bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic fat is a stronger correlate of key clinical and molecular abnormalities than visceral and abdominal subcutaneous fat in youth
Authors: Cioffi Catherine E , Narayan K M Venkat , Liu Ken , Uppal Karan , Jones Dean P , Tran ViLinh , Yu Tianwei , Alvarez Jessica A , Bellissimo Moriah P , Maner-Smith Kristal M , Pierpoint Bridget , Caprio Sonia , Santoro Nicola , Vos Miriam B 
Published: July 2020

IntroductionBody fat distribution is strongly associated with cardiometabolic disease (CMD), but the relative importance of hepatic fat as an underlying driver remains unclear. Here, we applied a systems biology approach to compare the clinical and molecular subnetworks that correlate with hepatic fat, visceral fat, and abdominal subcutaneous fat distribution.Research design and methodsThis was a cross-sectional sub-study of 283 children/adolescents (7–19 years) from the Yale Pediatric NAFLD Cohort. Untargeted, high-resolution metabolomics (HRM) was performed on plasma and combined with existing clinical variables including hepatic and abdominal fat measured by MRI. Integrative network analysis was coupled with pathway enrichment analysis and multivariable linear regression (MLR) to examine which metabolites and clinical variables associated with each fat depot.ResultsThe data divided into four communities of correlated variables (|r|>0.15, p<0.05) after integrative network analysis. In the largest community, hepatic fat was associated with eight clinical biomarkers, including measures of insulin resistance and dyslipidemia, and 878 metabolite features that were enriched predominantly in amino acid (AA) and lipid pathways in pathway enrichment analysis (p<0.05). Key metabolites associated with hepatic fat included branched-chain AAs (valine and isoleucine/leucine), aromatic AAs (tyrosine and tryptophan), serine, glycine, alanine, and pyruvate, as well as several acylcarnitines and glycerophospholipids (all q<0.05 in MLR adjusted for covariates). The other communities detected in integrative network analysis consisted of abdominal visceral, superficial subcutaneous, and deep subcutaneous fats, but no clinical variables, fewer metabolite features (280, 312, and 74, respectively), and limited findings in pathway analysis.ConclusionsThese data-driven findings show a stronger association of hepatic fat with key CMD risk factors compared with abdominal fats. The molecular network identified using HRM that associated with hepatic fat provides insight into potential mechanisms underlying the hepatic fat–insulin resistance interface in youth.
Association between topical beta-blockers and risks of cardiovascular and respiratory disease in patients with glaucoma: a retrospective cohort study
Authors: Chen Hsin-Yi , Huang Wei-Cheng , Lin Cheng-Li , Kao Chia-Hung 
Published: July 2020

ObjectiveTo determine if topical beta-blocker use is associated with increased risks of cardiovascular and respiratory diseases in patients with glaucoma.SettingA retrospective cohort analysis was conducted using the database from Taiwan’s National Health Insurance programme.ParticipantsIn total, 12 336 newly diagnosed patients with glaucoma from January 2000 to December 2010 were included. The patients with glaucoma were subdivided into two cohorts according to whether they used topical beta-blockers or combination drugs (BBCDs).Primary outcome measuresThe study endpoints included pneumonia, acute respiratory failure, stroke and coronary artery disease (CAD). Univariable and multivariable Cox proportional hazards regression models were used to estimate HRs and 95% CIs for the endpoints of both cohorts.ResultsThe BBCD cohort had a slightly higher risk of acute respiratory failure (adjusted HRs=1.16, 95% CI 1.00 to 1.34) and lower risk of CAD (aHR=0.93, 95% CI 0.87 to 0.99) than the non-BBCD cohort. Additionally, the risk of stroke was significantly higher in BBCD cohort than in the non-BBCD cohort (aHR=1.39, 95% CI 1.23 to 1.58), especially the ischaemic stroke (aHR=1.44, 95% CI 1.26 to 1.64; aHR=1.44, 98.75% CI 1.21 to 1.71). After considering the multiplicative interaction of age and sex, the BBCD cohort do not have higher risk of all outcomes than the non-BBCD cohort. Further time-dependent regression analysis revealed BBCD cohort had higher risk of acute respiratory failure (aHR=1.17, 95% CI 1.01 to 1.35) and ischaemic stroke (aHR=1.44, 95% CI 1.26 to 1.65) than non-BBCD cohort. However, after considering the multiplicative interaction of age and sex, the BBCD cohort had no significantly higher risk of all outcomes than the non-BBCD cohort.ConclusionTopical beta-blocker is not associated with increased risks of cardiovascular and respiratory diseases in patients with glaucoma.
Cohort profile: targeted antenatal screening for haemoglobinopathies in Basel
Authors: Amstad Bencaiova Gabriela , Geissler Franziska , Hoesli Irene 
Published: July 2020

