bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimalarial Drug Pyrimethamine Plays a Dual Role in Antitumor Proliferation and Metastasis through Targeting DHFR and TP
Authors: Liu Huijuan , Qin Yuan , Zhai Denghui , Zhang Qiang , Gu Ju , Tang Yuanhao , Yang Jiahuan , Li Kun , Yang Lan , Chen Shuang , Zhong Weilong , Meng Jing , Liu Yanrong , Sun Tao , Yang Cheng 
Published: January 2019

Abstract
Pyrimethamine (Pyr), an antimalarial drug that targeting plasmodium dihydrofolate reductase (pDHFR), has been proved to have antitumor activity. However, its direct target on cancer cells remains unclear. Methotrexate (MTX) is a widely used anticancer drug that blocks human dihydrofolate reductase (hDHFR). In this work, we examined the anticancer effects of Pyr in vitro and in vivo. Our results showed that hDHFR and pDHFR have similar secondary and three-dimensional structures and that Pyr can inhibit the activity of hDHFR in lung cancer cells. Although Pyr and MTX can inhibit the proliferation of lung cancer cells by targeting DHFR, only Pyr can inhibit the epithelial–mesenchymal transition (EMT), metastasis and invasion of lung cancer cells. These results indicated that hDHFR is not the only target of Pyr. We further found that thymidine phosphorylase (TP), an enzyme that is closely associated with the EMT of cancer cells, is also a target protein of Pyr. The data retrieved from the Cancer Genome Atlas (TCGA) database revealed that TP overexpression is associated with poor prognosis of patients with lung cancer. In conclusion, Pyr plays a dual role in antitumor proliferation and metastasis by targeting DHFR and TP. Pyr may have potential clinical applications for the treatment of lung cancer.
Mitral Annulus Calcium Score
Authors: Brodov Yafim , Konen Eli , Di Segni Mattia , Samoocha David , Chernomordik Fernando , Barbash Israel , Regev Ehud , Raanani Ehud , Guetta Victor , Segev Amit , Fefer Paul , Glikson Michael , Goitein Orly 
Published: January 2019

Background:
The risk of conduction system abnormalities (CSA) after transcatheter aortic valve implantation remains high. We aimed to evaluate the impact of mitral annular calcium (MAC) score on the development of CSA after transcatheter aortic valve implantation.

Methods:
Consecutive patients (n=168), with severe AoV stenosis, without prior CSA, underwent computed tomography transcatheter AoV implantation followed by device implantation; CoreValve (n=72) and SAPIEN (n=96). MAC, AoV, and left ventricular outflow tract calcium (Ca++) scores were quantitated from noncontrast ECG-gated computed tomography using Agatston method. The primary end point was a combination of complete left bundle branch block or high-degree atrioventricular block. Logistic regression was used to analyze the predictive value of Ca++ scores of different locations.

Results:

The primary end point was documented in 62% of the fourth quartile MAC score (>2700) patients as compared with 31% of the first quartile (<140);
P
=0.03. Logistic regression analysis documented MAC score as an independent predictor either of primary end point as a continuous variable (odds ratio: 1.02, 95% [CI]: 1.00 – 1.03,
p
= 0.021) or as quartile cutoffs, whereas Q4 was a strong and independent predictor (odds ratio: 3.69, 95% [CI]: 1.37 – 9.95,
p
= 0.010).

Conclusions:
MAC score was found to be an independent predictor of CSA in patients undergoing transcatheter aortic valve implantation without preexisting CSA. Therefore, the current study suggests that patients with high MAC score category (fourth MAC score quartile) should be considered at high risk for CSA, warranting closer monitoring.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov.
Unique identifier: NCT02023060.
Safety of Men With Small and Medium Abdominal Aortic Aneurysms Under Surveillance in the NAAASP
Authors: Oliver-Williams Clare , Sweeting Michael J. , Jacomelli Jo , Summers Lisa , Stevenson Anne , Lees Tim , Earnshaw Jonothan J. 
Published: January 2019

Background:
Population screening for abdominal aortic aneurysm (AAA) has commenced in several countries, and has been shown to reduce AAA-related mortality by up to 50%. Most men who screen positive have an AAA <5.5 cm in diameter, the referral threshold for treatment, and are entered into an ultrasound surveillance program. This study aimed to determine the risk of ruptured AAA (rAAA) in men under surveillance.

