tbuckley/cabot-search huggingface dataset:
Mechanism of Persistent Ischemic Mitral Regurgitation After Annuloplasty
Authors: Fang Zhu, Yutaka Otsuji, Goichi Yotsumoto, Toshinori Yuasa, Takayuki Ueno, Bo Yu, Chihaya Koriyama, Shuichi Hamasaki, Sadatoshi Biro, Akira Kisanuki, Shinichi Minagoe, Robert A. Levine, Ryuzo Sakata, Chuwa Tei
Journal: Circulation (2005)

Background— We hypothesized that surgical annuloplasty for ischemic mitral regurgitation (MR) that displaces the posterior annulus anteriorly can potentially augment posterior leaflet (PML) tethering, leading to persistent MR. Relationships between leaflet configurations and persistent ischemic MR after the annuloplasty were investigated. Methods and Results— In 31 patients with surgical annuloplasty for ischemic MR and 20 controls, posterior and apical displacement of the leaflet coaptation, the anterior leaflet (AML) and PML tethering angles relative to the line connecting annuli, coaptation length (CL), and the MR grade were quantified before and early after surgery in echocardiographic left ventricular long-axis views. Six of the 31 patients showed persistent MR despite annuloplasty. Compared with patients without persistent MR, those with MR showed no improvement in the left ventricular ejection fraction and systolic volume, similar reduction in the annular area, significant increase in posterior displacement of the coaptation ( P &lt;0.01), no improvement in AML tethering, greater worsening in PML tethering ( P &lt;0.01), and no increase in the CL. All tethering variables were significantly correlated with both preoperative and postoperative MR in univariate analysis, and reduced CL was the primary independent determinant of both preoperative and postoperative MR. Although increased AML tethering was the primary determinant of the preoperative CL (r 2 =0.46, P &lt;0.0001), increased PML tethering was the primary determinant afterward (r 2 =0.60, P &lt;0.0001). Conclusion— Although tethering of both leaflets is the major determinant of ischemic MR before surgical annuloplasty, both leaflets tethering but with predominant and augmented PML tethering is related to persistent ischemic MR after the annnuloplasty.
Comparison of Risk-Standardized Readmission Rates of Surgical Patients at Safety-Net and Non–Safety-Net Hospitals Using Agency for Healthcare Research and Quality and American Hospital Association Data
Authors: Stephanie D. Talutis, Qi Chen, Na Wang, Amy K. Rosen
Journal: JAMA Surgery (2019)

