bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excess of singleton loss-of-function variants in Parkinson’s disease contributes to genetic risk
Authors: Bobbili Dheeraj Reddy , Banda Peter , Krüger Rejko , May Patrick 
Published: February 2020

BackgroundParkinson’s disease (PD) is a neurodegenerative disorder with complex genetic architecture. Besides rare mutations in high-risk genes related to monogenic familial forms of PD, multiple variants associated with sporadic PD were discovered via association studies.MethodsWe studied the whole-exome sequencing data of 340 PD cases and 146 ethnically matched controls from the Parkinson’s Progression Markers Initiative (PPMI) and performed burden analysis for different rare variant classes. Disease prediction models were built based on clinical, non-clinical and genetic features, including both common and rare variants, and two machine learning methods.ResultsWe observed a significant exome-wide burden of singleton loss-of-function variants (corrected p=0.037). Overall, no exome-wide burden of rare amino acid changing variants was detected. Finally, we built a disease prediction model combining singleton loss-of-function variants, a polygenic risk score based on common variants, and family history of PD as features and reached an area under the curve of 0.703 (95% CI 0.698 to 0.708). By incorporating a rare variant feature, our model increased the performance of the state-of-the-art classification model for the PPMI dataset, which reached an area under the curve of 0.639 based on common variants alone.ConclusionThe main finding of this study is to highlight the contribution of singleton loss-of-function variants to the complex genetics of PD and that disease risk prediction models combining singleton and common variants can improve models built solely on common variants.
Global and regional burden of chronic respiratory disease in 2016 arising from non-infectious airborne occupational exposures: a systematic analysis for the Global Burden of Disease Study 2016
Authors:   GBD 2016 Occupational Chronic Respiratory Risk Factors Collaborators
Published: February 2020

ObjectivesThis paper presents detailed analysis of the global and regional burden of chronic respiratory disease arising from occupational airborne exposures, as estimated in the Global Burden of Disease 2016 study.MethodsThe burden of chronic obstructive pulmonary disease (COPD) due to occupational exposure to particulate matter, gases and fumes, and secondhand smoke, and the burden of asthma resulting from occupational exposure to asthmagens, was estimated using the population attributable fraction (PAF), calculated using exposure prevalence and relative risks from the literature. PAFs were applied to the number of deaths and disability-adjusted life years (DALYs) for COPD and asthma. Pneumoconioses were estimated directly from cause of death data. Age-standardised rates were based only on persons aged 15 years and above.ResultsThe estimated PAFs (based on DALYs) were 17% (95% uncertainty interval (UI) 14%–20%) for COPD and 10% (95% UI 9%–11%) for asthma. There were estimated to be 519 000 (95% UI 441,000–609,000) deaths from chronic respiratory disease in 2016 due to occupational airborne risk factors (COPD: 460,100 [95% UI 382,000–551,000]; asthma: 37,600 [95% UI 28,400–47,900]; pneumoconioses: 21,500 [95% UI 17,900–25,400]. The equivalent overall burden estimate was 13.6 million (95% UI 11.9–15.5 million); DALYs (COPD: 10.7 [95% UI 9.0–12.5] million; asthma: 2.3 [95% UI 1.9–2.9] million; pneumoconioses: 0.58 [95% UI 0.46–0.67] million). Rates were highest in males; older persons and mainly in Oceania, Asia and sub-Saharan Africa; and decreased from 1990 to 2016.ConclusionsWorkplace exposures resulting in COPD, asthma and pneumoconiosis continue to be important contributors to the burden of disease in all regions of the world. This should be reducible through improved prevention and control of relevant exposures.
Prognostic significance of LINC00460 overexpression in solid tumours: a meta-analysis
Authors: Dai Chen , Zhang Yan , Ni Hao , Kuang Yuting , Xu Zhihua 
Published: February 2020