Methods:
Men in the National Health Service AAA Screening Programme who initially had a small (3–4.4 cm) or medium (4.5–5.4 cm) AAA were followed up. The screening program’s database collected data on ultrasound AAA diameter measurements, dates of referral, and loss to follow-up. Local screening programs recorded adverse outcomes, including rAAA and death. Rupture and mortality rates were calculated by initial and final known AAA diameter.

Results:
A total of 18 652 men were included (50 103 person-years of surveillance). Thirty-one men had rAAA during surveillance, of whom 29 died. Some 952 men died of other causes during surveillance, mainly cardiovascular complications (26.3%) and cancer (31.2%). The overall mortality rate was 1.96% per annum, similar for men with small and medium AAAs. The rAAA risk was 0.03% per annum (95% CI, 0.02%–0.05%) for men with small AAAs and 0.28% (0.17%–0.44%) for medium AAAs. The rAAA risk for men with AAAs just below the referral threshold (5.0–5.4 cm) was 0.40% (0.22%–0.73%).

Conclusions:
The risk of rAAA under surveillance is <0.5% per annum, even just below the present referral threshold of 5.5 cm, and only 0.4% of men under surveillance are estimated to rupture before referral. It can be concluded that men with small and medium screen-detected AAAs are safe provided they are enrolled in an intensive surveillance program, and that there is no evidence that the current referral threshold of 5.5 cm should be changed.
Ten-Year Clinical Outcomes From a Trial of Three Limus-Eluting Stents With Different Polymer Coatings in Patients With Coronary Artery Disease
Authors: Kufner Sebastian , Joner Michael , Thannheimer Anna , Hoppmann Petra , Ibrahim Tareq , Mayer Katharina , Cassese Salvatore , Laugwitz Karl-Ludwig , Schunkert Heribert , Kastrati Adnan , Byrne Robert A. ,   On behalf of the ISAR-TEST 4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents) Investigators
Published: January 2019

Background:
New-generation drug-eluting stents offer the potential for enhanced late outcomes in comparison with early generation drug-eluting stents. However, assessment of extended long-term outcomes for these devices is lacking, especially regarding the comparison between new-generation drug-eluting stents with biodegradable or permanent polymers. The aim of this study is to compare the efficacy and safety of biodegradable polymer-based sirolimus-eluting stents (BP-SES; Yukon Choice PC) versus permanent polymer-based everolimus-eluting stents (PP-EES; Xience) versus early generation permanent polymer-based sirolimus-eluting stents (PP-SES; Cypher) at 10-year follow-up.

Methods:
Overall, 2603 patients were randomized to treatment with BP-SES (n=1299), PP-EES (n=652), or PP-SES (n=652). The primary end point of this analysis was major adverse cardiac event, the composite of death, myocardial infarction, or target lesion revascularization. The main secondary end point of interest was definite/probable stent thrombosis. Follow-up at 10 years was available in 83% of the study patients.

Results:

The 10-year incidence of major adverse cardiac event (BP-SES 47.7% versus PP-EES 46.0% versus PP-SES 54.9%,
P
=0.003) and mortality (BP-SES 31.8% versus PP-EES 30.3% versus PP-SES 37.2%,
P
=0.02) was different among the groups. Definite/probable stent thrombosis was not significantly different among the groups (BP-SES 1.8% versus PP-EES 2.5% versus PP-SES 3.7%,
P
=0.09). Definite stent thrombosis was significantly different among the groups (BP-SES 1.1% versus PP-EES 0.8% versus PP-SES 2.4%,
P
=0.03). There were no significant differences between BP-SES and PP-EES.

Conclusions:
In this unique long-term outcome analysis, BP-SES and PP-EES showed comparable clinical outcomes out to 10 years. PP-SES had higher rates of major adverse cardiac events and definite stent thrombosis.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00598676.
Effectiveness of an mHealth-Based Electronic Decision Support System for Integrated Management of Chronic Conditions in Primary Care
Authors: Prabhakaran Dorairaj , Jha Dilip , Prieto-Merino David , Roy Ambuj , Singh Kavita , Ajay Vamadevan S. , Jindal Devraj , Gupta Priti , Kondal Dimple , Goenka Shifalika , Jacob Pramod , Singh Rekha , Kumar B. G. Prakash , Perel Pablo , Tandon Nikhil , Patel Vikram , Venkat C. , Ram S. , Saxena Sudhir , Venugopal K. , Gredsted Lars , Kumar Vikram Sheel , Mukherjee Shirshendu , Reddy K. Srinath , Naik Nitish , Dwivedi S.N. , Unnikrishnan A.G. , Sharma Meenakshi 
Published: January 2019

Background:
The burden of noncommunicable diseases and their risk factors has rapidly increased worldwide, including in India. Innovative management strategies with electronic decision support and task sharing have been assessed for hypertension, diabetes mellitus, and depression individually, but an integrated package for multiple chronic condition management in primary care has not been evaluated.

