bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin initiation and renal impairment: a cohort study in Denmark and the UK
Authors: Christiansen Christian Fynbo , Ehrenstein Vera , Heide-Jørgensen Uffe , Skovbo Stine , Nørrelund Helene , Sørensen Henrik Toft , Li Lin , Jick Susan 
Published: September 2015

ObjectivesTo estimate prevalence of renal impairment, rate of decline in kidney function and changes in metformin use after decline in kidney function, in metformin initiators.Design, setting and participantsWe conducted this 2-country cohort study using routine data from northern Denmark and the UK during 2000–2011. We included metformin initiators among patients aged ≥30 years with medically treated diabetes.Main outcome measuresWe described patients’ demographics, comorbidity, co-medications and their estimated glomerular filtration rates (eGFR). Furthermore, we described the patients’ characteristics according to eGFR level. Finally, we examined the rate of any decline in eGFR and changes in metformin use within 90 days after first decline in eGFR during follow-up.ResultsWe included 124 720 metformin initiators in the 2 countries. Prevalence of eGFR <60 mL/min/1.73 m2among metformin initiators was 9.0% in Denmark and 25.2% in the UK. In contrast, prevalence of eGFR values <30 mL/min/1.73 m2among metformin initiators was 0.3% in Denmark and 0.4% in the UK. Patients with renal impairment were older and more likely to have received cardiovascular drugs. Incidence rate of decline in renal function was 4.92 per 100 person-years (95% CI 4.76 to 5.09) in Denmark and 7.48 per 100 person-years (95% CI 7.39 to 7.57) in the UK. The proportion of patients continuing metformin use, even after a first decline brought the eGFR below 30 mL/min/1.73 m2, was 44% in Denmark and 62% in the UK. There was no clinically significant dose reduction with decreasing baseline eGFR level discernible from the data.ConclusionsMild to moderate renal impairment was common among metformin initiators, while severe renal impairment was uncommon. Patients with severe renal impairment frequently continued receiving/redeeming metformin prescriptions even 90 days after eGFR decline.
After the Liverpool Care Pathway—development of heuristics to guide end of life care for people with dementia: protocol of the ALCP study
Authors: Davies N , Manthorpe J , Sampson E L , Iliffe S 
Published: September 2015

IntroductionEnd of life care guidance for people with dementia is lacking and this has been made more problematic in England with the removal of one of the main end of life care guidelines which offered some structure, the Liverpool Care Pathway. This guidance gap may be eased with the development of heuristics (rules of thumb) which offer a fast and frugal form of decision-making.ObjectiveTo develop a toolkit of heuristics (rules of thumb) for practitioners to use when caring for people with dementia at the end of life.Method and analysisA mixed-method study using a co-design approach to develop heuristics in three phases. In phase 1, we will conduct at least six focus groups with family carers, health and social care practitioners from both hospital and community care services, using the ‘think-aloud’ method to understand decision-making processes and to develop a set of heuristics. The focus group topic guide will be developed from the findings of a previous study of 46 interviews of family carers about quality end-of-life care for people with dementia and a review of the literature. A multidisciplinary development team of health and social care practitioners will synthesise the findings from the focus groups to devise and refine a toolkit of heuristics. Phase 2 will test the use of heuristics in practice in five sites: one general practice, one community nursing team, one hospital ward and two palliative care teams working in the community. Phase 3 will evaluate and further refine the toolkit of heuristics through group interviews, online questionnaires and semistructured interviews.Ethics and disseminationThis study has received ethical approval from a local NHS research ethics committee (Rec ref: 15/LO/0156). The findings of this study will be presented in peer-reviewed publications and national and international conferences.
Advance directives and end-of-life decisions in Switzerland: role of patients, relatives and health professionals
Authors: Pautex Sophie , Gamondi Claudia , Philippin Yves , Gremaud Grégoire , Herrmann François , Camartin Cristian , Vayne-Bossert Petra 
Published: September 2015