PurposeThe pregnancy cohort was established to examine the prevalence and variety of haemoglobinopathies in a high-risk group of pregnant women.ParticipantsThe pregnancy cohort is located in the Department of Obstetrics and Antenatal Care, University Hospital of Basel. The pregnant women were recruited in the first trimester between June 2015 and May 2019. Family origin questionnaires were used to screen pregnant women for the risk of a haemoglobin variant. Based on the questionnaire, pregnant women were divided into two groups: women with a high risk and women with a low risk of a haemoglobin variant. In women with a high risk, red blood cell indices, iron status and chromatography were conducted.Findings to date1785 pregnant women were recruited. Out of the 1785 women, 929 were identified as a part of the high-risk group. Due to the missing data of 74 pregnant women with a high risk, the final analysis was conducted in the remaining 855 women. The prevalence of haemoglobinopathies in the high-risk group was 14.5% (124/855).Future plansThis cohort will be used to: (1) implement the screening in prenatal care in Basel; (2) recommend the screening among pregnant women with a high risk of a haemoglobin variant in Switzerland; (3) improve prenatal and neonatal care in patients with a haemoglobin variant; (4) examine adverse pregnancy outcomes in women with a haemoglobin variant and (5) reduce maternal and neonatal morbidity and mortality in the future.Trial registration numberClinicalTrials.gov Registry (NCT04029142).
A multicentre observational study on neonates exposed to SARS-CoV-2 in China: the Neo-SARS-CoV-2 Study protocol
Authors: Xiao Tiantian , Xia Shiwen , Zeng Linkong , Lin Guang , Wei Qiufen , Zhou Wei , Zhuang Deyi , Chen Xiao , Yi Bin , Li Long , Mi Hongying , Yin Zhaoqing , Cheng Xiuyong , Wang Laishuan , Hu Xiaojing , Zhou Wenhao 
Published: July 2020

IntroductionAn outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, China starting in December 2019. Yet the clinical features and long-term outcomes of neonates with SARS-CoV-2 exposure are lacking. The purpose of this study is to describe the clinical course and prognosis of the neonates exposed to SARS-CoV-2.Methods and analysisThis is a multicentre observational study conducted at the designated children and maternal and child hospitals in the mainland of China. Neonates exposed to SARS-CoV-2 infection will be recruited. The data to be collected via case report forms include demographic details, clinical features, laboratory and imaging results, as well as outcomes. Primary outcomes are the mortality of neonates with COVID-19 and SARS-CoV-2 infection of neonates born to mothers with COVID-19. Secondary outcomes are the birth weight, premature delivery and neurological development of neonates exposed to SARS-CoV-2. The neurological development is assessed by the Chinese standardised Denver Developmental Screening Test at the corrected age of 6 months.Ethics and disseminationThis study has been approved by the Children's Hospital of Fudan University ethics committee (No. (2020)31). The study findings will be disseminated in peer-reviewed journals and presented at national and international conferences in order to improve the understanding of the clinical course among neonates exposed to SARS-CoV-2 and to provide evidence-based treatment and prevention strategies for this group.Trial registration numberNCT04279899.
Development and preliminary validation of the Behçet’s syndrome Overall Damage Index (BODI)
Authors: Piga Matteo , Floris Alberto , Espinosa Gerard , Serpa Pinto Luísa , Kougkas Nikolaos , Lo Monaco Andrea , Lopalco Giuseppe , Orlando Ida , Pirani Vittorio , Santos Ernestina , Bertsias George , Cantarini Luca , Cauli Alberto , Cervera Ricard , Correia João , Govoni Marcello , Iannone Florenzo , Neri Piergiorgio , Martins Silva Ana , Vasconcelos Carlos , Muntoni Monica , Mathieu Alessandro 
Published: July 2020

