bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measuring clinical trial transparency: an empirical analysis of newly approved drugs and large pharmaceutical companies
Authors: Miller Jennifer E , Wilenzick Marc , Ritcey Nolan , Ross Joseph S , Mello Michelle M 
Published: December 2017

ObjectivesTo define a series of clinical trial transparency measures and apply them to large pharmaceutical and biotechnology companies and their 2014 FDA-approved drugs.DesignCross-sectional descriptive analysis of all clinical trials supporting 2014 Food and Drugs Administration (FDA)-approved new drug applications (NDAs) for novel drugs sponsored by large companies.Data sourcesData from over 45 sources, including Drugs@FDA.gov, ClinicalTrials.gov, corporate and international registries; PubMed, Google Scholar, EMBASE, corporate press releases, Securities and Exchange Commission (SEC) filings and personal communications with drug manufacturers.Outcome measuresTrial registration, results reporting, clinical study report (CSR) synopsis sharing, biomedical journal publication, and FDA Amendments Acts (FDAAA) compliance, analysed on the drug level.ResultsThe FDA approved 19 novel new drugs, sponsored by 11 large companies, involving 553 trials, in 2014. We analysed 505 relevant trials. Per drug, a median of 100% (IQR 86%–100%) of trials in patients were registered, 71% (IQR 57%–100%) reported results or shared a CSR synopsis, 80% (70%–100%) were published and 96% (80%–100%) were publicly available in some form by 13 months after FDA approval. Disclosure rates were lower at FDA approval (65%) and improved significantly by 6 months post FDA approval. Per drug, a median of 100% (IQR 75%–100%) of FDAAA-applicable trials were compliant. Half of reviewed drugs had publicly disclosed results for all trials in patients in our sample. One trial was uniquely registered in a corporate registry, and not ClinicalTrials.gov; 0 trials were uniquely registered in international registries.ConclusionsAmong large pharmaceutical companies and new drugs, clinical trial transparency is high based on several standards, although opportunities for improvement remain. Transparency is markedly higher for trials in patients than among all trials supporting drug approval, including trials in healthy volunteers. Ongoing efforts to publicly track companies’ transparency records and recognise exemplary companies may encourage further progress.
Impact of electronic clinical decision support on adherence to guideline-recommended treatment for hyperlipidaemia, atrial fibrillation and heart failure: protocol for a cluster randomised trial
Authors: Kessler Maya Elizabeth , Carter Rickey E , Cook David A , Kor Daryl Jon , McKie Paul M , Pencille Laurie J , Scheitel Marianne R , Chaudhry Rajeev 
Published: December 2017

IntroductionClinical practice guidelines facilitate optimal clinical practice. Point of care access, interpretation and application of such guidelines, however, is inconsistent. Informatics-based tools may help clinicians apply guidelines more consistently. We have developed a novel clinical decision support tool that presents guideline-relevant information and actionable items to clinicians at the point of care. We aim to test whether this tool improves the management of hyperlipidaemia, atrial fibrillation and heart failure by primary care clinicians.Methods/analysisClinician care teams were cluster randomised to receive access to the clinical decision support tool or passive access to institutional guidelines on 16 May 2016. The trial began on 1 June 2016 when access to the tool was granted to the intervention clinicians. The trial will be run for 6 months to ensure a sufficient number of patient encounters to achieve 80% power to detect a twofold increase in the primary outcome at the 0.05 level of significance. The primary outcome measure will be the percentage of guideline-based recommendations acted on by clinicians for hyperlipidaemia, atrial fibrillation and heart failure. We hypothesise care teams with access to the clinical decision support tool will act on recommendations at a higher rate than care teams in the standard of care arm.Ethics and disseminationThe Mayo Clinic Institutional Review Board approved all study procedures. Informed consent was obtained from clinicians. A waiver of informed consent and of Health Insurance Portability and Accountability Act (HIPAA) authorisation for patients managed by clinicians in the study was granted. In addition to publication, results will be disseminated via meetings and newsletters.Trial registration numberNCT02742545.
Retrospective, multicohort analysis of the Clinical Practice Research Datalink (CPRD) to determine differences in the cost of medication wastage, dispensing fees and prescriber time of issuing either short (<60 days) or long (≥60 days) prescription lengths in primary care for common, chronic conditions in the UK
Authors: Doble Brett , Payne Rupert , Harshfield Amelia , Wilson Edward C F 
Published: December 2017

