bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptome-Wide Association Study for Inflammatory Bowel Disease Reveals Novel Candidate Susceptibility Genes in Specific Colon Subsites and Tissue Categories
Authors: Díez-Obrero Virginia , Moratalla-Navarro Ferran , Ibáñez-Sanz Gemma , Guardiola Jordi , Rodríguez-Moranta Francisco , Obón-Santacana Mireia , Díez-Villanueva Anna , Dampier Christopher Heaton , Devall Matthew , Carreras-Torres Robert , Casey Graham , Moreno Victor 
Published: July 2021

Abstract

Background and Aims
Genome-wide association studies [GWAS] for inflammatory bowel disease [IBD] have identified 240 risk variants. However, the benefit of understanding the genetic architecture of IBD remains to be exploited. Transcriptome-wide association studies [TWAS] associate gene expression with genetic susceptibility to disease, providing functional insight into risk loci. In this study, we integrate relevant datasets for IBD and perform a TWAS to nominate novel genes implicated in IBD genetic susceptibility.

Methods
We applied elastic net regression to generate gene expression prediction models for the University of Barcelona and University of Virginia RNA sequencing project [BarcUVa-Seq] and correlated expression and disease association research [CEDAR] datasets. Together with Genotype-Tissue Expression project [GTEx] data, and GWAS results from about 60 000 individuals, we employed Summary-PrediXcan and Summary-MultiXcan for single and joint analyses of TWAS results, respectively.

Results
BarcUVa-Seq TWAS revealed 39 novel genes whose expression in the colon is associated with IBD genetic susceptibility. They included expression markers for specific colon cell types. TWAS meta-analysis including all tissues/cell types provided 186 novel candidate susceptibility genes. Additionally, we identified 78 novel susceptibility genes whose expression is associated with IBD exclusively in immune (N = 19), epithelial (N = 25), mesenchymal (N = 22) and neural (N = 12) tissue categories. Associated genes were involved in relevant molecular pathways, including pathways related to known IBD therapeutics, such as tumour necrosis factor signalling.

Conclusion
These findings provide insight into tissue-specific molecular processes underlying IBD genetic susceptibility. Associated genes could be candidate targets for new therapeutics and should be prioritized in functional studies.
Wells and Geneva decision rules to predict pulmonary embolism: can we use them in Covid-19 patients?
Authors: Silva BV , Jorge C , Rigueira J , Rodrigues T , Silverio Antonio P , Morais P , Pereira S , Alves Da Silva P , Brito J , Placido R , G Almeida A , J Pinto F 
Published: July 2021

Abstract

Funding Acknowledgements
Type of funding sources: None.

Introduction
Pulmonary embolism (PE) is a recognized complication of SARS-COV2 infection due to hypercoagulability. Before the COVID era, the need for computed tomography pulmonary angiography (CTPA) to rule out PE was determined by clinical probability, based on Wells and Geneva scores, in association with D-dimer measurements. However, patients with SARS-COV2 infection have a pro-thrombotic and pro-inflammatory state which may compromise the usefulness of these algorithms to select patients for CTPA.

Purpose
To evaluate the accuracy of the Wells and Geneva scores to predict PE in patients with SARS-COV2 infection.

Methods
Retrospective study of consecutive outpatients with SARS-COV2 infection proved by positive PCR who underwent CTPA due to suspected PE. The Wells and Geneva scores were calculated and the area under the curve (AUC) of the receiver operating characteristic curve was measured.

Results
We enrolled 235 patients (61% males, mean age 69.10 ± 16.69 years) and the incidence of pulmonary embolism was 15% (35 patients). In patients with PE, emboli were located mainly in segmental arteries (60%) and bilaterally (46%). Patients with PE were older (mean age 75.06 ± 2.23 vs. 68.06 ± 1.21 years, p = 0.022), and did not differ in sex or risk factors for thromboembolic diseases from the non-PE group. Patients with PE had higher D-dimer levels (median 15.41 mg/dl, IQR 1.17 – 20.00) compared to patients without PE (median 5.99 mg/dl, IQR 0.47 – 2.82, p &lt; 0.001).
There was no statically significant difference between the average Wells score in patients with PE and without PE (1.04 and 0.89 respectively, p = 0.733) and the AUC demonstrated that the Wells score had no discriminatory power (AUC = 0.52). Within patients with PE, 19 patients had a Wells score of zero. Regarding the Geneva score, there was also no difference between the average score in patients with and without PE (4.20 vs 3.93 respectively, p = 0.420). AUC for Geneva score was 0.54.
Clinical probability combined with D-dimer measurement had a 100% sensitivity for both Wells and Geneva scores, but a specificity of 10% and 11%, respectively.

