRM1 and RRM2 and binding activity to FUSE, it is able to displace repression competent FIR from FUSE in electrophoretic mobility shift assays, thus thwarting FIR-mediated transcriptional repression by FUSE. Thus aberrant FIRΔexon2 production in turn sustained c-Myc expression. In conclusion, altered FIR and c-myc pre-mRNA splicing, in addition to c-Myc expression by augmented FIR/FIRΔexon2-SAP155 complex, potentially contribute to colorectal cancer development.


Phenotype, Function, and Mobilization of 6-Sulfo LacNAc-Expressing Monocytes in Atopic Dermatitis.
Mononuclear phagocytes (MPs) are important immune regulatory cells in atopic dermatitis (AD). We previously identified 6-sulfo LacNAc-expressing monocytes (slanMo) as TNF-α- and IL-23-producing cells in psoriatic skin lesions and as inducers of IFN-γ-, IL-17-, and IL-22-producing T cells. These cytokines are also upregulated in AD and normalize with treatment, as recently shown for dupilumab-treated patients. We here asked for the role of slanMo in AD. Increased numbers of slanMo were found in AD skin lesions. In difference to other MPs in AD, slanMo lacked expression of FcɛRI, CD1a, CD14, and CD163. slanMo from blood of patients with AD expressed increased levels of CD86 and produced IL-12 and TNF-α at higher amounts than CD14+ monocytes and myeloid dendritic cells. While CD14+ monocytes from patients with AD revealed a reduced IL-12 production, we observed no difference in the cytokine production comparing slanMo in AD and healthy controls. Interestingly, experimentally induced mental stress, a common trigger of flares in patients with AD, rapidly mobilized slanMo which retained their high TNF-α-producing capacity. This study identifies slanMo as a distinct population of inflammatory cells in skin lesions and as proinflammatory blood cells in patients with AD. slanMo may, therefore, represent a potent future target for treatment of AD.


Identification of vibrio cholerae and vibrio mimicus by multilocus sequence analysis (MLSA).
Vibrio cholerae and Vibrio mimicus have similar phenotypes and genomes making rapid differentiation of these two species difficult. The first standard multilocus sequence analysis (MLSA) scheme for the identification of these species is described. A collection of 45 representative isolates from different geographical regions and hosts was examined using segments of the housekeeping genes pyrH, recA and rpoA. Overall, the closest phylogenetic neighbours of these species were Vibrio furnissii and Vibrio fluvialis. V. cholerae and V. mimicus formed separate species clusters on the basis of each gene, suggesting that these genes are useful as identification markers. These species clusters arose by the accumulation of point mutations. The pyrH gene showed the highest resolution for differentiating V. cholerae and V. mimicus. The maximum interspecies pyrH gene sequence similarity was 91 %. Clearly, V. mimicus strains were more heterogeneous than V. cholerae strains at the three loci. It is suggested that vibrio species may be defined on the basis of MLSA data. A vibrio species was defined as a group of strains forming a monophyletic group on the basis of these loci and with an intraspecific sequence similarity of at least 95 %. V. cholerae and V. mimicus isolates can be readily identified through the open database resource 'The Taxonomy of Vibrios' (http://www.taxvibrio.lncc.br/).


Respiratory symptoms in children living near busy roads and their relationship to vehicular traffic: results of an Italian multicenter study (SIDRIA 2).
Epidemiological studies have provided evidence that exposure to vehicular traffic increases the prevalence of respiratory symptoms and may exacerbate pre-existing asthma in children. Self-reported exposure to road traffic has been questioned as a reliable measurement of exposure to air pollutants. The aim of this study was to investigate whether there were specific effects of cars and trucks traffic on current asthma symptoms (i.e. wheezing) and cough or phlegm, and to examine the validity of self-reported traffic exposure. The survey was conducted in 2002 in 12 centers in Northern, Center and Southern Italy, different in size, climate, latitude and level of urbanization. Standardized questionnaires filled in by parents were used to collect information on health outcomes and exposure to traffic among 33,632 6-7 and 13-14 years old children and adolescents. Three questions on traffic exposure were asked: the traffic in the zone of residence, the frequency of truck and of car traffic in the street of residence. The presence of a possible response bias for the self-reported traffic was evaluated using external validation (comparison with measurements of traffic flow in the city of Turin) and internal validations (matching by census block, in the cities of Turin, Milan and Rome). Overall traffic density was weakly associated with asthma symptoms but there was a stronger association with cough or phlegm (high traffic density OR = 1.24; 95% CI: 1.04, 1.49). Car and truck traffic were independently associated with cough or phlegm. The results of the external validation did not support the existence of a reporting bias for the observed associations, for all the self-reported traffic indicators examined. The internal validations showed that the observed association between traffic density in the zone of residence and respiratory symptoms did not appear to be explained by an over reporting of traffic by parents of symptomatic subjects. Children living in zones with intense traffic are at higher risk for respiratory effects. Since population characteristics are specific, the results of validation of studies on self-reported traffic exposure can not be generalized.


Synthesis and Characterization of Zwitterionic Polymer Brush Functionalized Hydrogels with Ionic Responsive Coefficient of Friction.
Freeze-thaw poly(vinyl alcohol) hydrogels (PVA-H) offer great potential for several biomedical applications due to their biomimetic mechanical properties and biocompatibility. Despite these advantages, the use of PVA-H for load bearing applications has been limited due to poor performance in boundary lubrication compared to natural tissue such as articular cartilage. Recently, zwitterionic polymer brushes have been shown to act as effective boundary lubricants on rigid substrates; however, to the best of our knowledge, the synergistic effects of zwitterionic brushes coupled with the biomimetic fluid load support exhibited by hydrogels have not been reported. We report here on our investigation involving the synthesis and characterization of two unique types of polymer brush functionalized PVA hydrogels. The zwitterionic polymers that were compared contained either [2-(methacryloyloxy)ethyl]dimethyl-3-sulfopropylammonium hydroxide, PMEDSAH, or 2-methacryloyloxyethylphosphorylcholine, PMPC, repeating units. Both hydrogels coated with zwitterionic polymers were found to be cytocompatible. We report further on micrometer-scale surface properties via water contact angle goniometry, surface roughness measurements, and scanning electron microscopy. Finally, the impact of brush functionalization on the mechanics of the tribologically enhanced gels is reported with comparison to natural articular cartilage within the context of Hertzian contact theory.


A pilot study on the use of prednisolone-encapsulated liposomes for the treatment of moderate-to-severe Graves' orbitopathy with reduced systemic steroid exposure.
To demonstrate that long-circulating PEGylated liposomal prednisolone is a safe and effective therapy in patients with active moderate-to-severe Graves' orbitopathy. Open-label, proof-of-concept, multicentre pilot study. Ten patients with moderate-to-severe Graves's orbitopathy, who were euthyroid for at least three months. Long-circulating PEGylated liposomal prednisolone 150 mg was administered intravenously twice, with 2-week interval. Total follow-up was 12 months, with visits at baseline, week 2, 6, 13, 26 and 52. Physical, laboratory and ophthalmological examinations were performed. Response to treatment was defined as a reduction in Clinical Activity Score by ≥2 points; palpebral aperture by ≥3 mm; soft tissue signs by ≥2 grades; exophthalmos by ≥2 mm; and motility by >8 degrees or improvement in diplopia score. A response was sustained when equally observed at weeks 6 and 13. One patient achieved a sustained response according to the predetermined definition. All patients showed a decrease in Clinical Activity Score after one infusion, with a mean decrease of two points. The Clinical Activity Score was ≤1 at week 52 for all patients. Improvement was also observed in the soft tissue signs. Most of the adverse events were mild and of a transient nature. Two patients required further treatment with intravenous methylprednisolone. This pilot study showed a positive effect of long-circulating PEGylated liposomal prednisolone on the Clinical Activity Score in patients with moderate-to-severe Graves's orbitopathy, resulting in fewer hospital visits and possibly less glucocorticoid-related side-effects.