BackgroundLittle is known in Europe about end-of-life (EOL) decisions and advance directives (AD), particularly in patients with severe advanced disease. Switzerland is a multicultural and multilingual federal country and has the particularity of being divided into four linguistic and cultural regionsObjectiveTo understand better in different regions of Switzerland which specific patient's characteristics could have an impact on their decision to complete AD or not.Design/setting/participantsProspective study conducted in four palliative care units. Patients with an advanced oncological disease, fluent in French, German or Italian and with a Mini-Mental State Examination >20 were included. Demographic data, symptom burden (Edmonton Symptom Assessment System, ESAS; Hospital Anxiety and Depression Scale, HADS) and spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual well-being, FACIT-sp) have been assessed. A structured questionnaire has been completed by patients, their relatives and health professionals.Results143 patients were included (mean age 68.3 years; 62 male). 41 completed ADs. No particular features were associated with the completion of ADs. Most patients were satisfied with the medical information received. A third of them were not worrying about their future, especially those living in the German-speaking part. Should they become unable to communicate, 87 expected their relative to transmit their own wishes, but only 38 had spoken recently with them about what they wanted. 23 of the 69 included relatives would like to play a more active role in decision-making.ConclusionsThese results illustrate the fact that terminally ill patients wish to be active in decision-making, but only seldom transmit their wishes to their relative or complete a written document. The discussion about ACP should be defined according to the particularity of each region and the role of healthcare professionals’ attitudes towards ADs, but we should also be creative and find other ways to promote shared decision-making.
Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer
Authors: Shah Khyati N. , Wilson Elizabeth A. , Malla Ritu , Elford Howard L. , Faridi Jesika S. 
Published: September 2015

Abstract
Tamoxifen is widely used as an adjuvant therapy for patients with estrogen receptor (ERα)–positive tumors. However, the clinical benefit is often limited because of the emergence of drug resistance. In this study, overexpression of ribonucleotide reductase M2 (RRM2) in MCF-7 breast cancer cells resulted in a reduction in the effectiveness of tamoxifen, through downregulation of ERα66 and upregulation of the 36-kDa variant of ER (ERα36). We identified that NF-κB, HIF1α, and MAPK/JNK are the major pathways that are affected by RRM2 overexpression and result in increased NF-κB activity and increased protein levels of EGFR, HER2, IKKs, Bcl-2, RelB, and p50. RRM2-overexpressing cells also exhibited higher migratory and invasive properties. Through time-lapse microscopy and protein profiling studies of tamoxifen-treated MCF-7 and T-47D cells, we have identified that RRM2, along with other key proteins, is altered during the emergence of acquired tamoxifen resistance. Inhibition of RRM2 using siRRM2 or the ribonucleotide reductase (RR) inhibitor didox not only eradicated and effectively prevented the emergence of tamoxifen-resistant populations but also led to the reversal of many of the proteins altered during the process of acquired tamoxifen resistance. Because didox also appears to be a potent inhibitor of NF-κB activation, combining didox with tamoxifen treatment cooperatively reverses ER-α alterations and inhibits NF-κB activation. Finally, inhibition of RRM2 by didox reversed tamoxifen-resistant in vivo tumor growth and decreased in vitro migratory and invasive properties, revealing a beneficial effect of combination therapy that includes RRM2 inhibition to delay or abrogate tamoxifen resistance. Mol Cancer Ther; 14(11); 2411–21. ©2015 AACR.
Platelet microparticles reprogram macrophage gene expression and function
Authors: Rousseau Matthieu , Duchez Anne-Claire , Lee Chan Ho C. , Boilard Eric , Laffont Benoit , Corduan Aurélie , Provost Patrick 
Published: September 2015

