bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination and Interpretation of the QT Interval
Authors: Vink Arja Suzanne , Neumann Benjamin , Lieve Krystien V.V. , Sinner Moritz F. , Hofman Nynke , el Kadi Soufiane , Schoenmaker Melissa H.A. , Slaghekke Hanneke M.J. , de Jong Jonas S.S.G. , Clur Sally-Ann B. , Blom Nico A. , Kääb Stefan , Wilde Arthur A.M. , Postema Pieter G. 
Published: January 2019

Background:
Long QT syndrome (LQTS) is associated with potentially fatal arrhythmias. Treatment is very effective, but its diagnosis may be challenging. Importantly, different methods are used to assess the QT interval, which makes its recognition difficult. QT experts advocate manual measurements with the tangent or threshold method. However, differences between these methods and their performance in LQTS diagnosis have not been established. We aimed to assess similarities and differences between these 2 methods for QT interval analysis to aid in accurate QT assessment for LQTS.

Methods:

Patients with a confirmed pathogenic variant in
KCNQ1
(LQT1),
KCNH2
(LQT2), or
SCN5A
(LQT3) genes and their family members were included. Genotype-positive patients were identified as LQTS cases and genotype-negative family members as controls. ECGs were analyzed with both methods, providing inter- and intrareader validity and diagnostic accuracy. Cutoff values based on control population’s 95th and 99th percentiles, and LQTS-patients’ 1st and 5th percentiles were established based on the method to correct for heart rate, age, and sex.

Results:

We included 1484 individuals from 265 families, aged 33±21 years and 55% females. In the total cohort, QT
Tangent
was 10.4 ms shorter compared with QT
Threshold
(95% limits of agreement±20.5 ms,
P
<0.0001). For all genotypes, QT
Tangent
was shorter than QT
Threshold
(
P
<0.0001), but this was less pronounced in LQT2. Both methods yielded a high inter- and intrareader validity (intraclass correlation coefficient >0.96), and a high diagnostic accuracy (area under the curve >0.84). Using the current guideline cutoff (QTc interval 480 ms), both methods had similar specificity but yielded a different sensitivity. QTc interval cutoff values of QT
Tangent
were lower compared with QT
Threshold
and different depending on the correction for heart rate, age, and sex.

Conclusion:

The QT interval varies depending on the method used for its assessment, yet both methods have a high validity and can both be used in diagnosing LQTS. However, for diagnostic purposes current guideline cutoff values yield different results for these 2 methods and could result in inappropriate reassurance or treatment. Adjusted cutoff values are therefore specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for LQTS (
www.QTcalculator.org
) has been made available as an aid in the interpretation of the QT interval.
Probing the Virtual Proteome to Identify Novel Disease Biomarkers
Authors: Mosley Jonathan D. , Benson Mark D. , Smith J. Gustav , Melander Olle , Ngo Debby , Shaffer Christian M. , Ferguson Jane F. , Herzig Matthew S. , McCarty Catherine A. , Chute Christopher G. , Jarvik Gail P. , Gordon Adam S. , Palmer Melody R. , Crosslin David R. , Larson Eric B. , Carrell David S. , Kullo Iftikhar J. , Pacheco Jennifer A. , Peissig Peggy L. , Brilliant Murray H. , Kitchner Terrie E. , Linneman James G. , Namjou Bahram , Williams Marc S. , Ritchie Marylyn D. , Borthwick Kenneth M. , Kiryluk Krzysztof , Mentch Frank D. , Sleiman Patrick M. , Karlson Elizabeth W. , Verma Shefali S. , Zhu Yineng , Vasan Ramachandran S. , Yang Qiong , Denny Josh C. , Roden Dan M. , Gerszten Robert E. , Wang Thomas J. 
Published: January 2019

Background:
Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a “virtual proteomic” approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals.

Methods:
We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651).

Results:

In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08–1.58;
P
=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66–0.94;
P
=0.008) per 1-SD increment in platelet-derived growth factor receptor-β.