Biochemical and genetic analysis of the Drk SH2/SH3 adaptor protein of Drosophila.
The Drk SH3-SH2-SH3 adaptor protein has been genetically identified in a screen for rate-limiting components acting downstream of the Sevenless (Sev) receptor tyrosine kinase in the developing eye of Drosophila. It provides a link between the activated Sev receptor and Sos, a guanine nucleotide release factor that activates Ras1. We have used a combined biochemical and genetic approach to study the interactions between Sev, Drk and Sos. We show that Tyr2546 in the cytoplasmic tail of Sev is required for Drk binding, probably because it provides a recognition site for the Drk SH2 domain. Interestingly, a mutation at this site does not completely block Sev function in vivo. This may suggest that Sev can signal in a Drk-independent, parallel pathway or that Drk can also bind to an intermediate docking protein. Analysis of the Drk-Sos interaction has identified a high affinity binding site for Drk SH3 domains in the Sos tail. We show that the N-terminal Drk SH3 domain is primarily responsible for binding to the tail of Sos in vitro, and for signalling to Ras in vivo.


Hepatic glucose intolerance precedes hepatic steatosis in the male aromatase knockout (ArKO) mouse.
Estrogens are known to play a role in modulating metabolic processes within the body. The Aromatase knockout (ArKO) mice have been shown to harbor factors of Metabolic syndrome with central adiposity, hyperinsulinemia and male-specific hepatic steatosis. To determine the effects of estrogen ablation and subsequent replacement in males on whole body glucose metabolism, three- and six-month-old male ArKO mice were subjected to whole body glucose, insulin and pyruvate tolerance tests and analyzed for ensuing metabolic changes in liver, adipose tissue, and skeletal muscle. Estrogen-deficient male ArKO mice showed increased gonadal adiposity which was significantly reduced upon 17β-estradiol (E2) treatment. Concurrently, elevated ArKO serum leptin levels were significantly reduced upon E2 treatment and lowered serum adiponectin levels were restored to wild type levels. Three-month-old male ArKO mice were hyperglycemic, and both glucose and pyruvate intolerant. These phenotypes continued through to 6 months of age, highlighting a loss of glycemic control. ArKO livers displayed changes in gluconeogenic enzyme expression, and in insulin signaling pathways upon E2 treatment. Liver triglycerides were increased in the ArKO males only after 6 months of age, which could be reversed by E2 treatment. No differences were observed in insulin-stimulated ex vivo muscle glucose uptake nor changes in ArKO adipose tissue and muscle insulin signaling pathways. Therefore, we conclude that male ArKO mice develop hepatic glucose intolerance by the age of 3 months which precedes the sex-specific development of hepatic steatosis. This can be reversed upon the administration of exogenous E2.


Emotion recognition deficits among persons with schizophrenia: Beyond stimulus complexity level and presentation modality.
Studies have shown that persons with schizophrenia have lower accuracy in emotion recognition compared to persons without schizophrenia. However, the impact of the complexity level of the stimuli or the modality of presentation has not been extensively addressed. Forty three persons with a diagnosis of schizophrenia and 43 healthy controls, matched for age and gender, were administered tests assessing emotion recognition from stimuli with low and high levels of complexity presented via visual, auditory and semantic channels. For both groups, recognition rates were higher for high-complexity stimuli compared to low-complexity stimuli. Additionally, both groups obtained higher recognition rates for visual and semantic stimuli than for auditory stimuli, but persons with schizophrenia obtained lower accuracy than persons in the control group for all presentation modalities. Persons diagnosed with schizophrenia did not present a level of complexity specific deficit or modality-specific deficit compared to healthy controls. Results suggest that emotion recognition deficits in schizophrenia are beyond level of complexity of stimuli and modality, and present a global difficulty in cognitive functioning.


Synthesis, Characterization and Photophysical Properties of Pyridine-Carbazole Acrylonitrile Derivatives.
We synthesized three novel highly fluorescent compounds, 2-(2'-pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile, 2-(3"-pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile, and 2-(4-pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile by Knoevenagel condensation. The first two were synthesized without solvent in the presence of piperidine as a catalyst; the third was synthesized without a catalyst and with N,N-dimethylformamide as a solvent. In solution, the molar absorption coefficients showed absorptions at 380, 378, and 396 nm, respectively; in solid state, absorptions were at 398, 390, and 442 nm, respectively. The fluorescence emission was at 540, 540 and 604 nm, respectively, the 2-(4-pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile showed a red shift in the emission of 64 nm compared to the other two compounds. The fluorescence quantum yield for the compounds in powder form showed values of 0.05, 0.14, and 0.006, respectively; compared with the value measured for the Alq3 reference, 2-(3"-pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile had a lightly higher value. The third harmonic generation measurement for 2-(2'-pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile yielded a χ(3) value of 5.5 × 10-12 esu, similar to that reported for commercial polymers.


Virus-mediated killing of cells that lack p53 activity.
A major goal of molecular oncology is to identify means to kill cells lacking p53 function. Most current cancer therapy is based on damaging cellular DNA by irradiation or chemicals. Recent reports support the notion that, in the event of DNA damage, the p53 tumour-suppressor protein is able to prevent cell death by sustaining an arrest of the cell cycle at the G2 phase. We report here that adeno-associated virus (AAV) selectively induces apoptosis in cells that lack active p53. Cells with intact p53 activity are not killed but undergo arrest in the G2 phase of the cell cycle. This arrest is characterized by an increase in p53 activity and p21 levels and by the targeted destruction of CDC25C. Neither cell killing nor arrest depends upon AAV-encoded proteins. Rather, AAV DNA, which is single-stranded with hairpin structures at both ends, elicits in cells a DNA damage response that, in the absence of active p53, leads to cell death. AAV inhibits tumour growth in mice. Thus viruses can be used to deliver DNA of unusual structure into cells to trigger a DNA damage response without damaging cellular DNA and to selectively eliminate those cells lacking p53 activity.


Using Complexity Assessment to Inform the Development and Deployment of a Digital Dashboard for Schizophrenia Care: Case Study.
Health care is becoming more complex. For an increasing number of individuals, interacting with health care means addressing more than just one illness or disorder, engaging in more than one treatment, and interacting with more than one care provider. Individuals with severe mental illnesses such as schizophrenia are disproportionately affected by this complexity. Characteristic symptoms can make it harder to establish and maintain relationships. Treatment failure is common even where there is access to effective treatments, increasing suicide risk. Knowledge of complex adaptive systems has been increasingly recognized as useful in understanding and developing health care. A complex adaptive system is a collection of interconnected agents with the freedom to act based on their own internalized rules, affecting each other. In a complex health care system, relevant feedback is crucial in enabling continuous learning and improvement on all levels. New technology has potential, but the failure rate of technology projects in health care is high, arguably due to complexity. The Nonadoption, Abandonment, and challenges to Scale-up, Spread, and Sustainability (NASSS) framework and complexity assessment tool (NASSS-CAT) have been developed specifically to help identify and manage complexity in technology-related development projects in health care. This study aimed to use a pilot version of the NASSS-CAT instrument to inform the development and deployment of a point-of-care dashboard supporting schizophrenia care in west Sweden. Specifically, we report on the complexity profile of the project, stakeholders' experiences with using NASSS-CAT, and practical implications. We used complexity assessment to structure data collection and feedback sessions with stakeholders, thereby informing an emergent approach to the development and deployment of the point-of-care dashboard. We also performed a thematic analysis, drawing on observations and documents related to stakeholders' use of the NASSS-CAT to describe their views on its usefulness. Application of the NASSS framework revealed different types of complexity across multiple domains, including the condition, technology, value proposition, organizational tasks and pathways, and wider system. Stakeholders perceived the NASSS-CAT tool as useful in gaining perspective and new insights, covering areas that might otherwise have been neglected. Practical implications derived from feedback sessions with managers and developers are described. This case study shows how stakeholders can identify and plan to address complexities during the introduction of a technological solution. Our findings suggest that NASSS-CAT can bring participants a greater understanding of complexities in digitalization projects in general.


Youth's Awareness of and Reactions to The Real Cost National Tobacco Public Education Campaign.
In 2014, the Food and Drug Administration (FDA) launched its first tobacco-focused public education campaign, The Real Cost, aimed at reducing tobacco use among 12- to 17-year-olds in the United States. This study describes The Real Cost message strategy, implementation, and initial evaluation findings. The campaign was designed to encourage youth who had never smoked but are susceptible to trying cigarettes (susceptible nonsmokers) and youth who have previously experimented with smoking (experimenters) to reassess what they know about the "costs" of tobacco use to their body and mind. The Real Cost aired on national television, online, radio, and other media channels, resulting in high awareness levels. Overall, 89.0% of U.S. youth were aware of at least one advertisement 6 to 8 months after campaign launch, and high levels of awareness were attained within the campaign's two targeted audiences: susceptible nonsmokers (90.5%) and experimenters (94.6%). Most youth consider The Real Cost advertising to be effective, based on assessments of ad perceived effectiveness (mean = 4.0 on a scale from 1.0 to 5.0). High levels of awareness and positive ad reactions are requisite proximal indicators of health behavioral change. Additional research is being conducted to assess whether potential shifts in population-level cognitions and/or behaviors are attributable to this campaign. Current findings demonstrate that The Real Cost has attained high levels of ad awareness which is a critical first step in achieving positive changes in tobacco-related attitudes and behaviors. These data can also be used to inform ongoing message and media strategies for The Real Cost and other U.S. youth tobacco prevention campaigns.


Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection.
Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to increase the antiglioma efficacy. E1A mutant adenovirus Delta-24-RGD (DNX-2401) has shown a favorable toxicity profile and remarkable efficacy in a first-in-human phase I clinical trial. However, the comprehensive modulation of glioma metabolism in response to Delta-24-RGD infection is poorly understood. Integrating mass spectrometry based-quantitative proteomics, physical and functional interaction data, and biochemical approaches, we conducted a cell-wide study of cytosolic, nuclear, and secreted glioma proteomes throughout the early time course of Delta-24-RGD infection. In addition to the severe proteostasis impairment detected during the first hours post-infection (hpi), Delta-24-RGD induces a transient inhibition of signal transducer and activator of transcription 3 (STAT3), and transcription factor AP-1 (c-JUN) between 3 and 10hpi, increasing the nuclear factor kappa B (NF-κB) activity at 6hpi. Furthermore, Delta-24-RGD specifically modulates the activation dynamics of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) pathways early in infection. At extracellular level, Delta-24-RGD triggers a time -dependent dynamic production of multitasking cytokines, and chemotactic factors, suggesting potential pleiotropic effects on the immune system reactivation. Taken together, these data help us to understand the mechanisms used by Delta-24-RGD to exploit glioma proteome organization. Further mining of this proteomic resource may enable design and engineering complementary adenoviral based-vectors to increase the specificity and potency against glioma.


Management of chronic pressure ulcers: an evidence-based analysis.
In April 2008, the Medical Advisory Secretariat began an evidence-based review of the literature concerning pressure ulcers.Please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/tech/tech_mn.html to review these titles that are currently available within the Pressure Ulcers series.PRESSURE ULCER PREVENTION: an evidence based analysisThe cost-effectiveness of prevention strategies for pressure ulcers in long-term care homes in Ontario: projections of the Ontario Pressure Ulcer Model (field evaluation)MANAGEMENT OF CHRONIC PRESSURE ULCERS: an evidence-based analysis The Medical Advisory Secretariat (MAS) conducted a systematic review on interventions used to treat pressure ulcers in order to answer the following questions: Do currently available interventions for the treatment of pressure ulcers increase the healing rate of pressure ulcers compared with standard care, a placebo, or other similar interventions?Within each category of intervention, which one is most effective in promoting the healing of existing pressure ulcers? A pressure ulcer is a localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in conjunction with shear and/or friction. Many areas of the body, especially the sacrum and the heel, are prone to the development of pressure ulcers. People with impaired mobility (e.g., stroke or spinal cord injury patients) are most vulnerable to pressure ulcers. Other factors that predispose people to pressure ulcer formation are poor nutrition, poor sensation, urinary and fecal incontinence, and poor overall physical and mental health. The prevalence of pressure ulcers in Ontario has been estimated to range from a median of 22.1% in community settings to a median of 29.9% in nonacute care facilities. Pressure ulcers have been shown to increase the risk of mortality among geriatric patients by as much as 400%, to increase the frequency and duration of hospitalization, and to decrease the quality of life of affected patients. The cost of treating pressure ulcers has been estimated at approximately $9,000 (Cdn) per patient per month in the community setting. Considering the high prevalence of pressure ulcers in the Ontario health care system, the total cost of treating pressure ulcers is substantial. Wounds normally heal in 3 phases (inflammatory phase, a proliferative phase of new tissue and matrix formation, and a remodelling phase). However, pressure ulcers often fail to progress past the inflammatory stage. Current practice for treating pressure ulcers includes treating the underlying causes, debridement to remove necrotic tissues and contaminated tissues, dressings to provide a moist wound environment and to manage exudates, devices and frequent turning of patients to provide pressure relief, topical applications of biologic agents, and nutritional support to correct nutritional deficiencies. A variety of adjunctive physical therapies are also in use. Health technology assessment databases and medical databases were searched from 1996 (Medline), 1980 (EMBASE), and 1982 (CINAHL) systematically up to March 2008 to identify randomized controlled trials (RCTs) on the following treatments of pressure ulcers: cleansing, debridement, dressings, biological therapies, pressure-relieving devices, physical therapies, nutritional therapies, and multidisciplinary wound care teams. Full literature search strategies are reported in appendix 1. English-language studies in previous systematic reviews and studies published since the last systematic review were included if they had more than 10 subjects, were randomized, and provided objective outcome measures on the healing of pressure ulcers. In the absence of RCTs, studies of the highest level of evidence available were included. Studies on wounds other than pressure ulcers and on surgical treatment of pressure ulcers were excluded. A total of 18 systematic reviews, 104 RCTs, and 4 observational studies were included in this review. Data were extracted from studies using standardized forms. The quality of individual studies was assessed based on adequacy of randomization, concealment of treatment allocation, comparability of groups, blinded assessment, and intention-to-treat analysis. Meta-analysis to estimate the relative risk (RR) or weighted mean difference (WMD) for measures of healing was performed when appropriate. A descriptive synthesis was provided where pooled analysis was not appropriate or not feasible. The quality of the overall evidence on each intervention was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) criteria. Findings from the analysis of the included studies are summarized below: CLEANSING: There is no good trial evidence to support the use of any particular wound cleansing solution or technique for pressure ulcers. DEBRIDEMENT: There was no evidence that debridement using collagenase, dextranomer, cadexomer iodine, or maggots significantly improved complete healing compared with placebo.There were no statistically significant differences between enzymatic or mechanical debridement agents with the following exceptions:Papain urea resulted in better debridement than collagenase.Calcium alginate resulted in a greater reduction in ulcer size compared to dextranomer.Adding streptokinase/streptodornase to hydrogel resulted in faster debridement.Maggot debridement resulted in more complete debridement than conventional treatment.There is limited evidence on the healing effects of debridement devices. DRESSINGS: Hydrocolloid dressing was associated with almost three-times more complete healing compared with saline gauze. There is evidence that hydrogel and hydropolymer may be associated with 50% to 70% more complete healing of pressure ulcers than hydrocolloid dressing.No statistically significant differences in complete healing were detected among other modern dressings.There is evidence that polyurethane foam dressings and hydrocellular dressings are more absorbent and easier to remove than hydrocolloid dressings in ulcers with moderate to high exudates.In deeper ulcers (stage III and IV), the use of alginate with hydrocolloid resulted in significantly greater reduction in the size of the ulcers compared to hydrocolloid alone.Studies on sustained silver-releasing dressing demonstrated a tendency for reducing the risk of infection and promoting faster healing, but the sample sizes were too small for statistical analysis or for drawing conclusions. BIOLOGICAL THERAPIES: The efficacy of platelet-derived growth factors (PDGFs), fibroblast growth factor, and granulocyte-macrophage colony stimulating factor in improving complete healing of chronic pressure ulcers has not been established.Presently only Regranex, a recombinant PDGF, has been approved by Health Canada and only for treatment of diabetic ulcers in the lower extremities.A March 2008 US Food and Drug Administration (FDA) communication reported increased deaths from cancers in people given three or more prescriptions for Regranex.Limited low-quality evidence on skin matrix and engineered skin equivalent suggests a potential role for these products in healing refractory advanced chronic pressure ulcers, but the evidence is insufficient to draw a conclusion. ADJUNCTIVE PHYSICAL THERAPY: There is evidence that electrical stimulation may result in a significantly greater reduction in the surface area and more complete healing of stage II to IV ulcers compared with sham therapy. No conclusion on the efficacy of electrotherapy can be drawn because of significant statistical heterogeneity, small sample sizes, and methodological flaws.The efficacy of other adjunctive physical therapies [electromagnetic therapy, low-level laser (LLL) therapy, ultrasound therapy, ultraviolet light therapy, and negative pressure therapy] in improving complete closure of pressure ulcers has not been established. NUTRITION THERAPY: Supplementation with 15 grams of hydrolyzed protein 3 times daily did not affect complete healing but resulted in a 2-fold improvement in Pressure Ulcer Scale for Healing (PUSH) score compared with placebo.Supplementation with 200 mg of zinc three times per day did not have any significant impact on the healing of pressure ulcers compared with a placebo.Supplementation of 500 mg ascorbic acid twice daily was associated with a significantly greater decrease in the size of the ulcer compared with a placebo but did not have any significant impact on healing when compared with supplementation of 10 mg ascorbic acid three times daily.A very high protein tube feeding (25% of energy as protein) resulted in a greater reduction in ulcer area in institutionalized tube-fed patients compared with a high protein tube feeding (16% of energy as protein).Multinutrient supplements that contain zinc, arginine, and vitamin C were associated with a greater reduction in the area of the ulcers compared with standard hospital diet or to a standard supplement without zinc, arginine, or vitamin C.Firm conclusions cannot be drawn because of methodological flaws and small sample sizes. MULTIDISCIPLINARY WOUND CARE TEAMS: The only RCT suggests that multidisciplinary wound care teams may significantly improve healing in the acute care setting in 8 weeks and may significantly shorten the length of hospitalization. However, since only an abstract is available, study biases cannot be assessed and no conclusions can be drawn on the quality of this evidence.


