A pragmatic cluster randomized controlled trial of early intervention for chronic obstructive pulmonary disease by practice nurse-general practitioner teams : Study Protocol

Background: Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of disability, hospitalization, and premature mortality. General practice is well placed to diagnose and manage COPD, but there is a significant gap between evidence and current practice, with a low level of awareness and implementation of clinical practice guidelines. Under-diagnosis of COPD is a world-wide problem, limiting the benefit that could potentially be achieved through early intervention strategies such as smoking cessation, dietary advice, and exercise. General practice is moving towards more structured chronic disease management, and the increasing involvement of practice nurses in delivering chronic care. Design: A pragmatic cluster randomised trial will test the hypothesis that intervention by a practice nurse-general practitioner (GP) team leads to improved health-related quality of life and greater adherence with clinical practice guidelines for patients with newly-diagnosed COPD, compared with usual care. Forty general practices in greater metropolitan Sydney Australia will be recruited to identify patients at risk of COPD and invite them to attend a case finding appointment. Practices will be randomised to deliver either practice nurse-GP partnership care, or usual care, to patients newly-diagnosed with COPD. The active intervention will involve the practice nurse and GP working in partnership with the patient in developing and implementing a care plan involving (as appropriate), smoking cessation, immunisation, pulmonary rehabilitation, medication review, assessment and correction of inhaler technique, nutritional advice, management of psycho-social issues, patient education, and management of co-morbidities. The primary outcome measure is health-related quality of life, assessed with the St George’s Respiratory Questionnaire 12 months after diagnosis. Secondary outcome measures include validated disease-specific and general health related quality of life measures, smoking and immunisation status, medications, inhaler technique, and lung function. Outcomes will be assessed by project officers blinded to patients’ randomization groups. Discussion: This study will use proven case-finding methods to identify patients with undiagnosed COPD in general practice, where improved care has the potential for substantial benefit in health and healthcare utilization. The study provides the capacity to trial a new model of team-based assessment and management of newly diagnosed COPD in Australian primary care

The role of TcdB and TccC subunits in secretion of the photorhabdus Tcd toxin complex

The Toxin Complex (TC) is a large multi-subunit toxin encoded by a range of bacterial pathogens. The best-characterized examples are from the insect pathogens Photorhabdus, Xenorhabdus and Yersinia. They consist of three large protein subunits, designated A, B and C that assemble in a 5:1:1 stoichiometry. Oral toxicity to a range of insects means that some have the potential to be developed as pest control technology. The three subunit proteins do not encode any recognisable export sequences and as such little progress has been made in understanding their secretion. We have developed heterologous TC production and secretion models in E. coli and used them to ascribe functions to different domains of the crucial B+C sub-complex. We have determined that the B and C subunits use a secretion mechanism that is either encoded by the proteins themselves or employ an as yet undefined system common to laboratory strains of E. coli. We demonstrate that both the N-terminal domains of the B and C subunits are required for secretion of the whole complex. We propose a model whereby the N-terminus of the C-subunit toxin exports the B+C sub-complex across the inner membrane while that of the B-subunit allows passage across the outer membrane. We also demonstrate that even in the absence of the B-subunit, that the C-subunit can also facilitate secretion of the larger A-subunit. The recognition of this novel export system is likely to be of importance to future protein secretion studies. Finally, the identification of homologues of B and C subunits in diverse bacterial pathogens, including Burkholderia and Pseudomonas, suggests that these toxins are likely to be important in a range of different hosts, including man

Supersymmetric Charged Clouds in AdS_5

We consider supersymmetric holographic flows that involve background gauge fields dual to chemical potentials in the boundary field theory. We use a consistent truncation of gauged N=8 supergravity in five dimensions and we give a complete analysis of the supersymmetry conditions for a large family of flows. We examine how the well-known supersymmetric flow between two fixed points is modified by the presence of the chemical potentials and this yields a new, completely smooth, solution that interpolates between two global AdS spaces of different radii and with different values of the chemical potential. We also examine some black-hole-like singular flows and a new non-supersymmetric black hole solution. We comment on the interpretation of our new solutions in terms of giant gravitons and discuss the implications of our work for finding black-hole solutions in AdS geometries.Comment: 31 pages, 6 figures; minor corrections, updated reference

