bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation and management of patients with acute chest pain in China (EMPACT): protocol for a prospective, multicentre registry study
Authors: Zheng Wen , Wang Jiali , Xu Feng , Zheng Jiaqi , Zhang He , Ma Jingjing , Wang Guangmei , Wang Hao , Chew Derek P , Chen Yuguo 
Published: January 2018

IntroductionAcute chest pain represents a major healthcare burden in emergency departments (ED) throughout the world. Among these patients, rapidly determining whether an acute coronary syndrome (ACS) is evolving remains difficult. In China, there are limited data correlating the baseline characteristics, evaluation and management of ED patients with acute chest pain and ACS-related symptoms with clinical outcomes. Nor has there been an evaluation of outcomes at different levels of hospitals. The Evaluation and Management of Patients with Acute ChesT pain in China (EMPACT) study will address this evidence gap through a regional representative prospective registry.Methods and analysisTwenty-two public hospitals with ED in Shandong province have been selected based on a stratified random sampling approach. A total of 10 000 patients with acute chest pain or suspected ACS presenting to the ED will be consecutively enrolled from January 2016 to September 2017. Episodes of care will be evaluated for key performance measures such as the time to first ECG, receipt of troponin testing, receipt of reperfusion therapy for ST segment elevation ACS and provision of angiography for troponin-positive patients. All patients will be assessed for the composite endpoint of adjudicated major adverse cardiac events in 30 days after presentation, including death from all causes, non-fatal myocardial infarction, urgent revascularisation, stroke, cardiac arrest and cardiogenic shock. The secondary outcomes include revisit to ED and rehospitalisation within 30 days.Ethics and disseminationEthics approval was obtained at all participating centres. The registry is the first attempt to comprehensively evaluate the current emergency care of acute chest pain from a regional representative sample in China. Findings will allow new opportunities to facilitate the clinical quality improvements and ultimately reduce the mortality in patients with acute chest pain and suspected ACS.Trial registration numberNCT02536677; Pre-results.
Incremental predictive value of screening for anxiety and depression beyond current type 2 diabetes risk models: a prospective cohort study
Authors: Atlantis Evan , Ghassem Pour Shima , Girosi Federico 
Published: January 2018

ObjectivesWe sought to determine whether screening for anxiety and depression, an emerging risk factor for type 2 diabetes (T2D), adds clinically meaningful information beyond current T2D risk assessment tools.DesignProspective cohort.Participants and settingThe 45 and Up Study is a large-scale prospective cohort of men and women aged 45 years and over, randomly sampled from the general population of New South Wales, Australia. 51 588 participants without self-reported diabetes at baseline (2006–2009) were followed up for approximately 3 years (2010).MethodsT2D status was determined by self-reported doctor who diagnosed diabetes after the age of 30 years, and/or current use of metformin. Current symptoms of anxiety and/or depression were measured by the 10-item Kessler Psychological Distress Scale (K10). We determined the optimal cut-off point for K10 for predicting T2D using Tjur’s R2 and tested risk models with and without the K10 using logistic regression. We assessed performance measures for the incremental value of the K10 using the area under the receiver operating characteristic (AROC), net reclassification improvement (NRI) and net benefit (NB) decision analytics with sensitivity analyses.ResultsT2D developed in 1076 individuals (52.4% men). A K10 score of ≥19 (prevalence 8.97%), adjusted for age and gender, was optimal for predicting incident T2D (sensitivity 77%, specificity 53% and positive predictive value 3%; OR 1.70 (95% CI 1.41 to 2.03, P<0.001). K10 score predicted incident T2D independent of current risk models, but did not improve corresponding AROC, NRI and NB statistics. Sensitivity analyses showed that this was partially explained by the baseline model and the small effect size of the K10 that was similar compared with other risk factors.ConclusionsAnxiety and depressing screening with the K10 adds no meaningful incremental value in addition to current T2D risk assessments. The clinical importance of anxiety and depression screening in preventing T2D requires ongoing consideration.
Inversed relationship between completeness of follow-up and coverage of postoperative complications in gallstone surgery and ERCP: a potential source of bias in patient registers
Authors: Enochsson Lars , Blohm My , Sandblom Gabriel , Jonas Eduard , Hallerbäck Bengt , Lundell Lars , Österberg Johanna 
Published: January 2018

