tbuckley/cabot-search huggingface dataset:
Abstract 18055: Induced Growth of Hypoplastic Cardiac Structures to Facilitate Repair of Congenital Defects
Authors: Daniel F Labuz, Lee A Pyles, James A Berry, John E Foker
Journal: Circulation (2015)

Introduction: Congenital heart defects (CHD) may include hypoplastic valves, ventricles and vessels which complicate repairs. Our hypotheses were that hypoplastic structures are developmental rather than primarily genetic in origin and the correct biomechanical signal would induce catch up growth. Our corollary hypothesis was that the growth signal is provided by flow, not pressure. First stage operations, therefore, were designed to increase flow and induce growth. Once growth was sufficient, a second operation would often complete the repair. We report our results using flow induced growth of hypoplastic structures to facilitate repair in 3 types of CHD. Methods: Three groups of CHD patients with associated hypoplastic structures: unbalanced atrioventricular canal defects (UAVC); pulmonary atresia with intact ventricular septum (PAIVS); and coarctation of the aorta (CoA) were reviewed. Operations increased flow through the hypoplastic structures, such as creating restrictive septal defects to increase flow through the hypoplastic AV valves and ventricles (UAVC, PAIVS) or relieving obstruction (CoA) to enhance aortic valve and arch flow. Results: On follow up, virtually all (85/90) hypoplastic structures reached normal size and the rest had nearly comparable growth (Table). Conclusions: 1) Operations designed to increase flow through hypoplastic structures reliably induced catch up growth of UAVC, PAIVS and CoA lesions. 2) The growth response supported underdevelopment as the cause of hypoplasia and flow as the growth signal to reverse it. 3) Growth induction allowed two ventricle repairs in UAVC and PAIVS patients and avoided extended arch repairs in CoA; all with decreased operative risk. 4) Following catch up growth of the hypoplastic lesions, the outlook improved to that of patients with balanced AVCs, normal sized RVs in pulmonary atresia and well repaired CoA. 5) Once normal size was reached growth continued, producing a durable result.
Circular RNAs function as ceRNAs to regulate and control human cancer progression
Authors: Yaxian Zhong, Yajun Du, Xue Yang, Yongzhen Mo, Chunmei Fan, Fang Xiong, Daixi Ren, Xin Ye, Chunwei Li, Yumin Wang, Fang Wei, Can Guo, Xu Wu, Xiaoling Li, Yong Li, Guiyuan Li, Zhaoyang Zeng, Wei Xiong
Journal: Molecular Cancer (2018)

Circular RNAs (circRNAs) are connected at the 3′ and 5′ ends by exon or intron cyclization, forming a complete ring structure. circRNA is more stable and conservative than linear RNA and abounds in various organisms. In recent years, increasing numbers of reports have found that circRNA plays a major role in the biological functions of a network of competing endogenous RNA (ceRNA). circRNAs can compete together with microRNAs (miRNAs) to influence the stability of target RNAs or their translation, thus, regulating gene expression at the transcriptional level. circRNAs are involved in biological processes such as tumor cell proliferation, apoptosis, invasion, and migration as ceRNAs. circRNAs, therefore, represent promising candidates for clinical diagnosis and treatment. Here, we review the progress in studying the role of circRNAs as ceRNAs in tumors and highlight the participation of circRNAs in signal transduction pathways to regulate cellular functions.
Identification of <i>ST3AGL4</i>, <i>MFHAS1, CSNK2A2</i> and <i>CD226</i> as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning
Authors: Yong-Fei Wang, Yan Zhang, Zhengwei Zhu, Ting-You Wang, David L Morris, Jiangshan Jane Shen, Huoru Zhang, Hai-Feng Pan, Jing Yang, Sen Yang, Dong-Qing Ye, Timothy J Vyse, Yong Cui, Xuejun Zhang, Yujun Sheng, Yu Lung Lau, Wanling Yang
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. Methods We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. Results We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, p meta =4.40E-08), MFHAS1 (rs2428, p meta =1.17E-08) and CSNK2A2 (rs2731783, p meta =1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, p meta =2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. Conclusion This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.
Technical Pitfall in 68Ga–Prostate Specific Membrane Antigen Imaging
Authors: Nir Hod, Reut Anconina, Daniel Levin, Dina Ezroh Kazap, Sophie Lantsberg
Journal: Clinical Nuclear Medicine (2018)