Conclusions:
We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.
Safely Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge
Authors: Mahler Simon A. , Lenoir Kristin M. , Wells Brian J. , Burke Gregory L. , Duncan Pamela W. , Case L. Douglas , Herrington David M. , Diaz-Garelli Jose-Franck , Futrell Wendell M. , Hiestand Brian C. , Miller Chadwick D. 
Published: January 2019

Background:
The HEART Pathway (history, ECG, age, risk factors, and initial troponin) is an accelerated diagnostic protocol designed to identify low-risk emergency department patients with chest pain for early discharge without stress testing or angiography. The objective of this study was to determine whether implementation of the HEART Pathway is safe (30-day death and myocardial infarction rate <1% in low-risk patients) and effective (reduces 30-day hospitalizations) in emergency department patients with possible acute coronary syndrome.

Methods:
A prospective pre-post study was conducted at 3 US sites among 8474 adult emergency department patients with possible acute coronary syndrome. Patients included were ≥21 years old, investigated for possible acute coronary syndrome, and had no evidence of ST-segment–elevation myocardial infarction on ECG. Accrual occurred for 12 months before and after HEART Pathway implementation from November 2013 to January 2016. The HEART Pathway accelerated diagnostic protocol was integrated into the electronic health record at each site as an interactive clinical decision support tool. After accelerated diagnostic protocol integration, ED providers prospectively used the HEART Pathway to identify patients with possible acute coronary syndrome as low risk (appropriate for early discharge without stress testing or angiography) or non-low risk (appropriate for further in-hospital evaluation). The primary safety and effectiveness outcomes, death, and myocardial infarction (MI) and hospitalization rates at 30 days were determined from health records, insurance claims, and death index data.

Results:
Preimplementation and postimplementation cohorts included 3713 and 4761 patients, respectively. The HEART Pathway identified 30.7% as low risk; 0.4% of these patients experienced death or MI within 30 days. Hospitalization at 30 days was reduced by 6% in the postimplementation versus preimplementation cohort (55.6% versus 61.6%; adjusted odds ratio, 0.79; 95% CI, 0.71–0.87). During the index visit, more MIs were detected in the postimplementation cohort (6.6% versus 5.7%; adjusted odds ratio, 1.36; 95% CI, 1.12–1.65). Rates of death or MI during follow-up were similar (1.1% versus 1.3%; adjusted odds ratio, 0.88; 95% CI, 0.58–1.33).

Conclusions:
HEART Pathway implementation was associated with decreased hospitalizations, increased identification of index visit MIs, and a very low death and MI rate among low-risk patients. These findings support use of the HEART Pathway to identify low-risk patients who can be safely discharged without stress testing or angiography.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02056964.
Genetic determinants of blood pressure traits are associated with carotid arterial thickening and plaque formation in patients with type 2 diabetes
Authors: Engelbrechtsen Line , Appel Vincent E , Schnurr Theresia M , Lundby-Christensen Louise , Skaaby Thea , Linneberg Allan , Drivsholm Thomas , Witte Daniel R , Jorgensen Marit E , Grarup Niels , Pedersen Oluf , Hansen Torben , Vestergaard Henrik ,   The CIMT Trial Group10
Published: January 2019

Objectives: The aim of this study is to explore the contribution of genetically driven cardiometabolic risk factors for development of carotid arterial thickening in patients with type 2 diabetes. Methods: In total, 12 genetic risk scores for blood pressure, blood lipids and glycaemic traits were constructed. The genetic risk scores were tested for association with carotid intima-media thickness and plaques in patients with type 2 diabetes ( n = 401) and in non-diabetic individuals ( n = 648) and for association with glucose levels in two population-based cohorts ( n = 1328 and n = 6161). Results: In patients with type 2 diabetes, the genetic risk scores for pulse pressure were positively associated with plaque formation ( β = 0.036 ± 0.01 standard deviation/allele, p = 0.003). The genetic risk score for diastolic blood pressure was negatively associated with carotid intima-media thickness ( β = –0.037 ± 0.01 standard deviation/allele, p = 0.005), although not significant after correction for multiple testing ( p < 0.0042). In a meta-analysis of individuals with and without type 2 diabetes, the high-density lipoprotein genetic risk scores showed a trend towards an inverse association with carotid intima-media thickness and plaques, while the low-density lipoprotein genetic risk scores showed a trend towards a positive association with plaque formation but did reach the statistical threshold. Conclusion: Genetic loci for pulse pressure are associated with plaque formation among patients with type 2 diabetes, suggesting an underlying genetic contribution to arterial stiffening and atherosclerosis.
The involvement of mitochondrial fission in maintenance of the stemness of bone marrow mesenchymal stem cells
Authors: Feng Xiaorong , Zhang Wenjing , Yin Wen , Kang Y James 
Published: January 2019