ObjectiveTo analyse the completeness in GallRiks of the follow-up frequency in relation to the intraoperative and postoperative outcome.DesignPopulation-based register study.SettingData from the national Swedish Registry for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (ERCP), GallRiks.PopulationAll cholecystectomies and ERCPs recorded in GallRiks between 1 January 2006 and 31 December 2014.Main outcome measuresOutcomes for intraprocedural as well as postprocedural adverse events between units with either a 30-day follow-up of ≥90% compared with those with a less frequent follow-up (<90%).ResultsBetween 2006 and 2014, 162 212 cholecystectomies and ERCP procedures were registered in GallRiks. After the exclusion of non-index procedures and those with incomplete data 152 827 procedures remained for final analyses. In patients having a cholecystectomy, there were no differences regarding the adverse event rates, irrespective of the follow-up frequency. However, in the more complicated endoscopic ERCP procedures, the postoperative adverse event rates were significantly higher in those with a more frequent and complete 30-day follow-up (OR 1.92; 95% CI 1.76 to 2.11).ConclusionsDifferences in the follow-up frequency in registries affect the reported outcomes as exemplified by the complicated endoscopic ERCP procedures. A high and complete follow-up rate shall serve as an additional quality indicator for surgical registries.
Does vitamin D supplementation improve bone density in vitamin D-deficient children? Protocol for an individual patient data meta-analysis
Authors: Winzenberg Tania , Lamberg-Allardt Christel , El-Hajj Fuleihan Ghada , Mølgaard Christian , Zhu Kun , Wu Feitong , Riley Richard D 
Published: January 2018

IntroductionOur previous study-level (aggregate data) meta-analysis suggested that vitamin D supplements may be beneficial for bone density specifically in children with vitamin D deficiency. However, the misclassification of vitamin D status inherent in study-level data means that the results are not definitive and cannot provide an accurate assessment of the size of any effect. Therefore, we propose to undertake an individual patient data (IPD) meta-analysis to determine whether the effect of vitamin D supplementation on bone density in children differs according to baseline vitamin D status, and to specifically estimate the effect of vitamin D in children who are vitamin D deficient.Methods and analysisThis study has been designed to adhere to the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement. We will include randomised placebo-controlled trials of vitamin D supplementation reporting bone density outcomes at least 6 months after the study commenced in children and adolescents (aged <20 years) without coexistent medical conditions or treatments causing osteoporosis. We will update the search of the original review to cover the period 2009–2017, using the same methods as the original review. Fully anonymised data on all randomised patients will be requested. Outcomes will be femoral neck, total hip, lumbar spine and proximal and distal forearm bone mineral density, and total body bone mineral content. A two-stage IPD meta-analysis will be used to examine the effect of baseline serum 25-hydroxyvitamin D (25(OH)D) on treatment effect for each bone density outcome. Restricted maximum likelihood will be used to estimate the random-effects meta-analysis models, with 95% CI for summary effects. Heterogeneity will be assessed by I2and potential publication bias (small-study effects) and availability bias by funnel plots, Egger’s test and Peter’s test.Ethics and disseminationEthics approval will not be required as the data are to be used for the primary purpose for which they were collected and all original individual studies had ethics approval. Results of the IPD meta-analysis will be submitted for publication in a peer-reviewed journal.PROSPERO registration numberCRD42017068772.
Investigation assessing the publicly available evidence supporting postmarketing withdrawals, revocations and suspensions of marketing authorisations in the EU since 2012
Authors: Lane Samantha , Lynn Elizabeth , Shakir Saad 
Published: January 2018