ObjectivesTo investigate patterns of early repeat prescriptions and treatment switching over an 11-year period to estimate differences in the cost of medication wastage, dispensing fees and prescriber time for short (<60 days) and long (≥60 days) prescription lengths from the perspective of the National Health Service in the UK.SettingRetrospective, multiple cohort study of primary care prescriptions from the Clinical Practice Research Datalink.ParticipantsFive random samples of 50 000 patients each prescribed oral drugs for (1) glucose control in type 2 diabetes mellitus (T2DM); (2) hypertension in T2DM; (3) statins (lipid management) in T2DM; (4) secondary prevention of myocardial infarction; and (5) depression.Primary and secondary outcome measuresThe volume of medication wastage from early repeat prescriptions and three other types of treatment switches was quantified and costed. Dispensing fees and prescriber time were also determined. Total unnecessary costs (TUC; cost of medication wastage, dispensing fees and prescriber time) associated with <60 day and ≥60 day prescriptions, standardised to a 120-day period, were then compared.ResultsLonger prescription lengths were associated with more medication waste per prescription. However, when including dispensing fees and prescriber time, longer prescription lengths resulted in lower TUC. This finding was consistent across all five cohorts. Savings ranged from £8.38 to £12.06 per prescription per 120 days if a single long prescription was issued instead of multiple short prescriptions. Prescriber time costs accounted for the largest component of TUC.ConclusionsShorter prescription lengths could potentially reduce medication wastage, but they may also increase dispensing fees and/or the time burden of issuing prescriptions.
X-ray angiography perfusion imaging with an intra-arterial injection: comparative study with15O-gas/water positron emission tomography
Authors: Asai Katsunori , Nakamura Hajime , Watabe Tadashi , Nishida Takeo , Sakaguchi Manabu , Hatazawa Jun , Yoshimine Toshiki , Kishima Haruhiko 
Published: December 2017

BackgroundX-ray angiography perfusion (XAP) is a perfusion imaging technique based on conventional DSA.ObjectiveIn this study, we aimed to validate parameters derived from XAP by comparing them with15O-gas/water positron emission tomography (PET), using data from patients with chronic ischemic cerebrovascular disease.Methods18 consecutive patients were included. XAP was performed with intra-arterial infusion of contrast media, and a time–density curve was constructed for each cerebral hemisphere. From the curves, the relative values of mean transit time (rMTT) and wash-in rate (rWiR) were obtained by dividing the values of the right hemisphere by those of the left hemisphere. These were then compared with the relative values of cerebral blood flow (rCBF) and rMTT calculated from the PET data.ResultsXAP rWiR correlated strongly with PET rCBF (r=0.86, P<0.0001). rMTT measurements from the two modalities were also strongly correlated (r=0.85, P<0.0001). Bland–Altman analysis revealed a bias of 0.14±0.18 (95% limits of agreement −0.22 to 0.51) for PET rCBF versus XAP rWiR, and 0.016±0.093 (95% limits of agreement −0.17 to 0.20) for rMTT between the two modalities.ConclusionsThe relative values obtained from XAP were validated across a population of patients with chronic ischemic cerebrovascular disease.
Mechanical thrombectomy and rescue therapy for intracranial large artery occlusion with underlying atherosclerosis
Authors: Jia BaiXue , Feng Lei , Liebeskind David S , Huo Xiaochuan , Gao Feng , Ma Ning , Mo Dapeng , Liao Xiaoling , Wang Chunjuan , Zhao Xingquan , Pan Yuesong , Li Hao , Liu Liping , Wang Yilong , Wang Yongjun , Miao Zhong-Rong 
Published: December 2017