Non-invasive imaging of atherosclerotic plaque macrophage in a rabbit model with F-18 FDG PET: a histopathological correlation.
Coronary atherosclerosis and its thrombotic complications are the major cause of mortality and morbidity throughout the industrialized world. Thrombosis on disrupted atherosclerotic plaques plays a key role in the onset of acute coronary syndromes. Macrophages density is one of the most critical compositions of plaque in both plaque vulnerability and thrombogenicity upon rupture. It has been shown that macrophages have a high uptake of 18F-FDG (FDG). We studied the correlation of FDG uptake with histopathological macrophage accumulation in atherosclerotic plaques in a rabbit model. Atherosclerosis was induced in rabbits (n = 6) by a combination of atherogenic diet and balloon denudation of the aorta. PET imaging was performed at baseline and 2 months after atherogenic diet and coregistered with magnetic resonance (MR) imaging. Normal (n = 3) rabbits served as controls. FDG uptake by the thoracic aorta was expressed as concentration (muCi/ml) and the ratio of aortic uptake-to-blood radioactivity. FDG uptake and RAM-11 antibody positive areas were analyzed in descending aorta. Atherosclerotic aortas showed significantly higher uptake of FDG than normal aortas. The correlation of aortic FDG uptake with macrophage areas assessed by histopathology was statistically significant although it was not high (r = 0.48, p < 0.0001). When uptake was expressed as the ratio of aortic uptake-to-blood activity, it correlated better (r = 0.80, p < 0.0001) with the macrophage areas, due to the correction for residual blood FDG activity. PET FDG activity correlated with macrophage content within aortic atherosclerosis. This imaging approach might serve as a useful non-invasive imaging technique and potentially permit monitoring of relative changes in inflammation within the atherosclerotic lesion.


An E2F1-HOXB9 transcriptional circuit is associated with breast cancer progression.
Homeobox B9 (HOXB9), a member of the homeobox gene family, is overexpressed in breast cancer and promotes tumor progression and metastasis by stimulating epithelial-to-mesenchymal transition and angiogenesis within the tumor microenvironment. HOXB9 activates the TGFβ-ATM axis, leading to checkpoint activation and DNA repair, which engenders radioresistance in breast cancer cells. Despite detailed reports of the role of HOXB9 in breast cancer, the factors that regulate HOXB9 transcription have not been extensively examined. Here we uncover an underlying mechanism that may suggest novel targeting strategies for breast cancer treatment. To identify a transcription factor binding site (TFBS) in the HOXB9 promoter region, a dual luciferase reporter assay was conducted. Protein candidates that may directly attach to a TFBS of HOXB9 were examined by Q-PCR, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and mutation analysis. A HOXB9 promoter region from -404 to -392 was identified as TFBS, and E2F1 was a potential binding candidate in this region. The induction of HOXB9 expression by E2F1 was observed by Q-PCR in several breast cancer cell lines overexpressing E2F1. The stimulatory effect of E2F1 on HOXB9 transcription and its ability to bind the TFBS were confirmed by luciferase, EMSA and ChIP assay. Immunohistochemical analysis of 139 breast cancer tissue samples revealed a significant correlation between E2F1 and HOXB9 expression (p<0.001). Furthermore, a CDK4/6 inhibitor suppressed E2F1 expression and also reduced expression of HOXB9 and its downstream target genes. Our in vitro analysis identified the TFBS of the HOXB9 promoter region and suggested that E2F1 is a direct regulator of HOXB9 expression; these data support the strong correlation we found between E2F1 and HOXB9 in clinical breast cancer samples. These results suggest that targeting the E2F1/HOXB9 axis may be a novel strategy for the control or prevention of cancer progression and metastasis.


Comparison of serum and cell-specific cytokines in humans.
Cytokines function at the cellular, microenvironmental level, but human cytokine assessment is most commonly done at the macro level, by measuring serum cytokines. The relationships between serum and cellular cytokines, if there are any, are undefined. In a study of hospitalized patients in Malawi, we compared cytometrically assessed, cell-specific cytokine data to serum interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) levels in 16 children and 71 (IL-2, -4, -6, -10) or 159 (IL-8, IFN-gamma, and TNF-alpha) adults, using Wilcoxon rank sum tests and Pearson's (r(p)) and Spearman's (r(s)) rank correlations. For the entire study group, correlations between identical serum and cellular cytokines mainly involved IL-8 and IFN-gamma, were few, and were weakly positive (r < 0.40). Blood culture-positive persons had the most and strongest correlations, including those between serum IL-2 levels and the percentages of lymphocytes spontaneously making IL-2 (r(s) = +0.74), serum IL-8 levels and the percentages of lymphocytes spontaneously making IL-8 (r(p) = +0.66), and serum IL-10 levels and the percentages of CD8(+) T cells making TNF-alpha (r(p) = +0.89). Human immunodeficiency virus (HIV)-positive persons had the next largest number of correlations, including several serum IL-8 level correlations, correlation of serum IL-10 levels with the percentages of lymphocytes producing induced IL-10 (r(s) = +0.36), and correlation of serum IFN-gamma levels and the percentages of lymphocytes spontaneously making both IL-6 and IFN-gamma in the same cell (r(p) = +0.59). HIV-negative, malaria smear-positive, and pediatric patients had few significant correlations; for the second and third of these subgroups, serum IL-8 level was correlated with the percentage of CD8(-) T cells producing induced IL-8 (r(s) = +0.40 and r(s) = +0.56, respectively). Thus, the strength of associations between serum and cellular cytokines varied with the presence or absence of bloodstream infection, HIV status, and perhaps other factors we did not assess. These results strongly suggest that serum cytokines at best only weakly reflect peripheral blood cell cytokine production and balances.


Implications for human adipose-derived stem cells in plastic surgery.
Adipose-derived stem cells (ADSCs) are a subset of mesenchymal stem cells (MSCs) that possess many of the same regenerative properties as other MSCs. However, the ubiquitous presence of ADSCs and their ease of access in human tissue have led to a burgeoning field of research. The plastic surgeon is uniquely positioned to harness this technology because of the relative frequency in which they perform procedures such as liposuction and autologous fat grafting. This review examines the current landscape of ADSC isolation and identification, summarizes the current applications of ADSCs in the field of plastic surgery, discusses the risks associated with their use, current barriers to universal clinical translatability, and surveys the latest research which may help to overcome these obstacles.


Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice.
Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton's Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts; total inflammatory cells were decreased in the BALF; Fulton's Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate.


Banded surface flow maintained by convection in a model of the rapidly rotating giant planets.
In three-dimensional numerical simulations of a rapidly rotating Boussinesq fluid shell, thermally driven convection in the form of columns parallel to the rotation axis generates an alternately directed mean zonal flow with a cylindrical structure. The mean structure at the outer spherical surface consists of a broad eastward flow at the equator and alternating bands of westward and eastward flows at higher latitudes in both hemispheres. The banded structure persists even though the underlying convective motions are time-dependent. These results, although still far from the actual motions seen on Jupiter and Saturn, provide support for theoretical suggestions that thermal convection can account for the remarkable banded flow structures on these planets.