Mitochondrial dynamics, a complicated cellular process consisting of mitochondrial fusion and fission, has been suggested to be involved in regulating the stemness of bone marrow mesenchymal stem cells (BMSCs). This study was undertaken to explore the relationship between mitochondrial dynamics and the maintenance of BMSCs’ stemness. Rat BMSCs were treated with fibroblast growth factor 2 (FGF2) and epithelial growth factor (EGF) to induce differentiation. Mitochondrial dynamics was determined by mitochondrial length observed by confocal microscope and DLP1 (a protein promoting mitochondrial fission), OPA1 (a protein promoting mitochondrial fusion) expression revealed by Western blotting analysis. BMSCs’ stemness was determined by flow cytometry and osteogenic/adipogenic differentiation ability. We found that in the process of BMSCs differentiation, mitochondrial length was increased, along with a decreased protein level of DLP1 and an increased protein level of OPA1 in the mitochondria, indicating a shift toward mitochondrial fusion in BMSCs during differentiation. Notably, when the mitochondrial fission was inhibited by Mdivi-1, the stemness marker, CD90, was deceased along with the reduction of DLP1 expression. Under the same condition, the potential of BMSCs to be induced into adipocytes or osteocytes was decreased. Correspondingly, when BMSCs were treated with tyrphostin A9, a reagent promoting mitochondrial fission by increasing DLP1, the stemness marker, CD54, was increased with an increased potential of BMSCs to be induced into adipocytes or osteocytes. Hence, our results demonstrated that mitochondrial fission contributed to the maintenance of BMSCs’ stemness. Impact statement How to maintain the stemness of bone marrow mesenchymal stem cells (BMSCs) in cultures is a long-standing question. The present study found that mitochondrial dynamics affects the stemness of BMSCs in cultures and the retaining of mitochondrial fission enhances the stemness of BMSCs. This work thus provides a novel insight into strategic approaches to maintain the stemness of BMSCs in cultures in relation to the clinical application of bone-marrow stem cells.
Lower Body Acceleration and Muscular Responses to Rotational and Vertical Whole-Body Vibration at Different Frequencies and Amplitudes
Authors: Zaidell Lisa N. , Pollock Ross D. , James Darren C. , Bowtell Joanna L. , Newham Di J. , Sumners David P. , Mileva Katya N. 
Published: January 2019

Aim: The aim of this study was to characterize acceleration transmission and neuromuscular responses to rotational vibration (RV) and vertical vibration (VV) at different frequencies and amplitudes. Methods: Twelve healthy males completed 2 experimental trials (RV vs VV) during which vibration was delivered during either squatting (30°; RV vs VV) or standing (RV only) with 20, 25, and 30 Hz, at 1.5 and 3.0 mm peak-to-peak amplitude. Vibration-induced accelerations were assessed with triaxial accelerometers mounted on the platform and bony landmarks at ankle, knee, and lumbar spine. Results: At all frequency/amplitude combinations, accelerations at the ankle were greater during RV (all P < .03) with the greatest difference observed at 30 Hz, 1.5 mm. Transmission of RV was also influenced by body posture (standing vs squatting, P < .03). Irrespective of vibration type, vibration transmission to all skeletal sites was generally greater at higher amplitudes but not at higher frequencies, especially above the ankle joint. Acceleration at the lumbar spine increased with greater vibration amplitude but not frequency and was highest with RV during standing. Conclusions/Implications: The transmission of vibration during whole-body vibration (WBV) is dependent on intensity and direction of vibration as well as body posture. For targeted mechanical loading at the lumbar spine, RV of higher amplitude and lower frequency vibration while standing is recommended. These results will assist with the prescription of WBV to achieve desired levels of mechanical loading at specific sites in the human body.
Academic oncology clinicians’ understanding of biosimilars and information needed before prescribing
Authors: Cook John W. , McGrath Megan K. , Dixon Margie D. , Switchenko Jeffrey M. , Harvey R. Donald , Pentz Rebecca D. 
Published: January 2019