AbstractThe prognostic value of long intergenic non-protein coding RNA 460 (LINC00460) overexpression in human solid malignant tumours remains unclear. Therefore, we conducted the meta-analysis to systematically review and assess the evidence for the correlation between LINC00460 overexpression and clinicopathological features and overall survival (OS) of patients with solid malignant tumour. An electronic search of PubMed, EMBASE, Web of Science, CNKI, Cochrane Library, Chinese Biological Medical Literature database and WanFang database was applied to select eligible articles. Pooled ORs or HRs with their 95% CIs were calculated to estimate the effects. 9 eligible studies with a total of 935 patients were enrolled in this meta-analysis. The results revealed that high LINC00460 expression was associated with positive lymph node metastasis (positive vs negative: OR=2.97, 95% CI 1.74 to 5.05, p=0.812), advanced tumour-node-metastasis stage (III+IV vs I+II: OR=2.82, 95% CI 1.64 to 4.85, p=0.193) and poorer differentiation (high vs low: OR=0.60, 95% CI 0.36 to 0.99, p=0.569). Additionally, the overexpression of LINC00460 could predict a poorer OS (HR=1.57, 95% CI 1.39 to 1.77) and the shorter disease-free survival (HR=2.32, 95% CI 1.25 to 4.31). Furthermore, according to subgroup analysis and meta-regression results, the heterogeneity of current meta-analysis may be attributed to the differences of cancer type and follow-up months. High expression of LINC00460 could predict poor prognosis in patients with solid malignant tumour. LINC00460 may serve as potential prognostic biomarker for clinical outcomes in various human solid malignant tumours.
The improving effects of biotin on hepatic histopathology and related apolipoprotein mRNA expression in laying hens with fatty liver hemorrhagic syndrome
Authors: Huang Jiamei , Li Guyue , Cao Hongfeng , Yang Fei , Xing Chenghong , Zhuang Yu , Zhang Caiying , Liu Ping , Cao Huabin , Hu Guoliang 
Published: February 2020

Fatty liver hemorrhagic syndrome (FLHS) is a metabolic disease mostly observed in laying hens that causes an economic toll on the poultry industry. To investigate the improving effects of biotin on FLHS in laying hens, a total of 135 Hy-Line Brown layers of 300-d-old were randomly divided into three groups and treated for 60 d. The hens from these three groups were fed with different diets: control group (the basal diet), pathology group [high-energy-low-protein diet (HELP)], and treatment group (HELP containing a biotin dosage of 0.3 mg kg−1). The results showed that the mRNA expression level of apolipoprotein A I (apoA I) in pathology group significantly (P < 0.01) decreased on day 60 compared with the control group, while the mRNA level of apolipoprotein B100(apoB100) increased significantly in pathology group on day 30, whereas it decreased significantly on day 60 (P < 0.05). Significantly increased mRNA levels of apoA I and apoB100were observed in treatment group compared with the pathology group on days 30 and 60 (P < 0.05 or P < 0.01). These results indicated that biotin could effectively alleviate the pathological changes and abnormal expression of apoA I and apoB100induced by FLHS, which might closely relate to the ability of biotin to promote egg production.
Development of an app for fluid dynamics simulations in small and large vessels
Authors: Fragomeni Gionata , Gaudio Lina Teresa 
Published: February 2020

The rheological properties of the blood depend on numerous factors among which the geometry and the size of the conduit in which the blood circulates. The human body is made up by vessels having a different structure and characteristics, which depend on the function they perform, above all on the pressure they have to bear generated at the cardiac level.
So, a great criticality when approaching a study on blood flow behavior in the circulatory system is to use an appropriate mathematical model for the circulating fluid.
Though the CFD analysis (computational fluid dynamics), going to investigate what are the differences produced by the use of models in the study of vessels of different caliber can be a valid support in the study of vessel fluid dynamics, in particular if they are affected by pathologies.
In this regard, the aim of this work, is through the implementation of an application, to carry out a statistical analysis of the effects of different blood flow models in arteries to identifying a prediction about the percentage variation of the shear stress indices involved in the impact of atherosclerotic plaque.
Sinais de risco para o suicídio em mulheres com história de violência doméstica
Authors: Correia Cíntia Mesquita , Diniz Normélia Maria Freire , Gomes Nadirlene Pereira , Andrade Isabela Carolyne Sena de , Campos Luana Moura , Carneiro Jordana Brock 
Published: February 2020