As with any new molecular imaging modality, accurate characterization of abnormalities on Ga-PSMA PET/CT imaging can be accomplished only if one is aware of the normal distribution pattern, physiological variants, and potential sources of false imaging findings. Altered biodistribution can have a significant impact on scan interpretation. Presented here is a rare case in which radiopharmaceutical radiolysis occurred causing excessive free Ga-citrate showing as an increased vascular activity. As Ga-PSMA PET/CT imaging is a relatively new imaging technique, it is important to be aware of such a potential technical pitfall in clinical practice in order to prevent scan misinterpretation.
Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life
Authors: Dinh S Bui, Caroline J Lodge, John A Burgess, Adrian J Lowe, Jennifer Perret, Minh Q Bui, Gayan Bowatte, Lyle Gurrin, David P Johns, Bruce R Thompson, Garun S Hamilton, Peter A Frith, Alan L James, Paul S Thomas, Deborah Jarvis, Cecilie Svanes, Melissa Russell, Stephen C Morrison, Iain Feather, Katrina J Allen, Richard Wood-Baker, John Hopper, Graham G Giles, Michael J Abramson, Eugene H Walters, Melanie C Matheson, Shyamali C Dharmage
Journal: The Lancet Respiratory Medicine (2018)
Advances in the diagnosis and classification of gastric and intestinal motility disorders
Authors: Jutta Keller, Gabrio Bassotti, John Clarke, Phil Dinning, Mark Fox, Madhusudan Grover, Per M. Hellström, Meiyun Ke, Peter Layer, Carolina Malagelada, Henry P. Parkman, S. Mark Scott, Jan Tack, Magnus Simren, Hans Törnblom, Michael Camilleri
Journal: Nature Reviews Gastroenterology & Hepatology (2018)

Gastrointestinal motor disorders affect a large proportion of the population worldwide. In this Consensus Statement, the authors describe recommended tests for the investigation of gastric, small bowel and colonic motility, with an emphasis on how best to classify gastrointestinal motor disorders to guide treatment decisions. Disturbances of gastric, intestinal and colonic motor and sensory functions affect a large proportion of the population worldwide, impair quality of life and cause considerable health-care costs. Assessment of gastrointestinal motility in these patients can serve to establish diagnosis and to guide therapy. Major advances in diagnostic techniques during the past 5–10 years have led to this update about indications for and selection and performance of currently available tests. As symptoms have poor concordance with gastrointestinal motor dysfunction, clinical motility testing is indicated in patients in whom there is no evidence of causative mucosal or structural diseases such as inflammatory or malignant disease. Transit tests using radiopaque markers, scintigraphy, breath tests and wireless motility capsules are noninvasive. Other tests of gastrointestinal contractility or sensation usually require intubation, typically represent second-line investigations limited to patients with severe symptoms and are performed at only specialized centres. This Consensus Statement details recommended tests as well as useful clinical alternatives for investigation of gastric, small bowel and colonic motility. The article provides recommendations on how to classify gastrointestinal motor disorders on the basis of test results and describes how test results guide treatment decisions.
Abstract 14760: Evaluation of High Molecular Weight von Willebrand Factor Multimer Levels in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Milla J Kviatkovsky, Christina Tyrrell, Kyle Muir, Saurabh Gupta, Ed Kahl, Wohaib Hasan, Stephen Heitner
Journal: Circulation (2016)

Introduction:  Abnormal levels of circulating high molecular weight von Willebrand Factor multimers (HMWFm) are observed in patients with severe aortic stenosis (AS). Evidence suggests factor recovery after successful valve replacement. We aim to confirm factor recovery after transcatheter aortic valve replacement (TAVR), to determine the post-implantation time point when patients first demonstrate factor recovery and to observe association between degree of para-aortic regurgitation (PAR) and factor recovery. We also aim to evaluate correlation between HMWFm assay using traditional means (immunoblot) and a novel enzyme-linked immunosorbent collagen binding assay (CBA).   Methods:  Fifteen patients with severe AS underwent TAVR. Plasma was collected at multiple time points: pre-TAVR (T1), immediately after valve deployment (T2), post-operative day one (T3) and prior to discharge (T4). Levels of HMWFm were analyzed using immunoblot and CBA. PAR was assessed using vena contracta area (VCA) and longitudinal jet length methods.   Results:  Mean population age was 82.6 years. Baseline mean transvalvular gradient/aortic valve area (AVA) was 38.5 mmHg/0.88 cm2 respectively. After TAVR, mean gradient/AVA was 5.6 mmHg/2.7 cm2 respectively. PAR was classified as moderate in 4/14 and severe in 2/14 patients. Kappa statistic for agreement between both methods of PAR assessment was 0.32. HMWFm levels initially decreased at T2, but increased by T3. Using Immunoblot, HMWFm levels were significantly higher at T4 compared to T1. Using CBA, levels were significantly higher at T3 and T4 compared to T1. Stratification by degree of PAR demonstrated a trend towards greater HMWFm recovery in patients without PAR versus those with PAR. Post-TAVR NYHA symptoms did not significantly effect levels.   Conclusions:  We confirm that HMWFm levels improve after successful TAVR. Unlike a recent study by Belle et al (Circulation, 2016), we do not demonstrate immediate HMWFm recovery, rather only by post-operative day one. We demonstrate feasibility of CBA as a faster substitute to immunoblot method for factor analysis. We demonstrate intriguing differences in factor recovery between PAR strata, suggesting that levels of factor recovery are influenced by degree of PAR.
Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus
Authors: Alba Llibre, Yusuke Shimakawa, Estelle Mottez, Shaun Ainsworth, Tan-Phuc Buivan, Rick Firth, Elliott Harrison, Arielle R Rosenberg, Jean-François Meritet, Arnaud Fontanet, Pablo Castan, Antonio Madejón, Mark Laverick, Allison Glass, Raquel Viana, Stanislas Pol, C Patrick McClure, William Lucien Irving, Gino Miele, Matthew L Albert, Darragh Duffy
Journal: Gut (2018)