Methods:
In a prospective, multicenter, open-label, cluster-randomized controlled trial involving 40 community health centers, using hypertension and diabetes mellitus as entry points, we evaluated the effectiveness of mWellcare, an mHealth system consisting of electronic health record storage and an electronic decision support for the integrated management of 5 chronic conditions (hypertension, diabetes mellitus, current tobacco and alcohol use, and depression) versus enhanced usual care among patients with hypertension and diabetes mellitus in India. At trial end (12-month follow-up), using intention-to-treat analysis, we examined the mean difference between arms in change in systolic blood pressure and glycated hemoglobin as primary outcomes and fasting blood glucose, total cholesterol, predicted 10-year risk of cardiovascular disease, depression score, and proportions reporting tobacco and alcohol use as secondary outcomes. Mixed-effects regression models were used to account for clustering and other confounding variables.

Results:
Among 3698 enrolled participants across 40 clusters (mean age, 55.1 years; SD, 11 years; 55.2% men), 3324 completed the trial. There was no evidence of difference between the 2 arms for systolic blood pressure (Δ=−0.98; 95% CI, −4.64 to 2.67) and glycated hemoglobin (Δ=0.11; 95% CI, −0.24 to 0.45) even after adjustment of several key variables (adjusted differences for systolic blood pressure: – 0.31 [95% CI, −3.91 to 3.29]; for glycated hemoglobin: 0.08 [95% CI, −0.27 to 0.44]). The mean within-group changes in systolic blood pressure in mWellcare and enhanced usual care were −13.65 mm Hg versus −12.66 mm Hg, respectively, and for glycated hemoglobin were −0.48% and −0.58%, respectively. Similarly, there were no differences in the changes between the 2 groups for tobacco and alcohol use or other secondary outcomes.

Conclusions:
We did not find an incremental benefit of mWellcare over enhanced usual care in the management of the chronic conditions studied.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02480062.
Phase I/II Trial of Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia
Authors: Robinson Clifford G. , Samson Pamela P. , Moore Kaitlin M.S. , Hugo Geoffrey D. , Knutson Nels , Mutic Sasa , Goddu S. Murty , Lang Adam , Cooper Daniel H. , Faddis Mitchell , Noheria Amit , Smith Timothy W. , Woodard Pamela K. , Gropler Robert J. , Hallahan Dennis E. , Rudy Yoram , Cuculich Phillip S. 
Published: January 2019

Background:
Case studies have suggested the efficacy of catheter-free, electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia (VT) using stereotactic body radiation therapy, although prospective data are lacking.

Methods:
We conducted a prospective phase I/II trial of noninvasive cardiac radioablation in adults with treatment-refractory episodes of VT or cardiomyopathy related to premature ventricular contractions (PVCs). Arrhythmogenic scar regions were targeted by combining noninvasive anatomic and electric cardiac imaging with a standard stereotactic body radiation therapy workflow followed by delivery of a single fraction of 25 Gy to the target. The primary safety end point was treatment-related serious adverse events in the first 90 days. The primary efficacy end point was any reduction in VT episodes (tracked by indwelling implantable cardioverter defibrillators) or any reduction in PVC burden (as measured by a 24-hour Holter monitor) comparing the 6 months before and after treatment (with a 6-week blanking window after treatment). Health-related quality of life was assessed using the Short Form-36 questionnaire.