Conclusion
PE diagnosis may be challenging in patients with SARS-COV2 infection since both conditions may have similar signs and symptoms and may be associated with increased D-dimers. According to our results, traditional clinical prediction scores have little discriminatory power in these patients and a higher D-dimer cut-off should be considered to better select patients for CTPA to minimize radiation exposure and contrast-related complications in COVID-19 patients.
Anomalous origin of the right coronary artery with interarterial course: red flag or innocent bystander?
Authors: Albuquerque F , De Araujo Goncalves P , Marques H , Ferreira A , Freitas P , Lopes P , Goncalves M , Dores H , Cardim N 
Published: July 2021

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Anomalous origin of the right coronary artery (right ACAOS) with interarterial course (IAC) has been associated with increased risk of sudden cardiac death (SCD). Widespread use of coronary computed tomographic angiography (CCTA) has led to increasing recognition of this condition, even among healthy individuals. This study sought to examine the prevalence, anatomical characteristics and outcomes of right ACAOS with IAC in patients undergoing CCTA for all-indications.

Methods
We conducted a retrospective analysis of consecutive patients referred for CCTA at one tertiary hospital between January 2012 and December 2020. Right ACAOS patients with IAC were analyzed for cardiac symptoms (anginal chest pain, syncope, aborted SCD) and long-term outcomes were evaluated for myocardial infarction, ischemic test results, revascularization procedures and all-cause or cardiovascular (CV) mortality. CCTAs were reviewed for proposed high-risk features (ie., take-off angle, length and severity of proximal narrowing, intramural course, interarterial length) and concomitant coronary artery disease (CAD). Association between high-risk features was analyzed. Long-term outcomes were evaluated.

Results
Among 10,928 patients referred for CCTA during the study period, we identified 28 patients (0.3% prevalence) with right ACAOS and IAC. Mean age was 55 ± 17 years, 64% were male and 11 (39.3%) presented cardiac symptoms. During a median follow-up of 44.1 ± 31.8 months, there were no CV deaths and only 1 patient (3.65%) underwent surgical revascularization. Baseline characteristics and CCTA findings are presented in figure 1.

Conclusion
Right ACAOS and IAC is an uncommon finding, with an observed prevalence of 0.3%. CCTA provides excellent anatomical characterization of anomalous vessels, including suggested high-risk features. In a population of asymptomatic patients who survived this condition well into adulthood, the risk of events was very low and medical follow up might be a reasonable option.
Prognostic value of myocardial MIBG scintigraphy in acute ischemic stroke
Authors: Bourgeois S , Peeters I , Vanderschueren G , Nous A , De Keyser J , Nakajima K , Poel E , Verberne HJ , De Raedt S 
Published: July 2021

Abstract

Funding Acknowledgements
Type of funding sources: None.
Background Autonomic dysfunction is a common complication of acute ischemic stroke and has been associated with poor functional outcome and increased mortality. We investigated the potential relation between the myocardial washout rate (WOR) of 123I-meta-iodobenzylguanidine (123I-mIBG), as a measure of cardiac sympathetic activity, and functional outcome in acute ischemic stroke.
Methods 38 patients with ischemic stroke (11 females, 72 years old [61-81)), underwent myocardial 123I-mIBG scintigraphy within the first week after stroke onset. Early (10 minutes post-injection (pi)) and late (4 hours pi) planar scans of the thoracic region were made. Regions of interest (ROI) were drawn over the mediastinum and the heart, and heart-to-mediastinum ratio (HMR) was calculated. Myocardial WOR was calculated as follows: (ROI heart early – ROI heart late)/ (ROI heart early) x 100%. Counts were corrected for background and counts in ROI heart late were corrected for decay. Patients were divided in 2 groups: those with a good functional outcome, defined as modified Rankin Scale (mRS) ≤ 2 at 3 months after stroke (i.e., patient is functionally independent), and those with a poor functional outcome, defined as a mRS &gt; 2.
Results Median WOR was 27,4 % (IQR 10,4-43,6). In univariate analysis, poor functional outcome after stroke was associated with age, stroke severity on admission (measured by the National Institutes of Health Stroke Scale (NIHSS)), beta-blocker use before and during hospitalization, WOR and late HMR. In subsequent multivariate analysis WOR (OR 1.087; 95% CI 1.003-1.177, p = 0.042) was an independent predictor of poor stroke outcome even after adjustment for age and NIHSS.
Conclusions In patients with acute ischemic stroke, myocardial washout of 123I-mIBG predicts stroke outcome, even after adjustment for age and stroke severity on admission.
Prognostic value of myocardial perfusion imaging in kidney transplant recipients: a systematic review and meta-analysis
Authors: Jolink FEJ , Kelderman JR , Monroy Gonzalez AG , Benjamens S , Slart RHJA , Pol RA 
Published: July 2021