Objetivo: Identificar sinais de risco para o suicídio em mulheres com história de violência doméstica. Método: Estudo exploratório-descritivo, com abordagem qualitativa. Participaram dez mulheres com história de violência doméstica e tentativa de suicídio por envenenamento. A pesquisa foi realizada no Núcleo de Estudo e Prevenção do Suicídio, vinculado a um Centro de Informação Toxicológica, em Salvador, Bahia, Brasil. Resultados: Sinaliza para a relação entre a vivência de violência doméstica e o comprometimento para a saúde mental, representado por: Comportamento depressivo e Comportamento suicida. Conclusão: O estudo revelou comportamentos que consistem em sinais de alerta para o risco de suicídio, ao tempo em que oferece subsídios para a promoção de estratégias de cuidado às mulheres com história de violência doméstica.
Angiocrine FSTL1 (Follistatin-Like Protein 1) Insufficiency Leads to Atrial and Venous Wall Fibrosis via SMAD3 Activation
Authors: Jiang Haijuan , Zhang Luqing , Liu Xuelian , Sun Wei , Kato Katsuhiro , Chen Chuankai , Li Xiao , Li Taotao , Sun Zhiliang , Han Wencan , Zhang Fujing , Xiao Qi , Yang Zhongzhou , Hu Junhao , Qin Zhihai , Adams Ralf H. , Gao Xiang , He Yulong 
Published: February 2020

Objective:
Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell–derived FSTL1 (follistatin-like protein 1) in vascular homeostasis.

Approach and Results:

Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells (
Fstl1

ECKO

) led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with
Fstl1
knockout in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers of
Fstl1

ECKO

mutants. The SMAD3 (mothers against decapentaplegic homolog 3) phosphorylation (pSMAD3) was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ (transforming growth factor β) signaling in vascular mural cells of
Fstl1

ECKO

mice. Consistently, treatment with a TGFβ pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels in
Fstl1

ECKO

mutant mice.

Conclusions:
The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.
Noninvasive Assessment of Complexity of Atrial Fibrillation
Authors: Rodrigo Miguel , Climent Andreu M. , Hernández-Romero Ismael , Liberos Alejandro , Baykaner Tina , Rogers Albert J. , Alhusseini Mahmood , Wang Paul J. , Fernández-Avilés Francisco , Guillem Maria S. , Narayan Sanjiv M. , Atienza Felipe 
Published: February 2020

Background:
It is difficult to noninvasively phenotype atrial fibrillation (AF) in a way that reflects clinical end points such as response to therapy. We set out to map electrical patterns of disorganization and regions of reentrant activity in AF from the body surface using electrocardiographic imaging, calibrated to panoramic intracardiac recordings and referenced to AF termination by ablation.

Methods:
Bi-atrial intracardiac electrograms of 47 patients with AF at ablation (30 persistent, 29 male, 63±9 years) were recorded with 64-pole basket catheters and simultaneous 57-lead body surface ECGs. Atrial epicardial electrical activity was reconstructed and organized sites were invasively and noninvasively tracked in 3-dimension using phase singularity. In a subset of 17 patients, sites of AF organization were targeted for ablation.

Results:

Body surface mapping showed greater AF organization near intracardially detected drivers than elsewhere, both in phase singularity density (2.3±2.1 versus 1.9±1.6;
P
=0.02) and number of drivers (3.2±2.3 versus 2.7±1.7;
P
=0.02). Complexity, defined as the number of stable AF reentrant sites, was concordant between noninvasive and invasive methods (r
2
=0.5; CC=0.71). In the subset receiving targeted ablation, AF complexity showed lower values in those in whom AF terminated than those in whom AF did not terminate (
P
<0.01).