Medical patients discharged from safety-net hospitals (SNHs) experience higher readmission rates compared with those discharged from non-SNHs. However, little is known about whether this association persists for surgical patients.To examine differences in readmission rates between SNHs and non-SNHs among surgical patients after discharge and determine whether hospital characteristics might account for some of the variation.This observational retrospective study linked the Healthcare Cost and Utilization Project State Inpatient Databases of the Agency for Healthcare Research and Quality from January 1, 2011, through December 31, 2014, for 4 states (New York, Florida, Iowa, and Washington) with data from the 2014 American Hospital Association annual survey. After identifying surgical discharges, SNHs were defined as those with the top quartile of inpatient stays paid by Medicaid or self-paid. Hospital-level risk-standardized readmission rates (RSRRs) for surgical discharges were calculated. The association between hospital RSRRs and hospital characteristics was evaluated with bivariate analyses. An estimated multivariable hierarchical linear regression model was used to examine variation in hospital RSRRs, adjusting for hospital characteristics, state, year, and SNH status. Data were analyzed from June 1, 2017, through March 1, 2018.Surgical care at an SNH.Readmission after an index surgical admission.A total of 1 252 505 patients across all 4 years and states were included in the analysis (51.7% women; mean [SD] age, 52.7 [18.1] years). Bivariate analyses found that SNHs had higher mean (SD) surgical RSRRs compared with non-SNHs; significant differences were found for New York (9.6 [0.1] vs 10.9 [0.1]; P < .001) and Florida (11.6 [0.1] vs 12.1 [0.1]; P = .001). The SNHs also had higher RSRRs in these 2 states when stratified by hospital funding (nonfederal government SNHs in New York, 11.9 [0.2]; for-profit, private SNHs in Florida, 13.1 [0.2]; P < .001 for both); however, bed size was a significant factor for higher mean (SD) RSRRs only for New York (200 to 399 beds, 12.0 [0.4]; P = .006). Similar results were found for multivariable linear regression models; RSRRs were 1.02% higher for SNHs compared with non-SNHs (95% CI, 0.75%-1.29%; P < .001). Increased RSRRs were observed for hospitals in New York and Florida, teaching hospitals, and investor-owned hospitals. Factors associated with reduced RSRRs included presence of an ambulatory surgery center, cardiac catheterization capabilities, and high surgical volume.According to results of this study, surgical patients treated at SNHs experienced slightly higher RSRRs compared with those treated at non-SNHs. This association persisted after adjusting for year, state, and hospital factors, including teaching status, hospital bed size, and hospital volume.
SP0127 From mendeliome to personalised medicine in childhood sle
Authors: A. Belot
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Pediatric-onset SLE is a rare condition where genetics traits are believed to play an important causal role. A few monogenic causes of SLE have been described mostly in familial forms, including complement deficiencies, so-called type I interferonopathies, and B cell-related defects. Genetic studies in mouse models and genome-wide associations studies in patients have also pointed to other genes potentially involved in juvenile SLE. However, large-scale sequencing analyses of paediatric SLE are lacking, and the overall contribution of genetic factors in disease onset is therefore unknown. Personalised medicine relies on the understanding of underlying mechanisms. Genetic discovery and functional chatacterization of the variants prefigure the precision medicine in complex diseases such as SLE. We have designed a NGS panel comprising genes for which mutations are known lupus causing (KLC) (also reported as the Mendeliome) as well as prospective candidate genes, potentially lupus causing (PLC), and analysed 117 children who fulfilled ACR criteria for SLE from two large cohorts of pediatric-onset SLE in the UK and France. Genetic variants were identified and filtered to select rare (ExAC database frequency of &lt;1% for homozygous variants and &lt;0.01% for heterozygous variants) and predicted <i>in silico</i> as damaging by different algorithms. We identified mutations in KLC genes for 8 patients. Variant segregation within families and functional analyses supported the causal role of these mutations. Other patients had monoallelic variants in recessive KLC genes, which may have contributed to disease onset and other patients displayed rare and pathogenic variants in PLC genes. This enrichment was specific to the lupus cohort compared to a control cohort of healthy patients. This large-scale analysis led to the identification of monogenic causes of lupus in about 7% of analysed patients in an unselected paediatric population of jSLE. 7/8 causes are related to an innate immune disorder with efferocytosis deficiency, emphasising the importance of apoptotic body clearance in the pathogenesis of lupus. Other variants in KLC or PLC genes may represent novel monogenic causes of lupus or could influence disease-onset by increasing the penetrance of more severe mutations. The treatment is still poorly adapted to the underlying mechanisms but progress in immunomonitoring together with the revolution in the field of genetics prompt clinician to set up targeted therapies considering genetic background and biomarkers. <h3>Disclosure of Interest</h3> A. Belot Grant/research support from: MERCK
Evaluation of the Mrp2-mediated flavonoid-drug interaction potential of quercetin in rats and in vitro models
Authors: Ju-Hee Oh, Joo Hyun Lee, Young-Joo Lee
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Quercetin is a biologically active flavonoid that has been used as a popular health supplement. It is reported that quercetin may cause flavonoid-drug interaction mediated by P-glycoprotein, the most predominant efflux transporter. In this study, we comprehensively evaluated the potential of the pharmacokinetic interaction of quercetin mediated by multidrug resistance-associated protein 2 (MRP2), another major efflux transporter. MRP2-transfected MDCKII cells and LS174T cells were used to evaluate the potential inhibition and induction of MRP2 by quercetin in vitro. To evaluate the induction effect of quercetin on Mrp2 in vivo, Mrp2 mRNA expression in rat liver, kidney, and small intestinal tissues was determined after the oral administration of quercetin (50, 100, or 250 mg/kg) for seven days. Mrp2-mediated interaction potential was also evaluated by the pharmacokinetic study of phenolsulfonphthalein in rats after single or multiple doses of quercetin. Additionally, the effect of quercetin on absorption of docetaxel, a P-glycoprotein and CYP3A4 substrate, was also evaluated. Quercetin inhibited the function of MRP2 at 10 µM and induced the mRNA expression of MRP2 at 50 µM in vitro. Additionally, at 100 mg/kg, quercetin markedly increased Mrp2 expression in the small intestine of rats. However, there was no significant change in phenolsulfonphthalein pharmacokinetics due to single- (50, 100, or 250 mg/kg) or multiple-dose (50, 100, or 250 mg/kg for seven days) quercetin co-administration. By contrast, a significant interaction caused by quercetin (100 mg/kg) was observed in the absorption of docetaxel. The results suggested that although quercetin modulates the function and expression of MRP2 in vitro, it may have a low potential of Mrp2-mediated interaction and present negligible safety concerns related to the interaction.
Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/RarÎ± Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: In Vitro and In Vivo studies
Authors: Dijiong Wu, Keding Shao, Qihao Zhou, Jie Sun, Ziqi Wang, Fei Yan, Tingting Liu, Xiangping Wu, Baodong Ye, He Huang, Yuhong Zhou
Journal: Blood (2018)
Abstract 18906: ACTRIIA-Fc Rebalances BMP and Activin/TGF-β Signaling to Attenuate Experimental Pulmonary Hypertension
Authors: LaiMing Yung, R. S Pearsall, Geoffrey Bocobo, Dianne S Sako, Teresa Dinter, John D Quisel, Ravindra Kumar, Paul B Yu
Journal: Circulation (2017)