Actogram analysis of free-flying migratory birds: new perspectives based on acceleration logging.
The use of accelerometers has become an important part of biologging techniques for large-sized birds with accelerometer data providing information about flight mode, wing-beat pattern, behaviour and energy expenditure. Such data show that birds using much energy-saving soaring/gliding flight like frigatebirds and swifts can stay airborne without landing for several months. Successful accelerometer studies have recently been conducted also for free-flying small songbirds during their entire annual cycle. Here we review the principles and possibilities for accelerometer studies in bird migration. We use the first annual actograms (for red-backed shrike Lanius collurio) to explore new analyses and insights that become possible with accelerometer data. Actogram data allow precise estimates of numbers of flights, flight durations as well as departure/landing times during the annual cycle. Annual and diurnal rhythms of migratory flights, as well as prolonged nocturnal flights across desert barriers are illustrated. The shifting balance between flight, rest and different intensities of activity throughout the year as revealed by actogram data can be used to analyse exertion levels during different phases of the life cycle. Accelerometer recording of the annual activity patterns of individual birds will open up a new dimension in bird migration research.


The dream and reality of histology agnostic cancer clinical trials.
Emerging technologies and progress in data processing allowed for new insights on gene expression, genomics and epigenomics, and mechanisms of cancer genesis and progression. The development of new therapeutic strategies should therefore be triggered by the understanding of the underlying biology through sophisticated clinical trials. Therefore, the methodology and the design of cancer clinical trials as well as the methods of their implementation are under profound changes. Targeting specific pathways has open the hope of a more focused and personalized medicine which has the potential to bring more efficient and tailored treatments to patients. It has been questioned therefore whether clinical trials traditionally designed for specific tumor types could not re-visited towards trials gathering patients based on molecular features rather than pure pathology criteria. The complexity of the cancer biology being the result of so many different interactive mechanisms whether driving or not the process of cancer cells is an additional level of complexity to approach more inclusive clinical trial access. Nevertheless, a number of innovative solutions to address biological challenges across histologies have been initiated and the question of whether histology agnostic trials could be conceived is a logical next question. This paper questions the advantages and the limits of clinical trials performed across tumor types bearing similar selected molecular features and looks further into the feasibility of such histology agnostic trials.


Driving and dementia: Efficient approach to driving safety concerns in family practice.
To provide primary care physicians with an approach to driving safety concerns when older persons present with memory difficulties. The approach is based on an accredited memory clinic training program developed by the Centre for Family Medicine Primary Care Collaborative Memory Clinic. One of the most challenging aspects of dementia care is the assessment of driving safety. Drivers with dementia are at higher risk of motor vehicle collisions, yet many drivers with mild dementia might be safely able to continue driving for several years. Because safe driving is dependent on multiple cognitive and functional skills, clinicians should carefully consider many factors when determining if cognitive concerns affect driving safety. Specific findings on corroborated history and office-based cognitive testing might aid in the physician's decisions to refer for comprehensive on-road driving evaluation and whether to notify transportation authorities in accordance with provincial reporting requirements. Sensitive communication and a person-centred approach are essential. Primary care physicians must consider many factors when determining if cognitive concerns might affect driving safety in older drivers.


Real-time detection technique for Doppler optical coherence tomography.
We propose and demonstrate a novel detection technique, based on a modified electronic phase-locked loop, for Doppler optical coherence tomography. The technique permits real-time simultaneous reflectivity and continuous, bidirectional velocity mapping in turbid media over a wide velocity range with minimal sensitivity penalty compared with conventional optical coherence tomography, which is a major advance over current postprocessing and discrete parallel detection techniques.


In vivo fermentation of a Pleurotus eryngii polysaccharide and its effects on fecal microbiota composition and immune response.
A novel, homogeneous Pleurotus eryngii polysaccharide (PEP) (molecular weight 426 kDa, purity 91.25 ± 3.14%) which mainly consisted of glucose with β-type glycosidic linkages was used to investigate in vivo fermentation behavior and effects on immune response in mice. Different doses (0.2, 0.4, 0.8 g per kg body weight) were orally administered to the mice for a period of six weeks. The results showed that the SCFA concentration, pH value, and moisture contents of cecum and colon contents were significantly altered with high-dose PEP treatment compared to the control group (P < 0.05). Moreover, the fecal microbiota in the PEP treated group was found to be structurally different compared to the control group; especially, the Porphyromonadaceae, Rikenellaceae, Bacteroidaceae and Lactobacillaceae abundances were all increased at the family level. In addition, the exerted immune response was significantly altered after the high-dose PEP oral administration. This exploratory study indicated that intake of PEP could have a positive role in gastrointestinal tract health.


Functional phylotyping approach for assessing intraspecific diversity of Ruminococcus albus within the rumen microbiome.
Ruminococcus albus, a cellulolytic bacterium, is a critical member of the rumen community. Ruminococcus albus lacks a classical cellulosome complex, but it possesses a unique family 37 carbohydrate-binding module (CBM37), which is integrated into a variety of carbohydrate-active enzymes. We developed a potential molecular tool for functional phylotyping of the R. albus population in the rumen, based on a variable region in the cel48A gene. cel48A encodes a single copy of the CBM37-associated family 48 glycoside hydrolase in all known strains of this bacterium. A segment of the cel48A gene was amplified from rumen metagenomic samples of four bovines, and its abundance and diversity were evaluated. Analysis of the obtained sequences revealed the co-existence of multiple functional phylotypes of cel48A in all four animals. These included sequences identical or similar to those of R. albus isolates (reference strains), as well as several novel sequences. The dominant cel48A type varied among animals. This method can be used for detection of intraspecific diversity of R. albus in metagenomic samples. Together with scaC, a previously reported gene marker for R. flavefaciens, we present a set of two species-specific markers for phylotyping of Ruminococci in the herbivore rumen.


Religion and fertility in the United States: new patterns.
In the United States, the baby boom-era pattern of high Catholic and low Protestant fertility has ended. Among non-Hispanic whites in the 1980s, Catholic total fertility rates (TFRs) were about one-quarter of a child lower than Protestant rates (1.64 vs. 1.91). Most of the Protestant-Catholic difference is related to later and less frequent marriage among Catholics. Future research on the demography of religious groups should focus on explaining the delayed marriage pattern of Catholics, the high fertility of Mormons and frequently attending Protestants, and the very low fertility of those with no religious affiliation.


Extension of mental preparation positively affects motor imagery as compared to motor execution: a functional near-infrared spectroscopy study.
Motor imagery (MI) is widely used to study cognitive action control. Although, the neural simulation theory assumes that MI and motor execution (ME) share many common features, the extent of similarity and whether it spreads into the preparation phase is still under investigation. Here we asked, whether an extension of physiological mental preparation has a comparable effect on MI and ME. Data were recorded using wireless functional near-infrared spectroscopy (fNIRS) in a two-stage task design where subjects were cued with or without preparatory stimuli to either execute or imagine complex sequential thumb-finger tasks. The main finding is that the extended mental preparation has a significant positive effect on oxy-hemoglobin (∆[O(2)Hb]) in response to MI, which is proportionally larger as that found in response to ME. Furthermore, fNIRS was capable to discriminate within each task whether it was preceded by preparatory stimuli or not. Transition from mental preparation to actual performance (ME or MI) was reflected by a dip of the fNIRS signal presumably related to underlying cortical processes changing between preparation and task performance. Statistically significant main effects of 'Preparation' and 'Task' showed that ∆[O(2)Hb] during preparation was preparation-specific, i.e., positively affected by the presence of preparatory stimuli, whereas during task performance ∆[O(2)Hb] was both preparation- and task-specific, i.e., additionally affected by the task mode. These results are particularly appealing from a practical point of view for making use of MI in neuroscientific applications. Especially neurorehabilitation and neural interfaces may benefit from utilizing positive interactions between mental preparation and MI performance.