A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele

Orofacial clefts, including cleft lip and palate (CL/P), and neural tube defects (NTDs) are among the most common congenital anomalies but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesised that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) not only causes spinal NTDs in Axial defects (Axd) mice, but also multiple additional defects affecting the cranial region. These include orofacial clefts comprising midline cleft lip and palate, abnormalities of the craniofacial bones and frontal and/or basal encephalocele, in which brain tissue herniates through the cranium or into the nasal cavity. To investigate the causative mutation in the Grhl2Axd strain, whole genome sequencing identified an approximately 4 kb LTR retrotransposon insertion which disrupts the non-coding regulatory region, lying approximately 300 base pairs upstream of the 5' UTR. This insertion also lies within a predicted long non-coding RNA, oriented on the reverse strand, which like Grhl2 is over-expressed in Axd (Grhl2Axd) homozygous mutant embryos. Initial analysis of the GRHL2 upstream region in individuals with NTDs or cleft palate revealed rare or novel variants in a small number of cases. We hypothesise that mutations affecting the regulation of GRHL2 may contribute to craniofacial anomalies and NTDs in humans

Do ResearchGate Scores create ghost academic reputations?

[EN] The academic social network site ResearchGate (RG) has its own indicator, RG Score, for its members. The high profile nature of the site means that the RG Score may be used for recruitment, promotion and other tasks for which researchers are evaluated. In response, this study investigates whether it is reasonable to employ the RG Score as evidence of scholarly reputation. For this, three different author samples were investigated. An outlier sample includes 104 authors with high values. A Nobel sample comprises 73 Nobel winners from Medicine and Physiology, Chemistry, Physics and Economics (from 1975 to 2015). A longitudinal sample includes weekly data on 4 authors with different RG Scores. The results suggest that high RG Scores are built primarily from activity related to asking and answering questions in the site. In particular, it seems impossible to get a high RG Score solely through publications. Within RG it is possible to distinguish between (passive) academics that interact little in the site and active platform users, who can get high RG Scores through engaging with others inside the site (questions, answers, social networks with influential researchers). Thus, RG Scores should not be mistaken for academic reputation indicators.Alberto Martin-Martin enjoys a four-year doctoral fellowship (FPU2013/05863) granted by the Ministerio de Educacion, Cultura, y Deporte (Spain). Enrique Orduna-Malea holds a postdoctoral fellowship (PAID-10-14), from the Polytechnic University of Valencia (Spain).Orduña Malea, E.; Martín-Martín, A.; Thelwall, M.; Delgado-López-Cózar, E. (2017). Do ResearchGate Scores create ghost academic reputations?. Scientometrics. 112(1):443-460. https://doi.org/10.1007/s11192-017-2396-9S4434601121Bosman, J. & Kramer, B. (2016). Innovations in scholarly communication—data of the global 2015–2016 survey. Available at: http://zenodo.org/record/49583 #. Accessed December 11, 2016.González-Díaz, C., Iglesias-García, M., & Codina, L. (2015). Presencia de las universidades españolas en las redes sociales digitales científicas: Caso de los estudios de comunicación. El profesional de la información, 24(5), 1699–2407.Goodwin, S., Jeng, W., & He, D. (2014). Changing communication on ResearchGate through interface updates. Proceedings of the American Society for Information Science and Technology, 51(1), 1–4.Hicks, D., Wouters, P., Waltman, L., de Rijcke, S., & Rafols, I. (2015). The Leiden Manifesto for research metrics. Nature, 520(7548), 429–431.Hoffmann, C. P., Lutz, C., & Meckel, M. (2015). A relational altmetric? Network centrality on ResearchGate as an indicator of scientific impact. Journal of the Association for Information Science and Technology, 67(4), 765–775.Jiménez-Contreras, E., de Moya Anegón, F., & Delgado López-Cózar, E. (2003). The evolution of research activity in Spain: The impact of the National Commission for the Evaluation of Research Activity (CNEAI). Research Policy, 32(1), 123–142.Jordan, K. (2014a). Academics’ awareness, perceptions and uses of social networking sites: Analysis of a social networking sites survey dataset (December 