ObjectivesTo assess the sources of publicly available evidence supporting withdrawal, revocation or suspension of marketing authorisations (‘regulatory actions’) due to safety reasons in the EU since 2012 and to investigate the time taken since initial marketing authorisation to reach these regulatory decisions.SettingThis investigation examined the sources of evidence supporting 18 identified prescription medicinal products which underwent regulatory action due to safety reasons within the EU in the period 1 July 2012 to 31 December 2016.ResultsEighteen single or combined active substances (‘medicinal products’) withdrawn, revoked or suspended within the EU for safety reasons between 2012 and 2016 met the inclusion criteria. Case reports were most commonly cited, supporting 94.4% of regulatory actions (n=17), followed by randomised controlled trial, meta-analyses, animal and in vitro, ex vivo or in silico study designs, each cited in 72.2% of regulatory actions (n=13). Epidemiological study designs were least commonly cited (n=8, 44.4%). Multiple sources of evidence contributed to 94.4% of regulatory decisions (n=17). Death was the most common adverse drug reaction leading to regulatory action (n=5; 27.8%), with four of these related to medication error or overdose. Median (IQR) time taken to reach a decision from the start of regulatory review was found to be 204.5 days (143, 535 days) and decreased across the study period. Duration of marketing prior to regulatory action, from the medicinal product’s authorisation date, increased across the period 2012–2016.ConclusionsThe sources of evidence supporting pharmacovigilance regulatory activities appear to have changed since implementation of Directive 2010/84/EU and Regulation (EU) No. 1235/2010. This, together with a small improvement in regulatory efficiency, suggests progress towards more rapid regulatory decisions based on more robust evidence. Future research should continue to monitor sources of evidence supporting regulatory decisions and the time taken to reach these decisions over time.
Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study
Authors: Burisch Johan , Kiudelis Gediminas , Kupcinskas Limas , Kievit Hendrika Adriana Linda , Andersen Karina Winther , Andersen Vibeke , Salupere Riina , Pedersen Natalia , Kjeldsen Jens , D’Incà Renata , Valpiani Daniela , Schwartz Doron , Odes Selwyn , Olsen Jóngerð , Nielsen Kári Rubek , Vegh Zsuzsanna , Lakatos Peter Laszlo , Toca Alina , Turcan Svetlana , Katsanos Konstantinos H , Christodoulou Dimitrios K , Fumery Mathurin , Gower-Rousseau Corinne , Zammit Stefania Chetcuti , Ellul Pierre , Eriksson Carl , Halfvarson Jonas , Magro Fernando Jose , Duricova Dana , Bortlik Martin , Fernandez Alberto , Hernández Vicent , Myers Sally , Sebastian Shaji , Oksanen Pia , Collin Pekka , Goldis Adrian , Misra Ravi , Arebi Naila , Kaimakliotis Ioannis P , Nikuina Inna , Belousova Elena , Brinar Marko , Cukovic-Cavka Silvija , Langholz Ebbe , Munkholm Pia 
Published: January 2018

ObjectiveThe Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn’s disease (CD).DesignPatients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.ResultsIn total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5).ConclusionDespite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.
Flavour capsule cigarette use among US adult cigarette smokers
Authors: Emond Jennifer A , Soneji Samir , Brunette Mary F , Sargent James D 
Published: January 2018

IntroductionFlavour capsule cigarettes are a recent product worldwide, and little is known about the epidemiology of their use. We used data from a nationally representative survey to understand the sociodemographic characteristics of flavour capsule cigarette smokers and reasons for flavour capsule use.MethodsData were from the nationally representative, U.S. Population Assessment of Tobacco and Health survey (2013–2014). Analyses included 7181 adults, aged 18–44 years, who were current or former established (≥100 lifetime cigarettes) cigarette smokers. Participants reported their usual brand of cigarettes which were classified as non-menthol, menthol or flavour capsule. Analyses assessed differences in participant demographics, smoking patterns and reasons for use by product type among those aged 18–24 years. Analyses were weighted to account for the survey design.ResultsFlavour capsule cigarettes were the usual cigarettes among 9.4% of smokers aged 18–24 years and 6.0%, 3.7% and <1% of smokers aged 25–34, 35–44 and ≥45 years, respectively. Among smokers aged 18–24 year, a significantly higher percentage of Hispanic smokers (17.3%) usually used flavour capsule cigarettes versus non-Hispanic white (8.4%, P<0.05) and non-Hispanic black (3.2%, P<0.05) smokers. Flavour capsule use was associated with later onset of smoking and lower levels of nicotine dependency and flavour capsule users placed more emphasis on taste, lower price and pack design than menthol or non-menthol users.ConclusionsFlavour capsule cigarettes use is highest in young adults, particularly Hispanics. Young adult predominance, lower level of addiction symptoms and emphasis on pack design by flavour capsule users suggest that these products may be positioned as starter products.
The Random Assignment Problem with Submodular Constraints on Goods
Authors: Fujishige Satoru , Sano Yoshio , Zhan Ping 
Published: January 2018