Background: With increasing numbers of oncology biosimilars in the approval pipeline, it is important to investigate oncology clinicians’ understanding of biosimilars and what information they need prior to adoption. Methods: Between January and May 2018, 77 oncology clinicians (52 physicians, 16 pharmacists, and 9 advanced practice providers) completed a survey covering three domains: clinician understanding, prescription preferences, and patient involvement. An in-depth interview was designed based on themes identified in the first 50 surveys: cost, safety and efficacy, patient preference, and disease stage. Participants were chosen to participate in the interview based on outlying responses to survey questions. Results: When asked to define a biosimilar, 74% (57/77) of respondents could not give a satisfactory definition, and 40.3% (31/77) considered a biosimilar the same as a generic drug. The most important factor in biosimilar prescription was safety and efficacy (4.51 out of 5) followed closely by cost differences (4.34 out of 5). A 40% increase (53.2–94.8%) in clinicians’ prescribing likelihood was seen after a biosimilar is designated as interchangeable. Participants in this study were split regarding the importance of shared decision-making with patients [50.7% (39/77) important or extremely important, 39.0% (30/77) somewhat or not at all important]. Clinicians were also split concerning the role that pharmacists should play in the decision to prescribe or substitute biosimilars. Conclusion: Understanding of biosimilars is low, and educational needs are high. The information that clinicians deem important to assess, such as safety, efficacy and cost, will need to be provided before they are comfortable prescribing biosimilars.
The African Prospective study on the Early Detection and Identification of Cardiovascular disease and Hypertension (African-PREDICT): Design, recruitment and initial examination
Authors: Schutte Aletta E , Gona Philimon N , Delles Christian , Uys Aletta S , Burger Adele , Mels Catharina MC , Kruger Ruan , Smith Wayne , Fourie Carla MT , Botha Shani , Lammertyn Leandi , van Rooyen Johannes M , Gafane-Matemane Lebo F , Mokwatsi Gontse G , Breet Yolandi , Kruger H Salome , Zyl Tertia van , Pieters Marlien , Zandberg Lizelle , Louw Roan , Moss Sarah J , Khumalo Itumeleng P , Huisman Hugo W 
Published: January 2019

Background Globally hypertension is stabilising, but in sub-Saharan Africa the incidence of hypertension remains on an increase. Although this might be attributed to poor healthcare and ineffective antihypertensive treatment, there is a limited understanding of population and individual-specific cardiovascular pathophysiology – necessary for effective prevention and treatment strategies in Africa. As there is a lack of longitudinal studies tracking the early pathophysiological development of hypertension in black populations, the African-PREDICT study was initiated. The purpose of this paper is to describe the detailed methodology and baseline cohort profile of the study. Methods and results From 2013 to 2017, the study included 1202 black ( N = 606) and white ( N = 596) men and women (aged 20–30 years) from South Africa – screened to be healthy and clinic normotensive. At baseline, and each 5-year follow-up examination, detailed measures of health behaviours, cardiovascular profile and organ damage are taken. Also, comprehensive biological sampling for the ‘omics’ and biomarkers is performed. Overall, the baseline black and white cohort presented with similar ages, clinic and 24-hour blood pressures, but black adults had lower socioeconomic status and higher central systolic blood pressure than white individuals. Conclusions The prospective African-PREDICT study in young black and white adults will contribute to a clear understanding of early cardiovascular disease development.
Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections
Authors: Lounder Dana T. , Bin Qiong , de Min Cristina , Jordan Michael B. 
Published: January 2019

Key Points
Neutralization of IFN-γ with emapalumab can reverse severe, refractory hemophagocytic lymphohistiocytosis. Neutralizing IFN-γ did not impair control of multiple viral and other infections in a severely ill patient.
Targeting ubiquitin-activating enzyme induces ER stress–mediated apoptosis in B-cell lymphoma cells
Authors: Best Scott , Hashiguchi Taylor , Kittai Adam , Bruss Nur , Paiva Cody , Okada Craig , Liu Tingting , Berger Allison , Danilov Alexey V. 
Published: January 2019