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Kidney transplant recipients are at risk for major adverse cardiac events (MACE) and cardiovascular mortality. We aimed to assess the prognostic value of myocardial perfusion imaging (MPI) single-photon emission computed tomography (SPECT), in patients evaluated for transplantation, for MACE and cardiovascular mortality after kidney transplantation.

Methods
We performed a systematic literature search in PubMed, EMBASE, Web of Science, OvidSP, The Cochrane Library and Google Scholar. We retrieved studies investigating the prognostic value of MPI for MACE and mortality in kidney transplant recipients. After risk of bias assessment using QUIPS, a meta-analysis was conducted.

Results
Out of 1379 records, 14 studies (7 prospective and 7 retrospective) using MPI SPECT were included in the meta-analysis with a total of 4643 MPI procedures. No studies were excluded after QUIPS assessment. Median follow-up duration of patients ranged from 1 to 8 years. Kidney transplant recipients with perfusion defects on MPI showed an increased risk for MACE (RR 2.76, 95%-CI 1.73-4.42), cardiovascular mortality (RR 3.15, 95%-CI 1.94-5.13) and all-cause mortality (RR 2.12, 95%-CI 1.76-2.54) compared to recipients with normal MPI findings. Significant heterogeneity existed across the included studies investigating MACE.

Conclusions
Our results showed that MPI SPECT may identify patients at increased risk for MACE and mortality after kidney transplantation.
Value of coronary artery calcium score in reporting SPECT versus PET myocardial perfusion imaging
Authors: Van Dijk JD , Mouden M , Van Dalen JA , Jager PL 
Published: July 2021

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Although it is well known that coronary artery calcium score (CACS) adds value to reporting myocardial perfusion imaging (MPI) SPECT, its added value to reporting PET MPI is not clear.

Purpose
Hence, our aim was determine the value of adding CACS in the assessment of PET MPI and SPECT MPI and compare the value between both modalities in a low-risk population.

Methods
We retrospectively included 412 patients, half of them underwent SPECT with CACS and half underwent Rubidium-82 PET with CACS. We created comparable groups using propensity matching, where the PET group was 1:1 matched to a comparable SPECT group, obtained from a large cohort of 4018. Next, we created two types of image sets for the 412 included patients: MPI-only and MPI + CACS. Two experienced physicians interpreted the 824 images as normal, equivocal or abnormal for ischemia or irreversible defects and were blinded for the used modality. In addition, annualized event rates, defined as the occurrence of all-cause death, non-fatal myocardial infarction or revascularization therapy (PCI or CABG), were compared between the PET and SPECT groups using a follow-up period of 30 months.

Results
The percentage of scans interpreted as normal was 8% higher with PET-only than with SPECT-only (89 vs 80%, respectively, p = 0.014). Adding CACS to SPECT increased the percentage of scans interpreted as normal from 80% to 86% (p = 0.014), whereas this effect was absent for PET (p = 0.77). Adding CACS reduced the frequency of equivocal scans from 12% and 6% to 0% for both SPECT and PET, respectively. Furthermore, adding CACS resulted in 5% more abnormal interpreted scans for both PET (4.9 to 10%, p = 0.003) and SPECT (8.7 to 14%, p = 0.04). The annualized event rate was 2.7% for the SPECT and 3.5% for the PET group (p = 0.58). The annualized event rates for images interpreted as normal were comparable between all four types of image sets and varied between 0.7-2.0% (p &gt; 0.084). The annualized event rate for equivocal and abnormal scans was higher for PET-only (23%) compared to SPECT-only (4.8%, p &lt; 0.001). Moreover, the event rate for equivocal and abnormal SPECT + CACS (8.6%) was also higher than for SPECT-only (4.8%, p = 0.04), whereas this difference was absent for PET (p = 0.07).