Objective Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTi m e HCV test. Results The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions. Trial registration number NCT02992184 .
Changes in scoring of Direct Observation of Procedural Skills (DOPS) forms and the impact on competence assessment
Authors: Keith Siau, Paul Dunckley, Roland Valori, Mark Feeney, Neil Hawkes, John Anderson, Ian Beales, Christopher Wells, Siwan Thomas-Gibson, Gavin Johnson
Journal: Endoscopy (2018)

Abstract Background Direct Observation of Procedural Skills (DOPS) is an established competence assessment tool in endoscopy. In July 2016, the DOPS scoring format changed from a performance-based scale to a supervision-based scale. We aimed to evaluate the impact of changes to the DOPS scale format on the distribution of scores in novice trainees and on competence assessment. Methods We performed a prospective, multicenter (n = 276), observational study of formative DOPS assessments in endoscopy trainees with ≤ 100 lifetime procedures. DOPS were submitted in the 6-months before July 2016 (old scale) and after (new scale) for gastroscopy (n = 2998), sigmoidoscopy (n = 1310), colonoscopy (n = 3280), and polypectomy (n = 631). Scores for old and new DOPS were aligned to a 4-point scale and compared. Results 8219 DOPS (43 % new and 57 % old) submitted for 1300 trainees were analyzed. Compared with old DOPS, the use of the new DOPS was associated with greater utilization of the lowest score (2.4 % vs. 0.9 %; P &lt; 0.001), broader range of scores, and a reduction in competent scores (60.8 % vs. 86.9 %; P &lt; 0.001). The reduction in competent scores was evident on subgroup analysis across all procedure types (P &lt; 0.001) and for each quartile of endoscopy experience. The new DOPS was superior in characterizing the endoscopy learning curve by demonstrating progression of competent scores across quartiles of procedural experience. Conclusions Endoscopy assessors applied a greater range of scores using the new DOPS scale based on degree of supervision in two cohorts of trainees matched for experience. Our study provides construct validity evidence in support of the new scale format.
Abstract 12544: Evidence for Involvement of Inflammatory Changes of Perivascular Adipose Tissue in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stent in Pigs in vivo -Impact of Fluorodeoxyglucose Positron Emission Tomography Imaging
Authors: Kazuma Ohyama, Yasuharu Matsumoto, Hirokazu Amamizu, Hironori Uzuka, Kensuke Nishimiya, Susumu Morosawa, Michinori Hirano, Hiroshi Watabe, Yoshihito Funaki, Jun Takahashi, Kenta Ito, Hiroaki Shimokawa
Journal: Circulation (2016)