ObjectiveTo investigate the safety and efficacy of mechanical thrombectomy plus rescue therapy for intracranial large artery occlusion (ILAO) with underlying intracranial atherosclerosis (ICAS).MethodsPatients enrolled in the intervention group of EAST (Endovascular Therapy for Acute ischemic Stroke Trial) were analyzed. For underlying ICAS identified during the stent retrieval procedure, rescue treatment was required for those with (1) a degree of arterial stenosis >70% or (2) any degree of arterial with blood flow impairment or (3) evidence of re-occlusion. Outcomes were compared between the ICAS group and the embolic group. Multivariate logistic regression was performed to determine independent predictors of functional independence at 90 days.ResultsAmong the 140 patients included in the analysis, underlying ICAS was identified in 47 (34%), and 30 patients (21.4%) were considered to be eligible to receive rescue treatment. Of the 30 patients, 27 (90%) actually received rescue therapy. Recanalization rate (95.7% vs 96.8%, P=0.757) and functional independence at 90 days (63.8% vs 51.6%, P=0.169) were comparable between the ICAS group and the embolic group. No significant difference in symptomatic hemorrhage (4.3% vs 4.3%, P=1.000) or death (12.8% vs 12.9%, P=0.982) was found between the two groups. National Institutes of Health Stroke Scale score at presentation (OR=0.865, 95% CI 0.795 to 0.941; P=0.001) and modified Thrombolysis in Cerebral Infarction after the procedure (OR=2.864, 95% CI 1.018 to 8.061; P=0.046) were independently associated with functional independence at 90 days.ConclusionsMechanical thrombectomy is safe in patients with ILAO with underlying ICAS. By employing a standard rescue therapy, favorable outcomes could be achieved in such patients.Clinical trial registrationNCT02350283(Post-results).
Nitrogen and phosphorus uptake from solid and liquid pig manure in perennial and annual cropping systems
Authors: Karimi Rezvan , Akinremi Wole , Flaten Don 
Published: December 2017

Applying pig manure in excess of crop demand can result in nutrient loss to water bodies. We studied the effect of liquid and solid pig manures and their N- and P-based application rates on yield and nutrient uptake in annual and perennial cropping systems for 3 yr. The experiment had a split-plot design with five nutrient management treatments including liquid-N (annual N-based liquid pig manure), liquid-P (P-based liquid pig manure once every 5 yr), solid-N (annual N-based solid pig manure), solid-P (P-based solid pig manure once every 5 yr), and control (no manure). The liquid-P treatment showed high apparent nitrogen and phosphorus recovery (ANR and APR, respectively) in each cropping system and yields similar to that of the liquid-N treatment. The solid-N treatment had the smallest ANR in the perennial cropping system (9%–27%) and also the smallest APR in both cropping systems (typically <4%) possibly due to N deficiency and high P application rate. The current formula for estimating organic N mineralization overestimated the available N, particularly for solid pig manure, reducing crop yield. Based on the ANR obtained in this study, a more appropriate coefficient is 10%–15% of the organic N from solid pig manure for no-till perennial cropping systems.
Response of Bosc and Cold Snap™ pears to thinning with NAA, 6-BA, ACC, and s-ABA
Authors: Cline J.A. , Carter K. , Gunter A. , Bakker C. , Green A.C. 
Published: December 2017

Adjusting the crop load of European pears (Pyrus communis L.) by hand thinning is currently required to ensure marketable size of most cultivars grown in Ontario. The benefits of thinning pears chemically and its effect on fruit quality and fresh-market returns were investigated in a 3-yr study where a series of foliar chemical thinning sprays were applied during the 10-mm fruitlet stage to Bosc and Cold Snap™ pear trees growing in commercial orchards in the Niagara Peninsula, Ontario. Treatments included an untreated and hand-thinned control and two concentrations each of 6-benzyladenine (6-BA; 75 and 150 mg L−1), naphthalene acetic acid (10 and 20 mg L−1), 1-aminocyclopropane carboxylic acid (150 and 300 mg L−1), and s-abscisic acid (s-ABA; 150 and 300 mg L−1). Overall, all thinning products reduced crop load at least once in the 3-yr study, although this varied by year and cultivar. Higher concentrations were more effective than lower concentrations. Naphthalene acetic acid (both rates), 150 mg L−1 of 6-BA, and 300 mg L−1 of s-ABA were the most consistent at thinning the crop. As the crop load of control trees was not heavy, minimal hand thinning was required and all thinning treatments reduced crop value compared with the untreated trees. There were minimal effects on starch hydrolysis, soluble solids, fruit firmness, and skin colour at harvest.
Accelerating BLAS and LAPACK via Efficient Floating Point Architecture Design
Authors: Merchant Farhad , Chattopadhyay Anupam , Raha Soumyendu , Nandy S. K. , Narayan Ranjani 
Published: December 2017