ObjectiveTo develop and validate the evidence-based and consensus-based Behçet’s Syndrome Overall Damage Index (BODI).MethodsStarting from 120 literature-retrieved preliminary items, the BODI underwent multiple Delphi rounds with an international multidisciplinary panel consisting of rheumatologists, internists, ophthalmologists, neurologists, and patient delegates until consensus was reached on the final content. The BODI was validated in a cross-sectional multicentre cohort of 228 patients with Behçet’s syndrome (BS) through the study of (a) correlation between BODI and Vasculitis Damage Index (VDI) and (b) correlation between BODI and disease activity measures (ie, Behçet’s Disease Current Activity Form (BDCAF), Physician Global Assessment (PGA), Patient Global Assessment (PtGA)), c) content and face validity and (d) feasibility.ResultsThe final BODI consists of 4 overarching principles and 46 unweighted-items grouped into 9 organ domains. It showed good to excellent reliability, with a mean Cohen’s k of 0.84 (95% CI 0.78 to 0.90) and a mean intra-class correlation coefficient of 0.88 (95% CI 0.80 to 0.95). Overall, 128 (56.1%) patients had a BODI score ≥1, with a median score of 1.0 (range 0–14). The BODI significantly correlated with the VDI (r=0.693, p<0.001), demonstrating to effectively measure damage (construct validity), but had greater sensitivity in identifying major organ damage and did not correlate with disease activity measures (ie, BDCAF: p=0.807, PGA: p=0.820, PtGA: p=0.794) discriminating damage from the major confounding factor. The instrument was deemed credible (face validity), complete (content validity) and feasible by an independent group of clinicians.ConclusionsPending further validation, the BODI may be used to assess organ damage in patients with BS in the context of observational and controlled trials.
Born–Infeld black holes in 4D Einstein–Gauss–Bonnet gravity
Authors: Yang Ke , Gu Bao-Min , Wei Shao-Wen , Liu Yu-Xiao 
Published: July 2020

AbstractA novel four-dimensional Einstein-Gauss-Bonnet gravity was formulated by Glavan and Lin (Phys. Rev. Lett. 124:081301, 2020), which is intended to bypass the Lovelock’s theorem and to yield a non-trivial contribution to the four-dimensional gravitational dynamics. However, the validity and consistency of this theory has been called into question recently. We study a static and spherically symmetric black hole charged by a Born–Infeld electric field in the novel four-dimensional Einstein–Gauss–Bonnet gravity. It is found that the black hole solution still suffers the singularity problem, since particles incident from infinity can reach the singularity. It is also demonstrated that the Born-Infeld charged black hole may be superior to the Maxwell charged black hole to be a charged extension of the Schwarzschild-AdS-like black hole in this new gravitational theory. Some basic thermodynamics of the black hole solution is also analyzed. Besides, we regain the black hole solution in the regularized four-dimensional Einstein–Gauss–Bonnet gravity proposed by Lü and Pang (arXiv:2003.11552).
Network motif-based analysis of regulatory patterns in paralogous gene pairs
Authors: Melkus Gatis , Rucevskis Peteris , Celms Edgars , Čerāns Kārlis , Freivalds Karlis , Kikusts Paulis , Lace Lelde , Opmanis Mārtiņš , Rituma Darta , Viksna Juris 
Published: July 2020

Current high-throughput experimental techniques make it feasible to infer gene regulatory interactions at the whole-genome level with reasonably good accuracy. Such experimentally inferred regulatory networks have become available for a number of simpler model organisms such as S. cerevisiae, and others. The availability of such networks provides an opportunity to compare gene regulatory processes at the whole genome level, and in particular, to assess similarity of regulatory interactions for homologous gene pairs either from the same or from different species. We present here a new technique for analyzing the regulatory interaction neighborhoods of paralogous gene pairs. Our central focus is the analysis of S. cerevisiae gene interaction graphs, which are of particular interest due to the ancestral whole-genome duplication (WGD) that allows to distinguish between paralogous transcription factors that are traceable to this duplication event and other paralogues. Similar analysis is also applied to E. coli and C. elegans networks. We compare paralogous gene pairs according to the presence and size of bi-fan arrays, classically associated in the literature with gene duplication, within other network motifs. We further extend this framework beyond transcription factor comparison to obtain topology-based similarity metrics based on the overlap of interaction neighborhoods applicable to most genes in a given organism. We observe that our network divergence metrics show considerably larger similarity between paralogues, especially those traceable to WGD. This is the case for both yeast and C. elegans, but not for E. coli regulatory network. While there is no obvious cross-species link between metrics, different classes of paralogues show notable differences in interaction overlap, with traceable duplications tending toward higher overlap compared to genes with shared protein families. Our findings indicate that divergence in paralogous interaction networks reflects a shared genetic origin, and that our approach may be useful for investigating structural similarity in the interaction networks of paralogous genes.
Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy
Authors: Hinze Laura , Labrosse Roxane , Degar James , Han Teng , Schatoff Emma M. , Schreek Sabine , Karim Salmaan , McGuckin Connor , Sacher Joshua R. , Wagner Florence , Stanulla Martin , Yuan Chen , Sicinska Ewa , Giannakis Marios , Ng Kimmie , Dow Lukas E. , Gutierrez Alejandro 
Published: July 2020