Problems of allocating indivisible goods to agents in an efficient and fair manner without money have long been investigated in literature. The random assignment problem is one of them, where we are given a fixed feasible (available) set of indivisible goods and a profile of ordinal preferences over the goods, one for each agent. Then, using lotteries, we determine an assignment of goods to agents in a randomized way. A seminal paper of Bogomolnaia and Moulin (2001) shows a probabilistic serial (PS) mechanism to give an ordinally efficient and envy-free solution to the assignment problem.
In this article, we consider an extension of the random assignment problem to submodular constraints on goods. We show that the approach of the PS mechanism by Bogomolnaia and Moulin is powerful enough to solve the random assignment problem with submodular (matroidal and polymatroidal) constraints. Under the agents’ ordinal preferences over goods we show the following:
(1) The obtained PS solution for the problem with unit demands and matroidal constraints is ordinally efficient, envy-free, and weakly strategy-proof with respect to the associated stochastic dominance relation.
(2)For the multiunit demand and polymatroidal constraint problem, the PS solution is ordinally efficient and envy-free but is not strategy-proof in general. However, we show that under a mild condition (that is likely to be satisfied in practice) the PS solution is a weak Nash equilibrium.
Antiestrogen Therapy Increases Plasticity and Cancer Stemness of Prolactin-Induced ERα+ Mammary Carcinomas
Authors: Shea Michael P. , O'Leary Kathleen A. , Fakhraldeen Saja A. , Goffin Vincent , Friedl Andreas , Wisinski Kari B. , Alexander Caroline M. , Schuler Linda A. 
Published: January 2018

Abstract
Although antiestrogen therapies are successful in many patients with estrogen receptor alpha-positive (ERα+) breast cancer, 25% to 40% fail to respond. Although multiple mechanisms underlie evasion of these treatments, including tumor heterogeneity and drug-resistant cancer stem cells (CSC), further investigations have been limited by the paucity of preclinical ERα+ tumor models. Here, we examined a mouse model of prolactin-induced aggressive ERα+ breast cancer, which mimics the epidemiologic link between prolactin exposure and increased risk for metastatic ERα+ tumors. Like a subset of ERα+ patient cancers, the prolactin-induced adenocarcinomas contained two major tumor subpopulations that expressed markers of normal luminal and basal epithelial cells. CSC activity was distributed equally across these two tumor subpopulations. Treatment with the selective estrogen receptor downregulator (SERD), ICI 182,780 (ICI), did not slow tumor growth, but induced adaptive responses in CSC activity, increased markers of plasticity including target gene reporters of Wnt/Notch signaling and epithelial–mesenchymal transition, and increased double-positive (K8/K5) cells. In primary tumorsphere cultures, ICI stimulated CSC self-renewal and was able to overcome the dependence of self-renewal upon Wnt or Notch signaling individually, but not together. Our findings demonstrate that treatment of aggressive mixed lineage ERα+ breast cancers with a SERD does not inhibit growth, but rather evokes tumor cell plasticity and regenerative CSC activity, predicting likely negative impacts on patient tumors with these characteristics.
Significance: This study suggests that treatment of a subset of ERα+ breast cancers with antiestrogen therapies may not only fail to slow growth but also promote aggressive behavior by evoking tumor cell plasticity and regenerative CSC activity. Cancer Res; 78(7); 1672–84. ©2018 AACR.
Keratin 19 Expression in Hepatocellular Carcinoma Is Regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis
Authors: Rhee Hyungjin , Kim Hye-Young , Choi Ji-Hye , Woo Hyun Goo , Yoo Jeong Eun , Nahm Ji Hae , Choi Jin-Sub , Park Young Nyun 
Published: January 2018

Abstract
Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC); however, regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that cross-talk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK–ERK1/2 pathway, which upregulated KRT19 expression in HCC cells. Furthermore, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC (n = 339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype.
Significance: These findings reveal KRT19 expression in hepatocellular carcinoma is regulated by cross-talk between cancer-associated fibroblasts and HCC cells, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(7); 1619–31. ©2018 AACR.
Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus
Authors: Schrock Alexa B. , Pavlick Dean , Klempner Samuel J. , Chung Jon H. , Forcier Brady , Welsh Allison , Young Lauren , Leyland-Jones Bryan , Bordoni Rodolfo , Carvajal Richard D. , Chao Joseph , Kurzrock Razelle , Sicklick Jason K. , Ross Jeffrey S. , Stephens Philip J. , Devoe Craig , Braiteh Fadi , Ali Siraj M. , Miller Vincent A. 
Published: January 2018

Abstract
Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative.
Experimental Design: Hybrid capture–based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with gastrointestinal carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples.
Results: Evidence of ctDNA was detected in 344 of 417 samples (82%), and of these, ≥1 reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented.
Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with gastrointestinal carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced gastrointestinal cancers as a complementary approach to tissue testing, and further investigation is warranted. Clin Cancer Res; 24(8); 1881–90. ©2018 AACR.