Conclusions:
AF complexity tracked noninvasively correlates well with organized and disorganized regions detected by panoramic intracardiac mapping and correlates with the acute outcome by ablation. This approach may assist in bedside monitoring of therapy or in improving the efficacy of ongoing ablation procedures.
A Novel “Cut and Paste” Method for In Situ Replacement of cMyBP-C Reveals a New Role for cMyBP-C in the Regulation of Contractile Oscillations
Authors: Napierski Nathaniel C. , Granger Kevin , Langlais Paul R. , Moran Hannah R. , Strom Joshua , Touma Katia , Harris Samantha P. 
Published: February 2020

Rationale:
cMyBP-C (cardiac myosin-binding protein-C) is a critical regulator of heart contraction, but the mechanisms by which cMyBP-C affects actin and myosin are only partly understood. A primary obstacle is that cMyBP-C localization on thick filaments may be a key factor defining its interactions, but most in vitro studies cannot duplicate the unique spatial arrangement of cMyBP-C within the sarcomere.

Objective:
The goal of this study was to validate a novel hybrid genetic/protein engineering approach for rapid manipulation of cMyBP-C in sarcomeres in situ.

Methods and Results:

We designed a novel cut and paste approach for removal and replacement of cMyBP-C N′-terminal domains (C0–C7) in detergent-permeabilized cardiomyocytes from gene-edited Spy-C mice. Spy-C mice express a TEVp (tobacco etch virus protease) cleavage site and a SpyTag (st) between cMyBP-C domains C7 and C8. A cut is achieved using TEVp which cleaves cMyBP-C to create a soluble N′-terminal
γ
C0C7 (endogenous [genetically encoded] N′-terminal domains C0 to C7 of cardiac myosin binding protein-C) fragment and an insoluble C′-terminal SpyTag-C8-C10 fragment that remains associated with thick filaments. Paste of new recombinant (
r
)C0C7 domains is achieved by a covalent bond formed between SpyCatcher (-sc; encoded at the C′-termini of recombinant proteins) and SpyTag. Results show that loss of
γ
C0C7 reduced myofilament Ca
2+
sensitivity and increased cross-bridge cycling (
k
tr
) at submaximal [Ca
2+
]. Acute loss of
γ
C0C7 also induced auto-oscillatory contractions at submaximal [Ca
2+
]. Ligation of
r
C0C7 (exogenous [recombinant] N′-terminal domains C0 to C7 of cardiac myosin binding protein-C)-sc returned pCa
50
and
k
tr
to control values and abolished oscillations, but phosphorylated (p)-
r
C0C7-sc did not completely rescue these effects.

Conclusions:

We describe a robust new approach for acute removal and replacement of cMyBP-C in situ. The method revealed a novel role for cMyBP-C N′-terminal domains to damp sarcomere-driven contractile waves (so-called spontaneous oscillatory contractions). Because phosphorylated (p)-
r
C0C7-sc was less effective at damping contractile oscillations, results suggest that spontaneous oscillatory contractions may contribute to enhanced contractility in response to inotropic stimuli.
Value of Troponin Testing for Detection of Heart Disease in Previously Healthy Children
Authors: Dionne Audrey , Kheir John N. , Sleeper Lynn A. , Esch Jesse J. , Breitbart Roger E. 
Published: February 2020

Background
Troponin levels are frequently obtained in pediatric patients, but the benefit remains unclear.

Methods and Results

This retrospective study included 1993 patients aged 0 to 21 years without history of cardiac disease in whom troponin levels were obtained during clinical evaluation of cardiac and noncardiac presentations. Troponin was elevated (≥0.1 ng/mL) in 182 patients (9%). A cardiac diagnosis was made in 109 (60%) of those with elevated troponin and in 208 (12%) of those without (
P
<0.001). The positive predictive value of elevated troponin for a cardiac diagnosis was 60% for the entire cohort and 85% for patients with a cardiac presentation. The negative predictive value of nonelevated troponin was 89% for the entire cohort and 96% in patients without a cardiac presentation. Serial testing did not improve these predictive values. However, among 404 patients with initially nonelevated levels who had serial measurements, subsequent elevation was found in 80 (20%), of whom 15 (19%) had a cardiac diagnosis. The optimal troponin cutoff value to differentiate cardiac from noncardiac diagnosis was higher in children aged <3 months (0.045 ng/mL) compared with those aged ≥3 months (0.005 ng/mL).