Results:

Nineteen patients were enrolled (17 for VT, 2 for PVC cardiomyopathy). Median noninvasive ablation time was 15.3 minutes (range, 5.4–32.3). In the first 90 days, 2/19 patients (10.5%) developed a treatment-related serious adverse event. The median number of VT episodes was reduced from 119 (range, 4–292) to 3 (range, 0–31;
P
<0.001). Reduction was observed for both implantable cardioverter defibrillator shocks and antitachycardia pacing. VT episodes or PVC burden were reduced in 17/18 evaluable patients (94%). The frequency of VT episodes or PVC burden was reduced by 75% in 89% of patients. Overall survival was 89% at 6 months and 72% at 12 months. Use of dual antiarrhythmic medications decreased from 59% to 12% (
P
=0.008). Quality of life improved in 5 of 9 Short Form-36 domains at 6 months.

Conclusions:
Noninvasive electrophysiology-guided cardiac radioablation is associated with markedly reduced ventricular arrhythmia burden with modest short-term risks, reduction in antiarrhythmic drug use, and improvement in quality of life.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov/
. Unique identifier: NCT02919618.
Identifying Hypoperfusion in Moyamoya Disease With Arterial Spin Labeling and an [
15
O]-Water Positron Emission Tomography/Magnetic Resonance Imaging Normative Database
Authors: Fan Audrey P. , Khalighi Mohammad M. , Guo Jia , Ishii Yosuke , Rosenberg Jarrett , Wardak Mirwais , Park Jun Hyung , Shen Bin , Holley Dawn , Gandhi Harsh , Haywood Tom , Singh Prachi , Steinberg Gary K. , Chin Frederick T. , Zaharchuk Greg 
Published: January 2019

Background and Purpose—
Noninvasive imaging of brain perfusion has the potential to elucidate pathophysiological mechanisms underlying Moyamoya disease and enable clinical imaging of cerebral blood flow (CBF) to select revascularization therapies for patients. We used hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) technology to characterize the distribution of hypoperfusion in Moyamoya disease and its relationship to vessel stenosis severity, through comparisons with a normative perfusion database of healthy controls.

Methods—

To image CBF, we acquired [
15
O]-water PET as a reference and simultaneously acquired arterial spin labeling (ASL) MRI scans in 20 Moyamoya patients and 15 age-matched, healthy controls on a PET/MRI scanner. The ASL MRI scans included a standard single-delay ASL scan with postlabel delay of 2.0 s and a multidelay scan with 5 postlabel delays (0.7–3.0s) to estimate and account for arterial transit time in CBF quantification. The percent volume of hypoperfusion in patients (determined as the fifth percentile of CBF values in the healthy control database) was the outcome measure in a logistic regression model that included stenosis grade and location.

Results—

Logistic regression showed that anterior (
P
<0.0001) and middle cerebral artery territory regions (
P
=0.003) in Moyamoya patients were susceptible to hypoperfusion, whereas posterior regions were not. Cortical regions supplied by arteries with stenosis on MR angiography showed more hypoperfusion than normal arteries (
P
=0.001), but the extent of hypoperfusion was not different between mild-moderate versus severe stenosis. Multidelay ASL did not perform differently from [
15
O]-water PET in detecting perfusion abnormalities, but standard ASL overestimated the extent of hypoperfusion in patients (
P
=0.003).

Conclusions—
This simultaneous PET/MRI study supports the use of multidelay ASL MRI in clinical evaluation of Moyamoya disease in settings where nuclear medicine imaging is not available and application of a normative perfusion database to automatically identify abnormal CBF in patients.
Response of Extreme Precipitation to Urbanization over the Netherlands
Authors: Golroudbary Vahid Rahimpour , Zeng Yijian , Mannaerts Chris M. , Su Zhongbo 
Published: January 2019

AbstractKnowledge of the response of extreme precipitation to urbanization is essential to ensure societal preparedness for the extreme events caused by climate change. To quantify this response, this study scales extreme precipitation according to temperature using the statistical quantile regression and binning methods for 231 rain gauges during the period of 1985–2014. The positive 3%–7% scaling rates were found at most stations. The nonstationary return levels of extreme precipitation are investigated using monthly blocks of the maximum daily precipitation, considering the dependency of precipitation on the dewpoint, atmospheric air temperatures, and the North Atlantic Oscillation (NAO) index. Consideration of Coordination of Information on the Environment (CORINE) land-cover types upwind of the stations in different directions classifies stations as urban and nonurban. The return levels for the maximum daily precipitation are greater over urban stations than those over nonurban stations especially after the spring months. This discrepancy was found by 5%–7% larger values in August for all of the classified station types. Analysis of the intensity–duration–frequency curves for urban and nonurban precipitation in August reveals that the assumption of stationarity leads to the underestimation of precipitation extremes due to the sensitivity of extreme precipitation to the nonstationary condition. The study concludes that nonstationary models should be used to estimate the return levels of extreme precipitation by considering the probable covariates such as the dewpoint and atmospheric air temperatures. In addition to the external forces, such as large-scale weather modes, circulation types, and temperature changes that drive extreme precipitation, urbanization could impact extreme precipitation in the Netherlands, particularly for short-duration events.
Differences of early immunological responses in on-pump versus off-pump cardiac surgery
Authors: Lehmann Sven , Dieterlen Maja-Theresa , Flister Anja , Klaeske Kristin , Jawad Khalil , Garbade Jens , Borger Michael A , Kostelka Martin 
Published: January 2019