Conclusion
Adding CACS increases the percentage of scans interpreted as normal for SPECT MPI while the event rate remained unchanged. Adding CACS to PET did not influence the percentage of scans interpreted as normal, limiting the effect of adding CACS to PET in a low-risk population.
Macrophage depletion impairs adequate cardiac repair in mouse models of myocardial infarction with variable transmurality - insights from multimodality molecular imaging
Authors: Hess A , Langer LBN , Ross TL , Bengel FM , Thackeray JT 
Published: July 2021

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Introduction
Balanced myocardial tissue inflammation following acute myocardial infarction (MI) is needed for optimal cardiac repair. Macrophages contribute to wound healing, but may also be deleterious.

Purpose
We investigated the impact of macrophage depletion on early cardiac inflammation and later functional outcome in two models of MI with variable transmurality.

Methods
C57BL/6N mice received clodronate-liposomes for macrophage depletion (n = 49) or control PBS-liposomes (n = 23). After 24h, mice underwent permanent occlusion (PO) or transient ischemia-reperfusion (I/R, 60min) of the left coronary artery or sham surgery. Cardiac inflammation was assessed on MI + 1d, 3d, and 7d by CXCR4-targeted PET/CT using 68Ga-pentixafor. 99mTc-sestamibi SPECT/CT and cardiac magnetic resonance (CMR) calculated infarct sizes and left ventricular (LV) function at 1wk and 6wks. 18F-NaF PET/CT measured tissue microcalcification at 4wks. Imaging signals were validated by ex vivo autoradiography and immunohistochemistry.

Results
Clodronate macrophage depletion did not affect infarct size compared to PBS, but perfusion defects at 6wks were significantly larger after PO compared to I/R (%LV, 32 ± 11 vs 14 ± 10, p = 0.01). In both models, infarct CXCR4 expression was higher after macrophage depletion vs PBS at all timepoints (%injected dose (ID)/g; d3: PO: 1.4 ± 0.2 vs 0.9 ± 0.1; I/R: 1.4 ± 0.2 vs 1.0 ± 0.02; p &lt; 0.05), and confirmed by ex vivo autoradiography. Immunostaining demonstrated fewer macrophages and higher neutrophil content within the myocardium after macrophage depletion vs PBS at 1d, 3d, and 7d post-MI. Acute LV rupture after PO was more frequent in macrophage-depleted than PBS mice (37% vs 17%). Conversely, surviving PO mice showed a similarly impaired ejection fraction (EF) after macrophage depletion vs PBS at 6wks (%, 32 ± 9 vs 32 ± 11, p = 0.84). No acute LV rupture was observed after I/R, but macrophage depletion led to worse EF (%, 42 ± 11 vs 54 ± 3, p = 0.1). Macrophage-depleted mice exhibited a dense intracavity thrombus adherent to the infarct wall after either injury, as visualized on CMR at 1wk. 18F-NaF PET identified active calcification localized to the thrombus region 4wks after MI, which was colocalized to CT opaque regions at 6wks.

Conclusion
Macrophage depletion impairs cardiac repair via several mechanisms including neutrophil-dominated inflammation, LV thrombus formation and tissue calcification. This observation underscores the requirement of macrophages for effective healing and may explain adverse response to broad anti-inflammatory therapy in myocardial ischemia.
Level 1 of Entrustable Professional Activities in adult echocardiography: a position statement from the EACVI regarding the training and competence requirements for selecting and interpreting echocardiographic examinations
Authors: Stankovic Ivan , Muraru Denisa , Fox Kevin , Di Salvo Giovanni , Hasselberg Nina E , Breithardt Ole-A , Hansen Tina B , Neskovic Aleksandar N , Gargani Luna , Cosyns Bernard , Edvardsen Thor ,   Reviewers: This document was reviewed by members of the 2020-2022 EACVI Scientific Documents Committee: Daniele Andreini, Magnus Báck, Philippe B. Bertrand, Marc Dweck, Niall Keenan, Julien Magne, Leyla Elif Sade; and by the Chair of the 2020-2022 EACVI Scientific Documents Committee: Erwan Donal.
Published: July 2021