SummaryPlatelet microparticles (MPs) represent the most abundant MPs subtype in the circulation, and can mediate intercellular communication through delivery of bioactives molecules, such as cytokines, proteins, lipids and RNAs. Here, we show that platelet MPs can be internalised by primary human macrophages and deliver functional miR-126–3p. The increase in macrophage miR-126–3p levels was not prevented by actinomycin D, suggesting that it was not due to de novo gene transcription. Platelet MPs dose-dependently downregulated expression of four predicted mRNA targets of miR-126–3p, two of which were confirmed also at the protein level. The mRNA downregulatory effects of platelet MPs were abrogated by expression of a neutralising miR-126–3p sponge, implying the involvement of miR-126–3p. Transcriptome-wide, microarray analyses revealed that as many as 66 microRNAs and 653 additional RNAs were significantly and differentially expressed in macrophages upon exposure to platelet MPs. More specifically, platelet MPs induced an upregulation of 34 microRNAs and a concomitant downregulation of 367 RNAs, including mRNAs encoding for cytokines/chemokines CCL4, CSF1 and TNF. These changes were associated with reduced CCL4, CSF1 and TNF cytokine/chemokine release by macrophages, and accompanied by a marked increase in their phagocytic capacity. These findings demonstrate that platelet MPs can modify the transcriptome of macrophages, and reprogram their function towards a phagocytic phenotype.Supplementary Material to this article is available online at www.thrombosis-online.com.
Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction
Authors: Pal Nikhil , Sivaswamy Nadiya , Mahmod Masliza , Yavari Arash , Rudd Amelia , Singh Satnam , Dawson Dana K. , Francis Jane M. , Dwight Jeremy S. , Watkins Hugh , Neubauer Stefan , Frenneaux Michael , Ashrafian Houman 
Published: September 2015

Background—
Heart failure with preserved ejection fraction (HFpEF) is associated with significant morbidity and mortality but is currently refractory to therapy. Despite limited evidence, heart rate reduction has been advocated, on the basis of physiological considerations, as a therapeutic strategy in HFpEF. We tested the hypothesis that heart rate reduction improves exercise capacity in HFpEF.

Methods and Results—

We conducted a randomized, crossover study comparing selective heart rate reduction with the
I
f
blocker ivabradine at 7.5 mg twice daily versus placebo for 2 weeks each in 22 symptomatic patients with HFpEF who had objective evidence of exercise limitation (peak oxygen consumption at maximal exercise [

o
2
peak] <80% predicted for age and sex). The result was compared with 22 similarly treated matched asymptomatic hypertensive volunteers. The primary end point was the change in

o
2
peak. Secondary outcomes included tissue Doppler–derived E/e′ at echocardiography, plasma brain natriuretic peptide, and quality-of-life scores. Ivabradine significantly reduced peak heart rate compared with placebo in the HFpEF (107 versus 129 bpm;
P
<0.0001) and hypertensive (127 versus 145 bpm;
P
=0.003) cohorts. Ivabradine compared with placebo significantly worsened the change in

o
2
peak in the HFpEF cohort (-2.1 versus 0.9 mL·kg
−1
·min
−1
;
P
=0.003) and significantly reduced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope. No significant effects on the secondary end points were discernable.

Conclusion—
Our observations bring into question the value of heart rate reduction with ivabradine for improving symptoms in a HFpEF population characterized by exercise limitation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02354573.
Li Bai’s “Rhapsody on the Hall of Light”: A Singular Vision of Cosmic Order
Authors: Morrow Williams Nicholas 
Published: September 2015

Li Bai’s “Rhapsody on the Hall of Light” offers a grand tour and exuberant depiction of the Mingtang, an edifice central to traditional theories of government and ritual. The poem has often been dismissed as belonging to the poet’s juvenilia, but more likely reflects the ambition and self-confidence of his youthful prime. It has also been viewed with suspicion because of the Mingtang’s associations with the inter­regnum of Empress Wu, but this only increases its interest for the modern reader. Comparison with its primary models, the epideictic fu of the Han dynasty, shows Li Bai’s ability to transform his sources. He inserts his own flourishes within the cosmic order that the Mingtang represents, while recasting the edifice as a symbol of his own creative prowess. The article concludes with the first complete English trans­lation of the “Rhapsody on the Hall of Light.” La “Rhapsodie du Palais de lumière” de Li Bai nous fait visiter un édifice jouant un rôle essentiel dans les théories traditionnelles du gouvernement et du rituel, le Mingtang, et en propose une description exubérante. Cette pièce a souvent été rejetée comme œuvre de jeunesse, alors qu’elle reflète plutôt l’ambition et l’assurance d’un jeune poète en pleine possession de ses moyens. La “Rhapsodie” a aussi été considérée avec suspicion en raison de l’association du Mingtang avec l’interrègne de l’impératrice Wu, alors que pour le lecteur moderne cela en accroît plutôt l’intérêt. La comparaison avec ses principaux modèles, les fu épidictiques de l’époque des Han, révèle la capacité de Li Bai à transmuer ses sources. Il intègre sa propre ornementation à l’ordre cosmique représenté par le Mingtang, tout en transformant l’édifice en un symbole de ses propres pouvoirs créatifs. L’article se conclut avec la première traduction intégrale de l’œuvre en anglais.
Failure Stories: Interpretations of Rejected Papers in the Late Imperial Civil Service Examinations
Authors: Chu Shiuon 
Published: September 2015