3, 2014). Available at: http://dx.doi.org/10.2139/ssrn.2507318 . Accessed December 11, 2016.Jordan, K. (2014b). Academics and their online networks: Exploring the role of academic social networking sites. First Monday, 19(11). Available at: http://dx.doi.org/10.5210/fm.v19i11.4937 . Accessed December 11, 2016.Jordan, K. (2015). Exploring the ResearchGate score as an academic metric: reflections and implications for practice. Quantifying and Analysing Scholarly Communication on the Web (ASCW’15), 30 June 2015, Oxford. Available at: http://ascw.know-center.tugraz.at/wp-content/uploads/2015/06/ASCW15_jordan_response_kraker-lex.pdf . Accessed December 11, 2016.Kadriu, A. (2013). Discovering value in academic social networks: A case study in ResearchGate. Proceedings of the ITI 2013—35th Int. Conf. on Information Technology Interfaces Information Technology Interfaces, pp. 57–62.Kraker, P. & Lex, E. (2015). A critical look at the ResearchGate score as a measure of scientific reputation. Proceedings of the Quantifying and Analysing Scholarly Communication on the Web workshop (ASCW’15), Web Science conference 2015. Available at: http://ascw.know-center.tugraz.at/wp-content/uploads/2016/02/ASCW15_kraker-lex-a-critical-look-at-the-researchgate-score_v1-1.pdf . Accessed December 11, 2016.Li, L., He, D., Jeng, W., Goodwin, S. & Zhang, C. (2015). Answer quality characteristics and prediction on an academic Q&A Site: A case study on ResearchGate. Proceedings of the 24th International Conference on World Wide Web Companion, pp. 1453–1458.Martín-Martín, A., Orduna-Malea, E., Ayllón, J. M. & Delgado López-Cózar, E. (2016). The counting house: measuring those who count. Presence of Bibliometrics, Scientometrics, Informetrics, Webometrics and Altmetrics in the Google Scholar Citations, ResearcherID, ResearchGate, Mendeley & Twitter. Available at: https://arxiv.org/abs/1602.02412 . Accessed December 11, 2016.Martín-Martín, A., Orduna-Malea, E. & Delgado López-Cózar, E. (2016). The role of ego in academic profile services: Comparing Google Scholar, ResearchGate, Mendeley, and ResearcherID. Researchgate, Mendeley, and Researcherid. The LSE Impact of Social Sciences blog. Available at: http://blogs.lse.ac.uk/impactofsocialsciences/2016/03/04/academic-profile-services-many-mirrors-and-faces-for-a-single-ego . Accessed December 11, 2016.Matthews, D. (2016). Do academic social networks share academics’ interests?. Times Higher Education. Available at: https://www.timeshighereducation.com/features/do-academic-social-networks-share-academics-interests . Accessed December 11, 2016.Memon, A. R. (2016). ResearchGate is no longer reliable: leniency towards ghost journals may decrease its impact on the scientific community. Journal of the Pakistan Medical Association, 66(12), 1643–1647.Mikki, S., Zygmuntowska, M., Gjesdal, Ø. L. & Al Ruwehy, H. A. (2015). Digital presence of norwegian scholars on academic network sites-where and who are they?. Plos One 10(11). Available at: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142709 . Accessed December 11, 2016.Nicholas, D., Clark, D., & Herman, E. (2016). ResearchGate: Reputation uncovered. Learned Publishing, 29(3), 173–182.Orduna-Malea, E., Martín-Martín, A., & Delgado López-Cózar, E. (2016). The next bibliometrics: ALMetrics (Author Level Metrics) and the multiple faces of author impact. El profesional de la información, 25(3), 485–496.Ortega, Jose L. (2015). Relationship between altmetric and bibliometric indicators across academic social sites: The case of CSIC’s members. Journal of informetrics, 9(1), 39–49.Ortega, Jose L. (2016). Social network sites for scientists. Cambridge: Chandos.Ovadia, S. (2014). ResearchGate and Academia. edu: Academic social networks. Behavioral & Social Sciences Librarian, 33(3), 165–169.Thelwall, M., & Kousha, K. (2015). ResearchGate: Disseminating, communicating, and measuring Scholarship? Journal of the Association for Information Science and Technology, 66(5), 876–889.Thelwall, M. & Kousha, K. (2017). ResearchGate articles: Age, discipline, audience size and impact. Journal of the Association for Information Science and Technology, 68(2), 468–479.Van Noorden, R. (2014). Online collaboration: Scientists and the social network. Nature, 512(7513), 126–129.Wilsdon, J., Allen, L., Belfiore, E., Campbell, P., Curry, S., Hill, S. et al. (2015). The Metric Tide: Independent Review of the Role of Metrics in Research Assessment and Management. HEFCE. Available at: http://doi.org/10.13140/RG.2.1.4929.1363 . Accessed December 11, 2016