Culture-sensitive and standard pain neuroscience education improves pain, disability, and pain cognitions in first-generation Turkish migrants with chronic low back pain: a pilot randomized controlled trial.
Purpose: To compare the effectiveness of culture-sensitive and standard pain neuroscience education (PNE) on pain knowledge, pain intensity, disability, and pain cognitions in first-generation Turkish migrants with chronic low back pain (CLBP).Methods: Twenty-nine Turkish first-generation migrants with CLBP were randomly assigned to the culture-sensitive (n = 15) or standard PNE (n = 14) groups. Primary (pain knowledge, pain intensity, and disability) and secondary outcomes (pain beliefs, catastrophization, and fear of movement) were evaluated at baseline, immediately after the second session of PNE (week 1), and after 4 weeks.Results: There was a significant main effect of time in pain knowledge (p < .001), pain intensity (p = .03), disability (p = .002), organic and psychological pain beliefs (p = .002, p = .01), catastrophization (p = .002), and fear of movement (p = .02). However, no significant difference was found between groups in terms of all outcome measures (p > .05).Conclusions: Both PNE programs resulted in improvements in knowledge of pain, pain intensity, perceived disability, and pain cognitions. Nevertheless, the superiority of the culture-sensitive PNE approach could not be proved. Therefore, maybe migrants who are living in the host country for longer length of time do not need culturally adapted therapies due to cultural integration, while these adaptations might be essential for the recent migrants or the autochthonous population in Turkey. Further research is required to investigate the effects of culture-sensitive PNE alone or in combination with physiotherapy interventions in recent migrants or Turkish natives with CLBP.


Core outcome measures for exercise studies in people with multiple sclerosis: recommendations from a multidisciplinary consensus meeting.
Evidence shows that exercise is beneficial for people with multiple sclerosis (MS); however, statistical pooling of data is difficult because of the diversity of outcome measures used. The objective of this review is to report the recommendations of an International Consensus Meeting for a core set of outcome measures for use in exercise studies in MS. From the 100 categories of the International Classification of Function Core Sets for MS, 57 categories were considered as likely/potentially likely to be affected by exercise and were clustered into seven core groups. Outcome measures to address each group were evaluated regarding, for example, psychometric properties. The following are recommended: Modified Fatigue Impact Scale (MFIS) or Fatigue Severity Scale (FSS) for energy and drive, 6-Minute Walk Test (6MWT) for exercise tolerance, Timed Up and Go (TUG) for muscle function and moving around, Multiple Sclerosis Impact Scale (MSIS-29) or Multiple Sclerosis Quality of Life-54 Instrument (MSQoL54) for quality of life and body mass index (BMI) or waist-hip ratio (WHR) for the health risks associated with excess body fat. A cost effectiveness analysis and qualitative evaluation should be included where possible. Using these core measures ensures that future meta-analyses of exercise studies in MS are more robust and thus more effectively inform practice.


Lipopolysaccharide enhances the cytotoxicity of 2-chloroethyl ethyl sulfide.
The bacterial endotoxin, lipopolysaccharide (LPS), is a well-characterized inflammatory factor found in the cell wall of Gram-negative bacteria. In this investigation, we studied the cytotoxic interaction between 2-chloroethyl ethyl sulfide (CEES or ClCH2CH2SCH2CH3) and LPS using murine RAW264.7 macrophages. CEES is a sulfur vesicating agent and is an analog of 2,2'-dichlorodiethyl sulfide (sulfur mustard). LPS is a ubiquitous natural agent found in the environment. The ability of LPS and other inflammatory agents (such as TNF-alpha and IL-1beta) to modulate the toxicity of CEES is likely to be an important factor in the design of effective treatments. RAW 264.7 macrophages stimulated with LPS were found to be more susceptible to the cytotoxic effect of CEES than unstimulated macrophages. Very low levels of LPS (20 ng/ml) dramatically enhanced the toxicity of CEES at concentrations greater than 400 microM. The cytotoxic interaction between LPS and CEES reached a maximum 12 hours after exposure. In addition, we found that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1-beta) as well as phorbol myristate acetate (PMA) also enhanced the cytotoxic effects of CEES but to a lesser extent than LPS. Our in vitro results suggest the possibility that LPS and inflammatory cytokines could enhance the toxicity of sulfur mustard. Since LPS is a ubiquitous agent in the natural environment, its presence is likely to be an important variable influencing the cytotoxicity of sulfur mustard toxicity. We have initiated further experiments to determine the molecular mechanism whereby the inflammatory process influences sulfur mustard cytotoxicity.


Effect of nicotine and ephedrine on the accumulation of 18F-FDG in brown adipose tissue.
This study evaluated the effect of various beta-adrenergic agonists on (18)F-FDG uptake in brown adipose tissue (BAT) in rats using ex vivo biodistribution studies. Caffeine (10 mg/kg of body weight, n = 4), ephedrine (5 mg/kg of body weight, n = 4), nicotine (0.8 mg/kg of body weight, n = 9), or a mixture of nicotine and ephedrine (0.8 mg/kg of body weight and 5 mg/kg of body weight, respectively, n = 9) was injected into the peritoneal cavity of female Lewis rats 30 min before intravenous (18)F-FDG injection. One hour after injection of (18)F-FDG, the animals were sacrificed, and BAT, other major organs, and blood were extracted. The biodistribution results were compared with body temperature data. In the rats injected with nicotine or ephedrine, the mean uptake of (18)F-FDG, in percentage injected dose (%ID)/(g of interscapular BAT) x (kg of body weight), was significantly increased (7.9-fold for nicotine and 3.7-fold for ephedrine), compared to the control rats. Nicotine had the strongest effect on (18)F-FDG uptake in BAT. Caffeine increased BAT uptake slightly, but this increase did not reach statistical significance. The combination of nicotine and ephedrine increased the uptake 12.0-fold, compared with control rats; more than either nicotine or ephedrine alone. Uptake of (18)F-FDG in most other major organs did not change significantly. The effect of nicotine was blocked by prior injection of beta-adrenergic antagonists. A transient decrease in body temperature was observed in the nicotine-injected group, and this effect was canceled by prior injection of beta-adrenergic antagonists. No significant change in baseline temperature was seen before or after beta-adrenergic agonist injection. Nicotine caused a greater increase in (18)F-FDG uptake in BAT than did other interventions, and the effect was increased when nicotine was combined with ephedrine. The effect of nicotine was completely blocked by prior injection of beta-adrenergic antagonists, indicating that beta-adrenergic agonists increase the metabolism of BAT. These preclinical data suggest that patients should avoid nicotine and ephedrine before undergoing (18)F-FDG PET to minimize (18)F-FDG uptake in BAT.


Dirac node lines in two-dimensional Lieb lattices.
As a new type of quantum matter, Dirac node line (DNL) semimetals are currently attracting widespread interest in condensed matter physics and materials science. The DNL, featured by a closed line consisting of linear band crossings in the momentum space, was mostly predicted in three-dimensional materials. Here, we propose a tight-binding (TB) model of pz + px,y or pz + s orbitals defined on the two-dimensional (2D) Lieb lattice for the 2D version of DNL semimetals. The DNL states in these models are caused by the inversion of the bands with different symmetries and thus robust against spin-orbit interaction. By means of first-principles calculations, we demonstrate two candidate materials: Be2C and BeH2 monolayers, which have Fermi circles centred at Γ(0,0) and K(1/2,1/2) points, respectively. Their Fermi velocities are higher than that in graphene. The non-zero Z2 topological invariant accompanied by the edge states is revealed in these materials. This work opens an avenue for the design of 2D DNL semimetals.


Diversity of algal endosymbionts (zooxanthellae) in octocorals: the roles of geography and host relationships.
The presence, genetic identity and diversity of algal endosymbionts (Symbiodinium) in 114 species from 69 genera (20 families) of octocorals from the Great Barrier Reef (GBR), the far eastern Pacific (EP) and the Caribbean was examined, and patterns of the octocoral-algal symbiosis were compared with patterns in the host phylogeny. Genetic analyses of the zooxanthellae were based on ribosomal DNA internal transcribed spacer 1 (ITS1) region. In the GBR samples, Symbiodinium clades A and G were encountered with A and G being rare. Clade B zooxanthellae have been previously reported from a GBR octocoral, but are also rare in octocorals from this region. Symbiodinium G has so far only been found in Foraminifera, but is rare in these organisms. In the Caribbean samples, only Symbiodinium clades B and C are present. Hence, Symbiodinium diversity at the level of phylogenetic clades is lower in octocorals from the Caribbean compared to those from the GBR. However, an unprecedented level of ITS1 diversity was observed within individual colonies of some Caribbean gorgonians, implying either that these simultaneously harbour multiple strains of clade B zooxanthellae, or that ITS1 heterogeneity exists within the genomes of some zooxanthellae. Intracladal diversity based on ITS should therefore be interpreted with caution, especially in cases where no independent evidence exists to support distinctiveness, such as ecological distribution or physiological characteristics. All samples from EP are azooxanthellate. Three unrelated GBR taxa that are described in the literature as azooxanthellate (Junceella fragilis, Euplexaura nuttingi and Stereonephthya sp. 1) contain clade G zooxanthellae, and their symbiotic association with zooxanthellae was confirmed by histology. These corals are pale in colour, whereas related azooxanthellate species are brightly coloured. The evolutionary loss or gain of zooxanthellae may have altered the light sensitivity of the host tissues, requiring the animals to adopt or reduce pigmentation. Finally, we superimposed patterns of the octocoral-algal symbiosis onto a molecular phylogeny of the host. The data show that many losses/gains of endosymbiosis have occurred during the evolution of octocorals. The ancestral state (azooxanthellate or zooxanthellate) in octocorals remains unclear, but the data suggest that on an evolutionary timescale octocorals can switch more easily between mixotrophy and heterotrophy compared to scleractinian corals, which coincides with a low reliance on photosynthetic carbon gain in the former group of organisms.