This article investigates the practice of returning marked papers to rejected candidates in late imperial Chinese examinations. The practice—common from the sixteenth century to the abolition of imperial examinations in 1905—established a sense of personal communication between examiners and examinees and was an opportunity for rejected candidates to benefit from the examination system. The failed papers returned to their authors enabled them to make sense of their performance by interpreting, when not misconstruing, examiners’ comments. The examiners sometimes praised the papers and blamed the decision to fail on other examiners. As a result, most rejected candidates tended not to challenge the examiners through official channels or take collective action against the examination system. Thus, in the late imperial examination system, the ways in which rejecting decisions could be negotiated and construed were no less important than the awarding of degrees to an extremely small proportion of participants. Cet article s’intéresse à la pratique, particulière à la période impériale tardive, consistant à rendre leurs copies aux candidats ayant échoué aux examens. Courante depuis le xvie siècle et jusqu’à l’abolition des examens mandarinaux en 1905, cette pratique créait l’impression d’une relation personnelle entre les examinateurs et les candidats et était un moyen pour ceux qui avaient échoué de tirer profit du système. Les copies rejetées retournées à leurs auteurs permettaient à ces derniers de donner un sens à leur performance en interprétant, voire en dévoyant, les commentaires des examinateurs. Il arrivait que les examinateurs fassent l’éloge des copies et attribuent à autrui la décision de les rejeter. De ce fait, la plupart des candidats malheureux évitaient de contester les examinateurs par la voie réglementaire ou de manifester collectivement contre le système. Ainsi, dans le système des examens à la fin de la période impériale, la manière dont les décisions négatives pouvaient être négociées ou interprétées n’était pas moins importante que l’attribution de rangs académiques à une toute petite proportion de ceux qui concouraient.
Morocco: An Islamic Globalizing Monarchy within the Elusive Phenomenon of Arab Spring
Authors: Alicino Francesco 
Published: September 2015

Far from taking place in a vacuum, in Morocco the 2011 constitutional revision was assessed both from an internal political perspective and within the broader context of what has come to be called the ‘Arab Spring’. In this manner, the 2011 Moroccan Constitution has indeed marked an unprecedented change, declaring the State’s adherence to the protection of human rights, which are strictly related to the Western history of ‘secular constitutionalism’. Yet, in order to better understand the constitutional transition, one has to consider the religious characteristic of Moroccan monarchy which, on the other hand, makes it a prototype of a ‘globalizing monarchy’, especially within the context ofmena(Middle East and Nord African) region.The Moroccan constitutional transition can in fact be seen as a peculiar tool for taking into account endogenous and exogenous factors respectively. On the one hand, it allows us to investigate how an Islamic specific legal tradition interacts with some principles that represent the pillars of constitutional democracies and that, as such, have been universally recognised; at least in the West. On the other, the exceptionalism of ‘Moroccan spring’ lets us to evaluate how these very principles are contextualized in a peculiar context ofmenaregion; by which, for the same reasons, one can draw more general considerations concerning the relationship between the pressing process of globalization and post-colonial Muslim-majority States.
The Effects of Gridding Algorithms on the Statistical Moments and Their Trends of Daily Surface Air Temperature*
Authors: Cavanaugh Nicholas R. , Shen Samuel S. P. 
Published: September 2015