Abstract

Colorectal cancer is driven by mutations that activate canonical WNT/β-catenin signaling, but inhibiting WNT has significant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β-catenin–independent branch of WNT signaling that inhibits GSK3-dependent protein degradation induces asparaginase sensitivity in drug-resistant leukemias. To test predictions from our model, we turned to colorectal cancer because these cancers can have WNT-activating mutations that function either upstream (i.e., R-spondin fusions) or downstream (APC or β-catenin mutations) of GSK3, thus allowing WNT/β-catenin and WNT-induced asparaginase sensitivity to be unlinked genetically. We found that asparaginase had little efficacy in APC or β-catenin–mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3α inhibition was sufficient for asparaginase sensitization in APC or β-catenin–mutant colorectal cancer, but not in normal intestinal progenitors. Our findings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy.

Significance:
Solid tumors are thought to be asparaginase-resistant via de novo asparagine synthesis. In leukemia, GSK3α-dependent protein degradation, a catabolic amino acid source, mediates asparaginase resistance. We found that asparaginase is profoundly toxic to colorectal cancers with WNT-activating mutations that inhibit GSK3. Aberrant WNT activation can provide a therapeutic vulnerability in colorectal cancer.
See related commentary by Davidsen and Sullivan, p. 1632.
This article is highlighted in the In This Issue feature, p. 1611
Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin
Authors: Ahmed Muhammad Usman , Kaneva Valeria , Loyau Stéphane , Nechipurenko Dmitry , Receveur Nicolas , Le Bris Marion , Janus-Bell Emily , Didelot Mélusine , Rauch Antoine , Susen Sophie , Chakfé Nabil , Lanza François , Gardiner Elizabeth E. , Andrews Robert K. , Panteleev Mikhail , Gachet Christian , Jandrot-Perrus Martine , Mangin Pierre H. 
Published: July 2020

Objective:
Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation of a mural thrombus. Computational fluid dynamics and numerical models indicated that the mechanical stress applied to a thrombus increases dramatically as a thrombus grows, and that strong inter-platelet interactions are essential to maintain its stability. We investigated whether GPVI (glycoprotein VI)-mediated platelet activation helps to maintain thrombus stability by using real-time video-microscopy.

Approach and Results:
We showed that GPVI blockade with 2 distinct Fab fragments promoted efficient disaggregation of human thrombi preformed on collagen or on human atherosclerotic plaque material in the absence of thrombin. ACT017-induced disaggregation was achieved under arterial blood flow conditions, and its effect increased with wall shear rate. GPVI regulated platelet activation within a growing thrombus as evidenced by the loss in thrombus contraction when GPVI was blocked, and the absence of the disaggregating effect of an anti-GPVI agent when the thrombi were fully activated with soluble agonists. The GPVI-dependent thrombus stabilizing effect was further supported by the fact that inhibition of any of the 4 key immunoreceptor tyrosine-based motif signalling molecules, src-kinases, Syk, PI3Kβ, or phospholipase C, resulted in kinetics of thrombus disaggregation similar to ACT017. The absence of ACT017-induced disaggregation of thrombi from 2 afibrinogenemic patients suggests that the role of GPVI requires interaction with fibrinogen. Finally, platelet disaggregation of fibrin-rich thrombi was also promoted by ACT017 in combination with r-tPA (recombinant tissue plasminogen activator).