Revisiting the thrifty gene hypothesis via 65 loci associated with susceptibility to type 2 diabetes.
We have investigated the evidence for positive selection in samples of African, European, and East Asian ancestry at 65 loci associated with susceptibility to type 2 diabetes (T2D) previously identified through genome-wide association studies. Selection early in human evolutionary history is predicted to lead to ancestral risk alleles shared between populations, whereas late selection would result in population-specific signals at derived risk alleles. By using a wide variety of tests based on the site frequency spectrum, haplotype structure, and population differentiation, we found no global signal of enrichment for positive selection when we considered all T2D risk loci collectively. However, in a locus-by-locus analysis, we found nominal evidence for positive selection at 14 of the loci. Selection favored the protective and risk alleles in similar proportions, rather than the risk alleles specifically as predicted by the thrifty gene hypothesis, and may not be related to influence on diabetes. Overall, we conclude that past positive selection has not been a powerful influence driving the prevalence of T2D risk alleles.


Peripheral Blood Mitochondrial DNA Copy Number Obtained From Genome-Wide Genotype Data Is Associated With Neurocognitive Impairment in Persons With Chronic HIV Infection.
Mitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV. In the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders. Among 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P < 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P < 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance. Higher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction.


First Report of Bacterial Soft Rot on Tagetes patula Caused by Dickeya dieffenbachiae in China.
French marigold (Tagetes patula L.), originally from Mexico, is an annual herb widely planted in China because of its beautiful color, long flowering, and strong adaptability, and has been used widely for ornamentation and decorating. French marigold is also rich in patuletin, quercetagetin, and patulitrin, and is therefore applied medicinally for treating colds and coughs. In early summer 2012, soft rot symptoms on French marigold were found at three flower nurseries in Guangzhou, Guangdong Province, P. R. China, and approximately 25% of the plants had the symptoms. The symptoms included tissue collapse of the stems at the soil line followed by wilting of the whole plants. Within 1 week, the infected stems showed vascular discoloration, turned brown and then inky black, and eventually the whole plant collapsed after the basal stem was infected. Bacteria were successfully isolated from eight symptomatic plants on nutrient agar media incubated at 30°C for 48 h. Ten isolates were selected randomly for further characterization. They were gram negative, degraded pectate, negative for oxidase and positive for indole production, and utilized malonate, glucose, and sucrose but not glucopyranoside, trehalose, or palatinose. Polymerase chain reactions (PCR) were performed using the 16S primers 27f and 1495r (4) for molecular identification. Subsequent DNA sequencing showed that the representative tested strain TP1 (GenBank Accession No. JX575747) was 99% identical to that of Dickeya dieffenbachiae (JF419463) using BLASTn. Further genetic analysis of strain TP1 was performed targeting several housekeeping genes, i.e., dnaX (GenBank Accession No. JX575748) with primers dnaxf and dnaxr (3), gyrB (JX575749) with primers of gyrbf1 and gyrbr1 (1), and gapA (JX575750) with primers of gapa326f and gapa845r (2). They were most homologous to the sequences of D. dieffenbachiae, since they had 97%, 96%, and 97% identity with GenBank accessions GQ904794, JF311653, and GQ891968, respectively. Pathogenicity was confirmed by injecting all 10 original bacterial isolates into each of 10 French marigold seedlings, with approximately 100 μl of a bacterial suspension at 1 × 108 CFU/ml. Ten plants inoculated with 100 μl of sterile water served as controls. Plants were placed in a greenhouse at 30 to 32°C and 90% relative humidity. Within 48 h, soft rot symptoms appeared on all inoculated seedlings, while the control plants appeared normal. D. dieffenbachiae was reisolated from the diseased tissues, and confirmed to be the same as the inoculated pathogen by conducting a 16S rDNA sequence comparison. Previously, black spot, botrytis blight, oedema, powdery mildew, southern bacterial wilt, and damping off have been found on T. patula. To our knowledge, it is the first report of a soft rot caused by D. dieffenbachiae on French marigold. Because of the popularity and high economic value of French marigold, identification of this progressing bacterial disease is important to maintain safe production and beautiful scenery. References: (1) B. R. Lin et al. Plant Dis. 96:452, 2012. (2) S. Nabhan et al. Plant Pathol. 61:498, 2012. (3) M. Sławiak et al. Eur. J. Plant Pathol. 125:245, 2009. (4) W. G. Weisburg. J. Bacteriol. 173:697, 1991.


Cognitive behavioral therapy for misophonia: A randomized clinical trial.
Patients with misophonia suffer from anger or disgust confronted with specific sounds such as smacking or breathing. Avoidance of cue-related situations results in social isolation and significant functional impairment. This is the first randomized, controlled cognitive behavioral therapy (CBT) trial for misophonia, evaluating the short- and long-term efficacy. The evaluator-blinded, randomized clinical trial was conducted from May 2017 until December 2018 at an academic outpatient clinic. Misophonia patients were randomly assigned to 3 months of weekly group-CBT or a waiting list and tested at baseline, 3 months (following CBT or waiting list), 6 months (after cross-over), and 15/18 months (1-year follow-up). CBT consisted of task concentration and arousal reduction, positive affect labeling, and stimulus manipulation. Co-primary outcomes were symptom severity assessed by the Amsterdam Misophonia Scale-Revised (AMISOS-R) and improvement on the Clinical Global Impression-Improvement (CGI-I). Secondary outcomes were self-assessed ratings of general psychopathology (Symptom Checklist-90-Revised [SCL-90-R]) and quality of life (five-dimensional EuroQol [EQ5-D], Sheehan Disability Scale [SDS], WHO Quality of Life-BREF [WHOQoL-BREF]). In all, 54 out of 71 patients were included (mean age, 33.06 [SD, 14.13] years; 38 women [70.4%]) and 46 (85%) completed the study. In the randomized phase, CBT resulted in statistically significant less misophonia symptoms in the short-term (-9.7 AMISOS-R; 95% CI, -12.0 to -7.4; p < .001, d = 1.97). The CBT group had an observed clinical improvement (CGI-I < 3) in 37% compared to 0% in the waiting list group (p < .001). The effect of CBT was maintained at 1-year follow-up on primary and secondary outcomes. This first randomized control trial shows both short-term and long-term efficacy of CBT for misophonia.


Operative Treatment of Primary Hyperparathyroidism in Daycare Surgery.
The standard of care for primary hyperparathyroidism is surgical removal of hyperfunctional parathyroid tissue. Here, we describe 20 patients with primary hyperparathyroidism who were treated surgically in the setting of daycare surgery. Prospective observational study. A total of 20 patients with primary hyperparathyroidism were operated between March 2005 and May 2010. The follow-up period had a median of 41 weeks (5-245 weeks). Results are presented as mean (± standard deviation) or median (minimum-maximum). A total of 20 patients (15 women, mean age 54 ± 14 years) were included. Nine patients were provided with post-operative calcium supplementation. One of the patients visited the emergency department the next day with paresthesia and normocalcemia; this patient was sent home. Four patients, without prophylaxis, also reported themselves to the emergency department. Only one had mild hypocalcemia (2.09 mmol/L) and was supplemented. Comparing the emergency department group (n = 5) with the others, we found that pre-operative calcium levels were similar (p = 0.40); however, the emergency department group had significantly lower post-operative calcium levels (2.27 ± 0.14 vs 2.55 ± 0.25, p = 0.008) and the decrease-percentage was significantly higher (17.5% ± 5.4% vs 10.5% ± 6.4%, p = 0.21). Parathyroidectomy in the daycare setting is feasible and safe. However, many patients return to the emergency department. This could be related to the strict information that is provided or due to a large decrease in their calcium levels, albeit normocalcemia. Calcium supplementation is cheap and safe, so we will provide all future patients with calcium supplementation and herewith aim to reduce the amount of emergency department visits.