Abstract
This paper explores the effects from averaging weather station data onto a grid on the first four statistical moments of daily minimum and maximum surface air temperature (SAT) anomalies over the entire globe. The Global Historical Climatology Network–Daily (GHCND) and the Met Office Hadley Centre GHCND (HadGHCND) datasets from 1950 to 2010 are examined. The GHCND station data exhibit large spatial patterns for each moment and statistically significant moment trends from 1950 to 2010, indicating that SAT probability density functions are non-Gaussian and have undergone characteristic changes in shape due to decadal variability and/or climate change. Comparisons with station data show that gridded averages always underestimate observed variability, particularly in the extremes, and have altered moment trends that are in some cases opposite in sign over large geographic areas. A statistical closure approach based on the quasi-normal approximation is taken to explore SAT’s higher-order moments and point correlation structure. This study focuses specifically on relating variability calculated from station data to that from gridded data through the moment equations for weighted sums of random variables. The higher-order and nonlinear spatial correlations up to the fourth order demonstrate that higher-order moments at grid scale can be determined approximately by functions of station pair correlations that tend to follow the usual Kolmogorov scaling relation. These results can aid in the development of constraints to reduce uncertainties in climate models and have implications for studies of atmospheric variability, extremes, and climate change using gridded observations.
Evaluation of 22 Precipitation and 23 Soil Moisture Products over a Semiarid Area in Southeastern Arizona*
Authors: Stillman Susan , Zeng Xubin , Bosilovich Michael G. 
Published: September 2015

Abstract
Precipitation and soil moisture are rigorously measured or estimated from a variety of sources. Here, 22 precipitation and 23 soil moisture products are evaluated against long-term daily observed precipitation (Pobs) and July–September daily observationally constrained soil moisture (SM) datasets over a densely monitored 150 km2 watershed in southeastern Arizona, United States. Gauge–radar precipitation products perform best, followed by reanalysis and satellite products, and the median correlations of annual precipitation from these three categories with Pobs are 0.83, 0.68, and 0.46, respectively. Precipitation results from phase 5 of the Coupled Model Intercomparison Project (CMIP5) are the worst, including an overestimate of cold season precipitation and a lack of significant correlation of annual precipitation with Pobs from all (except one) models. Satellite soil moisture products perform best, followed by land data assimilation systems and reanalyses, and the CMIP5 results are the worst. For instance, the median unbiased root-mean-square difference (RMSD) values of July–September soil moisture compared with SM are 0.0070, 0.011, 0.014, and 0.029 m3 m−3 for these four product categories, respectively. All 17 (except 3) precipitation [17 (except 2) soil moisture] products with at least 20 years of data agree with Pobs (SM) without significant trends. The uncertainties associated with the scale mismatch between Pobs and coarser-resolution products are addressed using two 4-km gauge–radar precipitation products, and their impact on the results presented in this study is overall small. These results identify strengths and weaknesses of each product for future improvement; they also emphasize the importance of using multiple gauge–radar and satellite products along with their uncertainties in evaluating reanalyses and models.
Strongly Coupled Data Assimilation Using Leading Averaged Coupled Covariance (LACC). Part II: CGCM Experiments*
Authors: Lu Feiyu , Liu Zhengyu , Zhang Shaoqing , Liu Yun , Jacob Robert 
Published: September 2015

Abstract
This paper uses a fully coupled general circulation model (CGCM) to study the leading averaged coupled covariance (LACC) method in a strongly coupled data assimilation (SCDA) system. The previous study in a simple coupled climate model has shown that, by calculating the coupled covariance using the leading averaged atmospheric states, the LACC method enhances the signal-to-noise ratio and improves the analysis quality of the slow model component compared to both the traditional weakly coupled data assimilation without cross-component adjustments (WCDA) and the regular SCDA using the simultaneous coupled covariance (SimCC).
Here in Part II, the LACC method is tested with a CGCM in a perfect-model framework. By adding the observational adjustments from the low-level atmosphere temperature to the sea surface temperature (SST), the SCDA using LACC significantly reduces the SST error compared to WCDA over the globe; it also improves from the SCDA using SimCC, which performs better than the WCDA only in the deep tropics. The improvement in SST analysis is a result of the enhanced signal-to-noise ratio in the LACC method, especially in the extratropical regions. The improved SST analysis also benefits the subsurface ocean temperature and low-level atmosphere temperature analyses through dynamic and statistical processes.