Introduction: Cardiopulmonary bypass surgery is accompanied by an inflammatory response and pulmonary dysfunction that renders patients vulnerable to postoperative complications. The majority of studies investigating the inflammatory response in cardiopulmonary bypass focus on cytokine measurements. This study investigated the early response of peripheral blood cell types and early changes in lung tissue in on-pump versus off-pump cardiopulmonary bypass surgery. Methods: Landrace pigs were assigned to the following groups (n = 6 per group): 1. off-pump cardiopulmonary bypass, 2. conventional cardiopulmonary bypass, 3. heparin-coated cardiopulmonary bypass, 4. surface-reduced cardiopulmonary bypass, and 5. surface-reduced cardiopulmonary bypass plus lung perfusion. Surgery was performed under mild hyperthermia (32°C), with 90-minute ischemia and 180-minute reperfusion. Histological and flow cytometric analyses were performed. Results: Lung water content increased during reperfusion in heparin-coated (84.63 ± 2.99%) compared to conventional cardiopulmonary bypass (76.33 ± 4.56%, p = 0.04). Alveolar septal thickness increased during ischemia at heparin-coated (p < 0.01) and surface-reduced cardiopulmonary bypass plus lung perfusion (p = 0.05). Tumor necrosis factor expression increased significantly (p < 0.01) in peribronchial, perivascular, and peripheral lung areas in all on-pump groups, but not in off-pump cardiopulmonary bypass. The usage of heparin-coated cardiopulmonary bypass led to increased percentages of CD3+CD4+ (p = 0.03) and CD3+CD8+ (p = 0.01) T cells compared to an uncoated device. Natural killer and mature B lymphocytes decreased at conventional and surface-reduced cardiopulmonary bypass plus lung perfusion. Activated granulocytes and macrophages increased at conventional cardiopulmonary bypass and heparin-coated cardiopulmonary bypass. Conclusion: Off-pump cardiopulmonary bypass induces less immunological response and lung injury than on-pump surgery. The reduction of cardiopulmonary bypass surface reduces the inflammatory immune response induced by cardiopulmonary bypass. Lung perfusion of surface-reduced cardiopulmonary bypass diminished the extravasation caused by surface reduction of the cardiopulmonary bypass.
Enhancing Engagement With Socially Disadvantaged Older People in Organized Physical Activity Programs
Authors: Nau Tracy , Nolan Genevieve , Smith Ben J. 
Published: January 2019

Background and objectives Participation in physical activity (PA) is low among older adults in developed nations and even lower among several socially disadvantaged groups. This study aimed to identify the actions that can be taken in the promotion, design, and implementation of organized PA programs to improve engagement with socially disadvantaged and underrepresented older people. Research design and methods: Semistructured interviews were conducted with 30 community service providers and 5 focus groups with 42 older participants in existing PA programs. Data were analyzed thematically, and the PRECEDE-PROCEED model for program planning was used to broadly categorize themes. Results: Helpful strategies for addressing predisposing factors such as social anxiety and lack of confidence included user-centered program design and sensitive, informative messaging and promotion. Key enabling strategies were transport assistance and minimizing fees. Facilitating gentle entry to groups and fostering inclusion and safety were identified as valuable reinforcing strategies. Providers regarded organizational networks as beneficial for facilitating referral and addressing resource constraints. Discussion and implications: A multifactorial approach addressing a range of predisposing, reinforcing, and enabling factors is likely to be necessary to enhance engagement in organized PA by socially disadvantaged and underrepresented older people. Key factors relate to creating a positive sociocultural environment, identifying activities of interest, and enhancing ease of access.