Universal Health Coverage for Schizophrenia: A Global Mental Health Priority.
The growing momentum towards a global consensus on universal health coverage, alongside an acknowledgment of the urgency and importance of a comprehensive mental health action plan, offers a unique opportunity for a substantial scale-up of evidence-based interventions and packages of care for a range of mental disorders in all countries. There is a robust evidence base testifying to the effectiveness of drug and psychosocial interventions for people with schizophrenia and to the feasibility, acceptability and cost-effectiveness of the delivery of these interventions through a collaborative care model in low resource settings. While there are a number of barriers to scaling up this evidence, for eg, the finances needed to train and deploy community based workers and the lack of agency for people with schizophrenia, the experiences of some upper middle income countries show that sustained political commitment, allocation of transitional financial resources to develop community services, a commitment to an integrated approach with a strong role for community based institutions and providers, and a progressive realization of coverage are the key ingredients for scale up of services for schizophrenia.


Assessment of Preference for Hormonal Treatment-Related Health States among Patients with Breast Cancer.
1) To obtain preference scores from patients with breast cancer in Singapore for different stages of breast cancer and hormonal therapy-related adverse effects, and 2) to determine the association of patients' demographic and clinical characteristics with those preference scores. A total of 22 health states were used to elicit preference values from 64 patients with breast cancer. At each interview, 14 health states were randomly selected and rated by the patient using the visual analogue scale and standard gamble methods to derive health state preference scores, which were recalibrated to the scale of 0 (death) and 1 (perfect health). Mean adjusted visual analogue scale scores ranged from 0.25 (no recurrence with ischemic cerebrovascular events) to 0.82 (no recurrence with no adverse effects). Mean adjusted standard gamble scores ranged from 0.31 (distant recurrence with chemotherapy-related adverse effects) to 0.80 (no recurrence with no adverse effects). Adverse effects ischemic cerebrovascular events and spine fracture resulted in the greatest decline in health state preference scores. Age, ethnicity, education level, and prior chemotherapy were associated with preference scores. Having children was not found to be associated with the preference scores. Taking into account disease progression and hormonal therapy-related adverse effects as well as their impact on health-related quality of life, this study quantifies patients' preference for various breast cancer-related health states. The findings offer valuable information for future cost-utility analysis of breast cancer treatments.


Scope of global health training in U.S. obstetrics and gynecology residency programs.
To enumerate global health training activities in U.S. obstetrics and gynecology residency programs and to examine the worldwide distribution of programmatic activity relative to the maternal and perinatal disease burden. Using a systematic, web-based protocol, we searched for global health training opportunities at all U.S. obstetrics and gynecology residency programs. Country-level data on disability-adjusted life-years resulting from maternal and perinatal conditions were obtained from the Global Burden of Disease study. We calculated Spearman's rank correlation coefficients to estimate the cross-country association between programmatic activity and disease burden. Of the 243 accredited U.S. obstetrics and gynecology residency programs, we identified 41 (17%) with one of several possible predefined categories of programmatic activity. Thirty-three residency programs offered their residents opportunities to participate in one or more elective-based rotations, eight offered extended field-based training, and 18 offered research activities. A total of 128 programmatic activities were dispersed across 64 different countries. At the country level, the number of programmatic activities had a statistically significant association with the total disease burden resulting from maternal (Spearman's ρ=0.37, 95% confidence interval [CI] 0.14-0.57) and perinatal conditions (ρ=0.34, 95% CI 0.10-0.54) but not gynecologic cancers (ρ=-0.24, 95% CI -0.46 to 0.01). There are few global health training opportunities for U.S. obstetrics and gynecology residents. These activities are disproportionately distributed among countries with greater burdens of disease. II.


Creatine transporter and mitochondrial creatine kinase protein content in myopathies.
Total creatine or phosphocreatine, or both, are reduced in the skeletal muscle of patients with inflammatory myopathy, mitochondrial myopathy, and muscular dystrophy/congenital myopathy. We used Western blotting techniques to measure skeletal muscle creatine transporter protein and sarcomeric mitochondrial creatine kinase (mtCK) protein content in patients with inflammatory myopathy (N = 8), mitochondrial myopathy (N = 5), muscular dystrophy (N = 7), and congenital myopathy (N = 3), as compared to a control group without a neuromuscular diagnosis (N = 8). Creatine transporter protein content was lower for all groups compared to control subjects (P < 0.05; P < 0.01 for congenital myopathy). Mitochondrial CK (mtCK) was lower for inflammatory myopathy (P < 0.05), higher for mitochondrial myopathy (P < 0.05), not different for muscular dystrophy, and markedly lower for the congenital myopathy group (P < 0.01), compared to control subjects. Together, these data suggest that the reduction in total creatine or phosphocreatine in patients with certain myopathies is correlated with creatine transporter and not mtCK protein content. This further supports the belief that creatine monohydrate supplementation may benefit patients with low muscle creatine stores, although the reduction in creatine transporter protein may have implications for dosing.


Mortality in patients with small choroidal melanoma. COMS report no. 4. The Collaborative Ocular Melanoma Study Group.
To describe the clinical characteristics and survival experience of a prospectively followed up group of patients with small choroidal melanoma. The Collaborative Ocular Melanoma Study (COMS) is a set of clinical trials designed to compare the role of radiotherapy and enucleation in the treatment of medium and large-size choroidal melanoma. From December 1986 to August 1989, patients with small choroidal melanoma, not large enough to be eligible for the COMS clinical trials, were offered participation in a nonrandomized prospective follow-up study. Small choroidal melanomas were defined as 1.0 to 3.0 mm in apical height and at least 5.0 mm in basal diameter. A total of 204 patients were enrolled in the study. Patients were followed up annually through August 1989. Two additional assessments of treatment status and mortality were conducted in 1993-1994 and 1995-1996. The median length of follow-up was 92 months. Eight percent of patients were treated at the time of study enrollment and an additional 33% were treated during follow-up. Twenty-seven patients have died; 6 deaths were reported by the clinical center as due to metastatic melanoma. The Kaplan-Meier estimate of 5-year all-cause mortality was 6.0% (95% confidence interval, 2.7%-9.3%) and 8-year all-cause mortality was 14.9% (95% confidence interval, 9.6%-20.2%). Otherwise healthy patients, average age of 60 years, without a previous diagnosis of malignant disease who have small choroidal lesions judged to be melanoma have a low risk of dying within 5 years.


Visualizing the coupling between red and blue stark states using photoionization microscopy.
In nonhydrogenic atoms in a dc electric field, the finite size of the ionic core introduces a coupling between quasibound Stark states that leads to avoided crossings between states that would otherwise cross. Near an avoided crossing, the interacting states may have decay amplitudes that cancel each other, decoupling one of the states from the ionization continuum. This well-known interference narrowing effect, observed as a strongly electric field-dependent decrease in the ionization rate, was previously observed in several atoms. Here we use photoionization microscopy to visualize interference narrowing in helium atoms, thereby explicitly revealing the mechanism by which Stark states decay. The interference narrowing allows measurements of the nodal patterns of red Stark states, which are otherwise not observable due to their intrinsic short lifetime.


Selecting the best performing fire weather indices for Austrian ecoregions.
The interpretation and communication of fire danger warning levels based on fire weather index values are critical for fire management activities. A number of different indices have been developed for various environmental conditions, and many of them are currently applied in operational warning systems. To select an appropriate combination of such indices to work in different ecoregions in mountainous, hilly and flat terrain is challenging. This study analyses the performance of a total of 22 fire weather indices and two raw meteorological variables to predict wildfire occurrence for different ecological regions of Austria with respect to the different characteristics in climate and fire regimes. A median-based linear model was built based on percentile results on fire days and non-fire days to get quantifiable measures of index performance using slope and intercept of an index on fire days. We highlight the finding that one single index is not optimal for all Austrian regions in both summer and winter fire seasons. The summer season (May-November) shows that the Canadian build-up index, the Keetch Byram Drought Index and the mean daily temperature have the best performance; in the winter season (December-April), the M68dwd is the best performing index. It is shown that the index performance on fire days where larger fires appeared is better and that the uncertainties related to the location of the meteorological station can influence the overall results. A proposal for the selection of the best performing fire weather indices for each Austrian ecoregion is made.