Basic Linear Algebra Subprograms (BLAS) and Linear Algebra Package (LAPACK) form basic building blocks for several High Performance Computing (HPC) applications and hence dictate performance of the HPC applications. Performance in such tuned packages is attained through tuning of several algorithmic and architectural parameters such as number of parallel operations in the Directed Acyclic Graph of the BLAS/LAPACK routines, sizes of the memories in the memory hierarchy of the underlying platform, bandwidth of the memory, and structure of the compute resources in the underlying platform. In this paper, we closely investigate the impact of the Floating Point Unit (FPU) micro-architecture for performance tuning of BLAS and LAPACK. We present theoretical analysis for pipeline depth of different floating point operations like multiplier, adder, square root, and divider followed by characterization of BLAS and LAPACK to determine several parameters required in the theoretical framework for deciding optimum pipeline depth of the floating operations. A simple design of a Processing Element (PE) is presented and shown that the PE outperforms the most recent custom realizations of BLAS and LAPACK by 1.1X to 1.5X in GFlops/W, and 1.9X to 2.1X in Gflops/mm2. Compared to multicore, General Purpose Graphics Processing Unit (GPGPU), Field Programmable Gate Array (FPGA), and ClearSpeed CSX700, performance improvement of 1.8-80x is reported in PE.
Gully formation in the McMurdo Dry Valleys, Antarctica: multiple sources of water, temporal sequence and relative importance in gully erosion and deposition processes
Authors: Dickson James L. , Head James W. , Levy Joseph S. , Morgan Gareth A. , Marchant David R. 
Published: December 2017

Abstract

We report on a decade of fieldwork designed to determine the conditions required for erosion of Mars-like gully channels in the McMurdo Dry Valleys (MDV) of Antarctica. We have outlined the major factors in the morphological evolution of gullies in the Inland Mixed Zone of the MDV: (1) the distribution of ice sources; (2) the temporal aspects of ice melting; and (3) the relative significance of melting events in gullies. We show that significant erosion of gully channels can be achieved if geometrical and environmental conditions combine to concentrate ice where it can rapidly melt. In contrast, annual melting of surface ice and snow deposits during late-season discharge events contribute to transport of water, but flux rarely surpasses the infiltration capacity of the active layer. These small discharge events do not erode channels of significant width. Even when the flux is sufficient to carve a
c.
10–20 cm deep channel during late summer (January–February) runoff, these small channels seldom persist through multiple seasons, because they are seasonally muted and filled with aeolian deposits. We briefly discuss the application of these results to the study of gully systems on Mars.
Etk Interaction with PFKFB4 Modulates Chemoresistance of Small-cell Lung Cancer by Regulating Autophagy
Authors: Wang Qiongyao , Zeng Fanrui , Sun Yanqin , Qiu Qianqian , Zhang Jian , Huang Weimei , Huang Jie , Huang Xiaomin , Guo Linlang 
Published: December 2017