Conclusions:
This work identifies an unrecognized role for GPVI in maintaining thrombus stability and suggests that targeting GPVI could dissolve platelet aggregates with a poor fibrin content.
Fibrosis and Inflammatory Markers and Long-Term Risk of Peripheral Artery Disease
Authors: Ding Ning , Yang Chao , Ballew Shoshana H. , Kalbaugh Corey A. , McEvoy John W. , Salameh Maya , Aguilar David , Hoogeveen Ron C. , Nambi Vijay , Selvin Elizabeth , Folsom Aaron R. , Heiss Gerardo , Coresh Josef , Ballantyne Christie M. , Matsushita Kunihiro 
Published: July 2020

Objective:
Inflammatory markers, such as hs-CRP (high-sensitivity C-reactive protein), have been reported to be related to peripheral artery disease (PAD). Galectin-3, a biomarker of fibrosis, has been linked to vascular remodeling and atherogenesis. However, its prospective association with incident PAD is unknown; as is the influence of inflammation on the association between galectin-3 and PAD.

Approach and Results:

In 9851 Atherosclerosis Risk in Communities Study participants free of PAD at baseline (1996–1998), we quantified the association of galactin-3 and hs-CRP with incident PAD (hospitalizations with PAD diagnosis [
International Classification of Diseases
-
Ninth Revision
: 440.2–440.4] or leg revascularization [eg,
International Classification of Diseases
-
Ninth Revision
: 38.18]) as well as its severe form, critical limb ischemia (PAD cases with resting pain, ulcer, gangrene, or leg amputation) using Cox models. Over a median follow-up of 17.4 years, there were 316 cases of PAD including 119 critical limb ischemia cases. Log-transformed galectin-3 was associated with incident PAD (adjusted hazard ratio, 1.17 [1.05–1.31] per 1 SD increment) and critical limb ischemia (1.25 [1.05–1.49] per 1 SD increment). The association was slightly attenuated after further adjusting for hs-CRP (1.14 [1.02–1.27] and 1.22 [1.02–1.45], respectively). Log-transformed hs-CRP demonstrated robust associations with PAD and critical limb ischemia even after adjusting for galectin-3 (adjusted hazard ratio per 1 SD increment 1.34 [1.18–1.52] and 1.34 [1.09–1.65], respectively). The addition of galectin-3 and hs-CRP to traditional atherosclerotic predictors (C statistic of the base model 0.843 [0.815–0.871]) improved the risk prediction of PAD (ΔC statistics, 0.011 [0.002–0.020]).

Conclusions:
Galectin-3 and hs-CRP were independently associated with incident PAD in the general population, supporting the involvement of fibrosis and inflammation in the pathophysiology of PAD.
Bilateral Bundle Branch Area Pacing to Achieve Physiological Conduction System Activation
Authors: Lin Jinxuan , Chen Keping , Dai Yan , Sun Qi , Li Yuqiu , Jiang Yong , Zhou Yu’an , Chen Ruohan , Jin Yuanhao , Yan Lirong , Zhou Xiaohong , Cheng Alan , Zhang Xue , Gold Michael R. , Zhang Shu 
Published: July 2020

Background:
Left bundle branch pacing (LBBP) is a technique for conduction system pacing, but it often results in right bundle branch block morphology on the ECG. This study was designed to assess simultaneous pacing of the left and right bundle branch areas to achieve more synchronous ventricular activation.

Methods:
In symptomatic bradycardia patients, the distal electrode of a bipolar pacing lead was placed at the left bundle branch area via a transventricular-septal approach. This was used to pace the left bundle branch area, while the ring electrode was used to pace the right bundle branch area. Bilateral bundle branch area pacing (BBBP) was achieved by stimulating the cathode and anode in various pacing configurations. QRS duration, delayed right ventricular activation time, left ventricular activation time, and interventricular conduction delay were measured. Pacing stability and short-term safety were assessed at 3-month follow-up.

Results:

BBBP was successfully performed in 22 of 36 patients. Compared with LBBP, BBBP resulted in greater shortening of QRS duration (109.3±7.1 versus 118.4±5.7 ms,
P
<0.001). LBBP resulted in a paced right bundle branch block configuration, with a delayed right ventricular activation time of 115.0±7.5 ms and interventricular conduction delay of 34.0±8.8 ms. BBBP fully resolved the right bundle branch block morphology in 18 patients. In the remaining 4 patients, BBBP partially corrected the right bundle branch block with delayed right ventricular activation time decreasing from 120.5±4.7 ms during LBBP to 106.1±4.2 ms during BBBP (
P
=0.005).

Conclusions:
LBBP results in a relatively narrow QRS complex but with an interventricular activation delay. BBBP can diminish the delayed right ventricular activation, producing more physiological ventricular activation.

Graphic Abstract:

A
graphic abstract
is available for this article.