Background: Recent studies suggested that perivascular adipose tissue (PVAT) play important roles as a source of various inflammatory mediators in the pathogenesis of cardiovascular disease. We thus tested our hypothesis that inflammatory changes in the coronary PVAT are associated with coronary hyperconstricting responses after drug-eluting stent (DES) implantation by using FDG PET. Methods: Everolimus-eluting stents (EES) were randomly implanted in pigs into either the left anterior descending or circumflex coronary artery while non-stented artery was used as a control. After 1 month, coronary vasoconstricting responses to intracoronary serotonin were examined by coronary angiography in vivo, followed by FDG PET/CT ex vivo imaging and autoradiography for measurement of FDG uptake. Results: Coronary vasoconstricting responses were significantly enhanced at the edges of the EES site compared with the control site (P&lt;0.01, n=40) (Figures A-C). Notably, FDG PET/CT imaging showed enhanced FDG uptake at the EES-implanted coronary segment with significant association between the target to background ratio and the extent of coronary vasoconstricting responses (P&lt;0.01) (Figures D-F). In addition, autoradiography showed that the FDG accumulation was markedly enhanced at the edge of the EES site compared with the control site and was significantly associated with the extent of coronary vasoconstricting responses (P&lt;0.01) (Figures G-J, O). Furthermore, histological analysis and RT-PCR showed that the extent of inflammatory changes in the coronary PVAT were significantly enhanced at the edges of the EES site compared with the control site (Figures K-N). Conclusions: These results demonstrate for the first time that inflammatory changes in the coronary PVAT are involved in the pathogenesis of DES-induced coronary hyperconstricting responses in pigs in vivo and that FDG PET imaging may be useful for assessment of coronary PVAT inflammation.
The Lancet Countdown on PM 2·5 pollution-related health impacts of China's projected carbon dioxide mitigation in the electric power generation sector under the Paris Agreement: a modelling study
Authors: Wenjia Cai, Jingxuan Hui, Can Wang, Yixuan Zheng, Xin Zhang, Qiang Zhang, Peng Gong
Journal: The Lancet Planetary Health (2018)

BackgroundExcept for comparing the implementation costs of the Paris Agreement with potential health benefits at the national levels, previous studies have not explored the health impacts of the nationally determined contributions (NDCs) by countries and in regional details. In this Lancet Countdown study, we aimed to estimate and monetise the health benefits of China's NDCs in the electric power generation sector, and then compare them with the implementation costs, both at the national and regional levels.MethodsIn this modelling study, we linked the Multi-regional model for Energy Supply system and their Environmental ImpaCts, the Multi-resolution Emission Inventory for China model, the offline-coupled Weather Research and Forecasting model, the Community Multiscale Air Quality model, and the Integrated Health Impact Assessment model with a time scope from 2010 to 2050. We calculated the PM2·5 concentrations and compared the health impacts and implementation costs between two scenarios that reflect CO2 and air pollutant emissions—the reference (REF) scenario (no climate policy) and the NDC scenario (100% realisation of NDC targets: CO2 emission intensity needs to be about 40% below 2010 emissions by 2030 [roughly 35% below 2030 emissions in REF], and about 90% below 2010 emissions by 2050 [roughly 96% below 2050 emissions in REF]).FindingsUnder a comparatively optimistic health benefits valuation condition, at the national level, 18–62% of implementation costs could be covered by the health benefits in 2030. In 2050, the overall health benefits would substantially increase to 3–9 times of the implementation costs. However, northwest China would require the highest implementation costs and will also have more premature deaths because of a more carbon-intensive energy structure than business as usual. By 2030, people in northwest China (especially in Gansu, Shaanxi, and Xinjiang provinces) would need to bear worse air quality, and 10 083 (95% CI 3419–16 138) more premature deaths annually. This undesirable situation would diminish by about 2050. A solution that assumes no growth in air pollutant emissions in 2030 at the regional level is technically feasible, but would not be cost-effective.InterpretationOur results suggest that cost–benefit analysis of climate policy that omits regional air pollution could greatly underestimate benefits. A compensation mechanism for inter-regional interests (including financial, technological, and knowledge support) should be established for regions that give up their human health benefits for the sake of the whole nation to realise the climate change targets.FundingNational Natural Science Foundation of China and Cyrus Tang Foundation.
Evolution of New miRNAs and Cerebro-Cortical Development
Authors: Kenneth S. Kosik, Tomasz Nowakowski
Journal: Annual Review of Neuroscience (2018)

The noncoding portion of the genome, including microRNAs, has been fertile evolutionary soil for cortical development in primates. A major contribution to cortical expansion in primates is the generation of novel precursor cell populations. Because miRNA expression profiles track closely with cell identity, it is likely that numerous novel microRNAs have contributed to cellular diversity in the brain. The tools to determine the genomic context within which novel microRNAs emerge and how they become integrated into molecular circuitry are now in hand.
Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models
Authors: Santosh K. Panda, Valeria Facchinetti, Elisaveta Voynova, Shino Hanabuchi, Jodi L. Karnell, Richard N. Hanna, Roland Kolbeck, Miguel A. Sanjuan, Rachel Ettinger, Yong-Jun Liu
Journal: Journal of Clinical Investigation (2018)

Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap-mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.