Abstract
The goal of Level 1 training in echocardiography is to enable the trainee to select echocardiography appropriately for the evaluation of a specific clinical question, and then to interpret the report. It is not the goal of Level 1 training to teach how to perform the examination itself—that is the goal of higher levels of training. However, understanding the principles, indications, and findings of this crucial technique is valuable to many medical professionals including outside cardiology. This should be seen as part of a general understanding of cardiac imaging modalities. The purpose of this position statement is to define the scope and outline the general requirements for Level 1 training and competence in echocardiography. Moreover, the document aims to make a clear distinction between Level 1 competence in echocardiography and focus cardiac ultrasound (FoCUS).
‘Cyber Due Diligence’: A Patchwork of Protective Obligations in International Law
Authors: Coco Antonio , de Souza Dias Talita 
Published: July 2021

Abstract
With a long history in international law, the concept of due diligence has recently gained traction in the cyber context, as a promising avenue to hold states accountable for harmful cyber operations originating from, or transiting through, their territory, in the absence of attribution. Nonetheless, confusion surrounds the nature, content and scope of due diligence. It remains unclear whether it is a general principle of international law, a self-standing obligation or a standard of conduct, and whether there is a specific rule requiring diligent behaviour in cyberspace. This has created an ‘all-or-nothing’ discourse: either states have agreed to a rule or principle of ‘cyber due diligence’, or no obligation to behave diligently would exist in cyberspace. We propose to shift the debate from label to substance, asking whether states have duties to protect other states and individuals from cyber harms. By revisiting traditional cases, as well as surveying recent state practice, we contend that – whether or not there is consensus on ‘cyber due diligence’ – a patchwork of different protective obligations already applies, by default, in cyberspace. At their core is a flexible standard of diligent behaviour requiring states to take reasonable steps to prevent, halt and/or redress a range of online harms.
The effects of small-scale convection in the shallow lithosphere of the North Atlantic
Authors: Likerman Jeremías , Zlotnik Sergio , Li Chun-Feng 
Published: July 2021

SUMMARY
Curie point depth can be used as a proxy for plate temperatures. Data from the North Atlantic (10°–50°N) are used here to determine if the observed oscillations and patterns in Curie depths could be a subproduct of small-scale thermal instabilities arising at the bottom of the lithospheric plates. Our numerical models suggest that small-scale convection (SSC) cells could produce thermal perturbations at isotherms as low as the Curie point. These results are compatible with North Atlantic observations in terms of wavelengths (150–300 km), amplitudes (∼4 km) and orientations of the instabilities. Observed Curie-point depth oscillations before the onset (70 to 90 Myr) of SSC could also be linked to other different processes. We suggest that, in the case of the North Atlantic lithosphere, the spreading rate variation and the melt and upwelling could be intricately linked and cause a different pattern of SSC.
Bayesian seismic inversion: a fast sampling Langevin dynamics Markov chain Monte Carlo method
Authors: Izzatullah Muhammad , van Leeuwen Tristan , Peter Daniel 
Published: July 2021

SUMMARY
In this study, we aim to solve the seismic inversion in the Bayesian framework by generating samples from the posterior distribution. This distribution incorporates the uncertainties in the seismic data, forward model, and prior information about the subsurface model parameters; thus, we obtain more information through sampling than through a point estimate (e.g. maximum a posteriori method). Based on the numerical cost of solving the forward problem and the dimensions of the subsurface model parameters and observed data, sampling with Markov chain Monte Carlo (MCMC) algorithms can be prohibitively expensive. Herein, we consider the promising Langevin dynamics MCMC algorithm. However, this algorithm has two central challenges: (1) the step size requires prior tuning to achieve optimal performance and (2) the Metropolis–Hastings acceptance step is computationally demanding. We approach these challenges by proposing an adaptive step-size rule and considering the suppression of the Metropolis–Hastings acceptance step. We highlight the proposed method’s potential through several numerical examples and rigorously validate it via qualitative and quantitative evaluation of the sample quality based on the kernelized Stein discrepancy (KSD) and other MCMC diagnostics such as trace and autocorrelation function plots. We conclude that, by suppressing the Metropolis–Hastings step, the proposed method provides fast sampling at efficient computational costs for large-scale seismic Bayesian inference; however, this inflates the second statistical moment (variance) due to asymptotic bias. Nevertheless, the proposed method reliably recovers important aspects of the posterior, including means, variances, skewness and 1-D and 2-D marginals. With larger computational budget, exact MCMC methods (i.e. with a Metropolis–Hastings step) should be favoured. The results thus obtained can be considered a feasibility study for promoting the approximate Langevin dynamics MCMC method for Bayesian seismic inversion on limited computational resources.