Introduction: Therapies targeting underlying mechanisms of pulmonary arterial hypertension (PAH) could modify disease progression and improve outcomes. The genetics of PAH implicate deficient bone ...
THU0335 Factors associated with development and mortality of pulmonary hypertension in systemic lupus erythematosus patients
Authors: J.S. Kim, D. Kim, Y.B. Joo, S. Won, J. Lee, J. Shin, S.-C. Bae
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Pulmonary hypertension (PH) is a major cause of death in patients with systemic lupus erythematosus (SLE). In recent years, SLE with PH has become more common in the past few decades, and novel therapies has been developed to improve the prognosis of PH in SLE patients. Therefore, it is necessary to investigate further to identify serological and clinical factors for the development and mortality of PH in SLE patients. <h3>Objectives</h3> This study aims to estimate the prevalence of PH in SLE patients and identify the factors associated with the development of and mortality from PH in SLE patients. <h3>Methods</h3> We conducted a prospective study of SLE patients with fulfilling the American College of Rheumatology criteria (ACR) in a single tertiary centre from February 1998 to December 2013. PH was defined as a systolic pulmonary arterial pressure (sPAP) ≥30 mmHg at rest on transthoracic echocardiography (TTE). We assessed potential associated factors contributing to the development and mortality of PH in SLE patients using univariate and multivariable logistic regression models. <h3>Results</h3> Of 1110 patients with SLE, 48 patients were identified to have PH. Multivariable analysis indicated that pleuritis or pericarditis (odds ratio (OR)=4.62, 95% confidence interval (CI)=2.46 to 8.70, p&lt;0.01), anti-RNP antibody (OR=2.42, 95% CI=1.21 to 4.82, p=0.01), interstitial lung disease (ILD) (OR=8.34, 95% CI=2.21 to 31.54, p&lt;0.01), and cerebro-cardiovascular disease (OR=13.37, 95% CI=3.56 to 50.21, p&lt;0.01) were independently associated with the development of PH in SLE. Subgroup analysis among patients with PH demonstrated that there were no statistically significant factors associated with PH mortality in SLE. <h3>Conclusions</h3> The prevalence of PH was 4.3% in our cohort. There were significant associations with pleuritis or pericarditis, ILD, cerebro-cardiovascular disease, and anti-RNP antibody in SLE, which may contribute to the development of PH. However, there were no statistically significant factors correlating PH mortality in SLE. <h3>References</h3> [1] Prabu A, Patel K, Yee CS, et al. Prevalence and risk factors for pulmonary arterial hypertension in patients with lupus. Rheumatology (Oxford)2009; 48:1506–11. [2] Li M, Wang Q, Zhao J, et al. Chinese SLE Treatment and Research group (CSTAR) registry: II. Prevalence and risk factors of pulmonary arterial hypertension in Chinese patients with systemic lupus erythematosus. Lupus2014;23:1085–91. <h3>Disclosure of Interest</h3> None declared
Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma
Authors: Radhakrishnan Ramchandren, Ranjana H. Advani, Stephen M. Ansell, Nancy L. Bartlett, Robert Chen, Joseph M. Connors, Tatyana Feldman, Andres Forero-Torres, Jonathan W. Friedberg, Ajay K. Gopal, Leo I. Gordon, John Kuruvilla, Kerry J. Savage, Anas Younes, Gerald Engley, Thomas J. Manley, Keenan Fenton, David J. Straus
Journal: Clinical Cancer Research (2019)