Conclusions
Troponin can be a useful adjunctive test in the evaluation of children when the differential diagnosis includes cardiac etiologies. Serial measurement was not helpful when troponin was elevated at presentation but may merit consideration when the initial level is not elevated and there is ongoing concern about cardiac involvement. Lower reference values may be appropriate when evaluating children in contrast to adults.
Teaching Health and Human Rights in a Globalised Classroom
Authors: Ó Cathaoir Katharina 
Published: February 2020

Abstract
This article outlines the importance of human rights in the health law curriculum. The author reflects on her experiences of teaching Health and Human Rights at the Faculty of Law, University of Copenhagen. Health and human rights, it is argued, can have important implications for students’ understanding of health and the role of law. Namely, it underscores the obligations of states and the rights of individuals, as well as the need for health laws and policies to respect rights. This approach prohibits health laws that discriminate or stigmatise. Furthermore, it is put forth that the growing body of socioeconomic rights jurisprudence should be integrated into teaching. Equally, students should be prepared for the needs of the modern labour market: interdisciplinarity and digitalisation, and to assess the human rights implications. Finally, educators must acknowledge and discuss the limitations of rights so that students are equipped to address and solve challenges.
Testing the Limits and Breakdown of the Nonacceleration Theorem for Orographic Stationary Waves
Authors: Lutsko Nicholas J. 
Published: February 2020

AbstractThe nonacceleration theorem states that the torque exerted on the atmosphere by orography is exactly balanced by the convergence of momentum by the stationary waves that the orography excites. This balance is tested in simulations with a stationary wave model and with a dry, idealized general circulation model (GCM), in which large-scale orography is placed at the latitude of maximum surface wind speed. For the smallest mountain considered (maximum height H = 0.5 m), the nonacceleration balance is nearly met, but the damping in the stationary wave model induces an offset between the stationary eddy momentum flux (EMF) convergence and the mountain torque, leading to residual mean flow changes. A stationary nonlinearity appears for larger mountains (H ≥ 10 m), driven by preferential deflection of the flow around the poleward flank of the orography, and causes further breakdown of the nonacceleration balance. The nonlinearity grows as H is increased, and is stronger in the GCM than in the stationary wave model, likely due to interactions with transient eddies. The midlatitude jet shifts poleward for H ≤ 2 km and equatorward for larger mountains, reflecting changes in the transient EMFs, which push the jet poleward for smaller mountains and equatorward for larger mountains. The stationary EMFs consistently force the jet poleward. These results add to our understanding of how orography affects the atmosphere’s momentum budget, providing insight into how the nonacceleration theorem breaks down; the roles of stationary nonlinearities and transients; and how orography affects the strength and latitude of eddy-driven jets.
The Influence of Stratospheric Wave Reflection on North American Cold Spells
Authors: Matthias Vivien , Kretschmer Marlene 
Published: February 2020

AbstractUnderstanding and predicting midlatitude cold spells is of scientific and public interest, given often associated severe impacts. However, large-scale atmospheric dynamics related to these events are not fully understood. The winter of 2017/18 was characterized by several cold spells affecting large parts of North America and Eurasia. Here, the role of stratosphere–troposphere coupling for the occurrence of cold spells in this winter is investigated using different wave propagation diagnostics. While the European cold spell in late February 2018 was influenced by a major sudden stratospheric warming (SSW) associated with wave absorption, the cold spells over North America at the end of December 2017 and early February 2018 were related to downward reflected waves over the North Pacific. Previously proposed wave reflection indices, however, either miss these reflection events or are not able to distinguish them from the major SSW related to wave absorption. To overcome this, a novel simple index based on eddy heat flux is proposed here, capturing regional wave reflection over the North Pacific. Reflection events detected with this index are shown to be followed by North Pacific blocking and negative temperature anomalies over North America. An improved understanding of the contribution of wave reflection for cold spells is crucial to better predict such events in the future.