Real-world tyrosine kinase inhibitor treatment pathways, monitoring patterns and responses in patients with chronic myeloid leukaemia in the United Kingdom: the UK TARGET CML study.

Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Mimicry of Food Intake: The Dynamic Interplay between Eating Companions

Numerous studies have shown that people adjust their intake directly to that of their eating companions; they eat more when others eat more, and less when others inhibit intake. A potential explanation for this modeling effect is that both eating companions' food intake becomes synchronized through processes of behavioral mimicry. No study, however, has tested whether behavioral mimicry can partially account for this modeling effect. To capture behavioral mimicry, real-time observations of dyads of young females having an evening meal were conducted. It was assessed whether mimicry depended on the time of the interaction and on the person who took the bite. A total of 70 young female dyads took part in the study, from which the total number of bites (N = 3,888) was used as unit of analyses. For each dyad, the total number of bites and the exact time at which each person took a bite were coded. Behavioral mimicry was operationalized as a bite taken within a fixed 5-second interval after the other person had taken a bite, whereas non-mimicked bites were defined as bites taken outside the 5-second interval. It was found that both women mimicked each other's eating behavior. They were more likely to take a bite of their meal in congruence with their eating companion rather than eating at their own pace. This behavioral mimicry was found to be more prominent at the beginning than at the end of the interaction. This study suggests that behavioral mimicry may partially account for social modeling of food intake

Laboratory prediction of the requirement for renal replacement in acute falciparum malaria

BACKGROUND: Acute renal failure is a common complication of severe malaria in adults, and without renal replacement therapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation may increase mortality. Earlier identification of patients who will need RRT may improve outcomes. METHOD: Prospectively collected data from two intervention studies in adults with severe malaria were analysed focusing on laboratory features on presentation and their association with a later requirement for RRT. In particular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are used in other settings were examined. RESULTS: Data from 163 patients were available for analysis. Whether or not the patients should have received RRT (a retrospective assessment determined by three independent reviewers) was used as the reference. Forty-three (26.4%) patients met criteria for dialysis, but only 19 (44.2%) were able to receive this intervention due to the limited availability of RRT. Patients with impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had their laboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROC curve (AUC): 0.83 (95% confidence interval 0.74-0.92), significantly better than the AUCs for, urinary sodium level, the urea to creatinine ratio (UCR), the fractional excretion of urea (FeUN) and the urinary neutrophil gelatinase-associated lipocalcin (NGAL) level. The AUC for plasma creatinine was also greater than the AUC for blood urea nitrogen level, the fractional excretion of sodium (FeNa), the renal failure index (RFI), the urinary osmolality, the urine to plasma creatinine ratio (UPCR) and the creatinine clearance, although the difference for these variables did not reach statistical significance. CONCLUSIONS: In adult patients with severe malaria and impaired renal function on admission, none of the evaluated laboratory indices was superior to the plasma creatinine level when used to predict a later requirement for renal replacement therapy

Minimal Holographic Superconductors from Maximal Supergravity

We study a truncation of four-dimensional maximal gauged supergravity that provides a realization of the minimal model of a holographic superconductor. We find various flow solutions in this truncation at zero and finite temperature with a non-trivial profile for the charged scalar. Below a critical temperature we find holographic superconductor solutions that represent the thermodynamically preferred phase. Depending on the choice of boundary conditions, the superconducting phase transition is either first or second order. For vanishing temperature we find a flow with a condensing charged scalar that interpolates between two perturbatively stable AdS_4 vacua and is the zero-temperature ground state of the holographic superconductor.Comment: 25 pages, 9 figure