AbstractPurpose: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small-cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood.Experimental Design: We determined correlation of Etk with autophagy in SCLC. And direct inhibition of autophagy was performed to validate its effect on chemoresistance. Coimmunoprecipitation (co-IP) and GST-pull down experiments were conducted to verify the interaction of Etk and PFKFB4, after a microarray analysis. In vitro and in vivo gain or loss-of-function analyses and evaluation of PFKFB4 expression in SCLC specimens, were done to validate its role in chemoresistance. Ibrutinib was administrated in SCLC cells to verify its synergistic anti-tumor effect with chemotherapy using preclinical models including a PDX model.Results: Downregulation of Etk suppressed autophagy in chemoresistant SCLC cells, and direct inhibition of autophagy sensitized cells to chemotherapy. PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) was identified as a downstream target of Etk and an Etk-interacting protein, which promoted chemoresistance in SCLC and was associated with poor therapeutic response and prognosis. Furthermore, ibrutinib was found to exhibit a synergistic anti-tumor effect with chemotherapy in targeting Etk.Conclusions: Our results demonstrated for the first time that Etk interacts with PFKFB4 to promote SCLC chemoresistance through regulation of autophagy. Aberrant Etk and PFKFB4 can be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC. Clin Cancer Res; 24(4); 950–62. ©2017 AACR.
A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab
Authors: Berger Martin D. , Stintzing Sebastian , Heinemann Volker , Cao Shu , Yang Dongyun , Sunakawa Yu , Matsusaka Satoshi , Ning Yan , Okazaki Satoshi , Miyamoto Yuji , Suenaga Mitsukuni , Schirripa Marta , Hanna Diana L. , Soni Shivani , Puccini Alberto , Zhang Wu , Cremolini Chiara , Falcone Alfredo , Loupakis Fotios , Lenz Heinz-Josef 
Published: December 2017

Abstract
Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab.
Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed.
Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D–binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable (P = 0.001) and multivariable analyses (P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P = 0.033) and multivariable analyses (P = 0.046).
Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784–93. ©2017 AACR.
Vimentin Is Required for Lung Adenocarcinoma Metastasis via Heterotypic Tumor Cell–Cancer-Associated Fibroblast Interactions during Collective Invasion
Authors: Richardson Alessandra M. , Havel Lauren S. , Koyen Allyson E. , Konen Jessica M. , Shupe John , Wiles W.G. , Martin W. David , Grossniklaus Hans E. , Sica Gabriel , Gilbert-Ross Melissa , Marcus Adam I. 
Published: December 2017

Abstract
Purpose: Vimentin is an epithelial-to-mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis.
Experimental Design: We used the LSL-KrasG12D/Lkb1fl/fl/Vim−/− model (KLV−/−), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent LSL-KrasG12D/Lkb1fl/fl model (KLV+/+). We compared the metastatic phenotypes of the GEMMs and analyzed primary tumors from the KLV models and lung adenocarcinoma patients to assess vimentin expression and function.
Results: Characterization of KLV+/+ and KLV−/− mice shows that although vimentin is not required for primary lung tumor growth, vimentin is required for metastasis, and vimentin loss generates lower grade primary tumors. Interestingly, in the KLV+/+ mice, vimentin was not expressed in tumor cells but in cancer-associated fibroblasts (CAFs) surrounding collective invasion packs (CIPs) of epithelial tumor cells, with significantly less CIPs in KLV−/− mice. CIPs correlate with tumor grade and are vimentin-negative and E-cadherin–positive, indicating a lack of cancer cell EMT. A similar heterotypic staining pattern was observed in human lung adenocarcinoma samples. In vitro studies show that vimentin is required for CAF motility to lead tumor cell invasion, supporting a vimentin-dependent model of collective invasion.
Conclusions: These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell–CAF interactions during collective invasion. Clin Cancer Res; 24(2); 420–32. ©2017 AACR.
Losers of Primary Cilia Gain the Benefit of Survival
Authors: Goranci-Buzhala Gladiola , Gabriel Elke , Mariappan Aruljothi , Gopalakrishnan Jay 
Published: December 2017

Abstract
Summary: In this issue, Zhao and colleagues demonstrate that loss of primary cilia in medulloblastoma cells confers resistance to the Smoothened (SMO) inhibitor sonidegib. When treated with sonidegib, medulloblastoma cells lost their cilia and gained resistance. Surprisingly, loss of cilia is associated with recurrent mutations in ciliogenesis genes that are eventually able to drive drug resistance. These findings uncover a previously unknown mechanism of cancer cells in gaining a “persister-like” state against anticancer agents at the expense of losing primary cilia. Cancer Discov; 7(12); 1374–5. ©2017 AACR.
See related article by Zhao et al., p. 1436.