Abstract
Alterations in the ubiquitin proteasome system (UPS) leave malignant cells in heightened cellular stress, making them susceptible to proteasome inhibition. However, given the limited efficacy of proteasome inhibitors in non-Hodgkin lymphoma (NHL), novel approaches to target the UPS are needed. Here, we show that TAK-243, the first small-molecule inhibitor of the ubiquitin activating enzyme (UAE) to enter clinical development, disrupts all ubiquitin signaling and global protein ubiquitination in diffuse large B-cell lymphoma (DLBCL) cells, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Activation of the ER stress response protein kinase R (PKR)–like ER kinase and phosphorylation of eukaryotic translation initiator factor 2α led to upregulation of the proapoptotic molecule C/EBP homologous protein and cell death across a panel of DLBCL cell lines independent of cell of origin. Concurrently, targeting UAE led to accumulation of Cdt1, a replication licensing factor, leading to DNA rereplication, checkpoint activation, and cell cycle arrest. MYC oncoprotein sensitized DLBCL cells to UAE inhibition; engineered expression of MYC enhanced while genetic MYC knockdown protected from TAK-243–induced apoptosis. UAE inhibition demonstrated enhanced ER stress and UPR and increased potency compared with bortezomib in DLBCL cell lines. In vivo treatment with TAK-243 restricted the growth of xenografted DLBCL tumors, accompanied by reduced cell proliferation and apoptosis. Finally, primary patient-derived DLBCL cells, including those expressing aberrant MYC, demonstrated susceptibility to UAE inhibition. In sum, targeting UAE may hold promise as a novel therapeutic approach in NHL.
Shikonin inhibits cancer cell cycling by targeting Cdc25s
Authors: Zhang Shoude , Gao Qiang , Li Wei , Zhu Luwei , Shang Qianhan , Feng Shuo , Jia Junmei , Jia Qiangqiang , Shen Shuo , Su Zhanhai 
Published: January 2019

Abstract
Background
Shikonin, a natural naphthoquinone, is abundant in Chinese herb medicine Zicao (purple gromwell) and has a wide range of biological activities, especially for cancer. Shikonin and its analogues have been reported to induce cell-cycle arrest, but target information is still unclear. We hypothesized that shikonin, with a structure similar to that of quinone-type compounds, which are inhibitors of cell division cycle 25 (Cdc25) phosphatases, will have similar effects on Cdc25s. To test this hypothesis, the effects of shikonin on Cdc25s and cell-cycle progression were determined in this paper.

Methods
The in vitro effects of shikonin and its analogues on Cdc25s were detected by fluorometric assay kit. The binding mode between shikonin and Cdc25B was modelled by molecular docking. The dephosphorylating level of cyclin-dependent kinase 1 (CDK1), a natural substrate of Cdc25B, was tested by Western blotting. The effect of shikonin on cell cycle progression was investigated by flow cytometry analysis. We also tested the anti-proliferation activity of shikonin on cancer cell lines by MTT assay. Moreover, in vivo anti-proliferation activity was tested in a mouse xenograft tumour model.

Results
Shikonin and its analogues inhibited recombinant human Cdc25 A, B, and C phosphatase with IC50 values ranging from 2.14 ± 0.21 to 13.45 ± 1.45 μM irreversibly. The molecular modelling results showed that shikonin bound to the inhibitor binding pocket of Cdc25B with a favourable binding mode through hydrophobic interactions and hydrogen bonds. In addition, an accumulation of the tyrosine 15-phosphorylated form of CDK1 was induced by shikonin in a concentration-dependent manner in vitro and in vivo. We also confirmed that shikonin showed an anti-proliferation effect on three cancer cell lines with IC50 values ranging from 6.15 ± 0.46 to 9.56 ± 1.03 μM. Furthermore, shikonin showed a promising anti-proliferation effect on a K562 mouse xenograph tumour model.

Conclusion
In this study, we provide evidence for how shikonin induces cell cycle arrest and functions as a Cdc25s inhibitor. It shows an anti-proliferation effect both in vitro and in vivo by mediating Cdc25s.