To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA).ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles.The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD.The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.
Meet Your President: Michael W. Fried, M.D., F.A.A.S.L.D.
Authors: Adrian M. Di Bisceglie
Journal: Hepatology (2019)

1Division of Gastroenterology and HepatologySaint Louis University School of MedicineSt. LouisMO * Address Correspondence and Reprint Requests to: Adrian M. Di Bisceglie, M.D., F.A.A.S.L.D. Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine 3635 Vista Avenue St. Louis, MO 63110 E‐mail: [email protected] Tel.: +1‐314‐577‐8764
Infographic. The breathless athlete: EILO
Authors: Steffan Arthur Griffin, Emil S Walsted, James H Hull
Journal: British Journal of Sports Medicine (2019)

Exercise-induced laryngeal obstruction (EILO) describes a condition in which the voice box closes inappropriately during vigorous exercise to precipitate respiratory symptoms, such as cough, wheeze and breathlessness.1 This can occur secondary to adduction of the vocal cords (glottic mechanism) ± collapse of the arytenoid or aryepiglottic mucosa (supraglottic mechanism) with complete or incomplete obstruction of the larynx. The condition is highly prevalent in young athletes and estimated to affect between 5% and 10% of all adolescents.2 Despite this, EILO often remains overlooked as the cause of …
AB0015 The effect of rare coding variants on response of tnf inhibitors treatment in rheumatoid arthritis
Authors: S. Bang, Y. Park, H.-H. Kwon, H. Yoo, H.-S. Lee, S.-C. Bae
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Although pharmacogenetic studies of TNF inhibitors (TNFi) response presented the estimates of high heritability, only few loci with suggestive weak common association as biomarkers for TNFi response have been identified. <h3>Objectives</h3> We aimed to identify novel functional rare variants associated with response to etanercept using targeted exon sequencing in Korea. <h3>Methods</h3> Disease activity scores were assessed at baseline and after 6 months in 156 Korean RA patients who started etanercept due to moderate or high disease activity. We analysed targeted exon sequencing data of 399 genes selected from a multifaceted approach. We conducted a single-marker association test (MAF ≥1%) and a gene-based analysis [optimal sequence kernel association test (SKAT-O)] of rare variants (MAF &lt;1%). In addition, we performed gene set analyses of TNF pathway genes. <h3>Results</h3> We identified that clinical factors seem to influence the therapeutic good response of etanercept including male, high disease activity score at baseline, BMI. After stringent quality control, we analysed 14 024 variants of 399 genes in 156 RA patients. We identified two novel significant functional SNPs [rs16942564, rs61734378 (exon of AKAP13)] associated with response to etanercept, surpassing study-wide significant threshold (p&lt;3.0 × 10<sup>−5</sup>) in single variant association tests. Using a gene-based approach, we found two genes with nominal burden signals (p&lt;0.001) which did not reach study-wide significance. In the gene set enrichment test, we found no evidence for enrichment of association at genes involved in the TNF pathway. <h3>Conclusions</h3> We were unable to identify rare coding variants with large effect of 399 targeted genes. Our study suggests that rare coding variants of RA risk associated genes do not contribute to heritability of response to etanercept therapy. <h3>Disclosure of Interest</h3> None declared
Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis
Authors: Samuel P. Costello, Patrick A. Hughes, Oliver Waters, Robert V. Bryant, Andrew D. Vincent, Paul Blatchford, Rosa Katsikeros, Jesica Makanyanga, Melissa A. Campaniello, Chris Mavrangelos, Carly P. Rosewarne, Chelsea Bickley, Cian Peters, Mark N. Schoeman, Michael A. Conlon, Ian C. Roberts-Thomson, Jane M. Andrews
Journal: JAMA (2019)

High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity.To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool.A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017.Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months.The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events.Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group.In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety.anzctr.org.au Identifier: ACTRN12613000236796.
Therapy-Related Myeloid Neoplasms with Balanced Chromosome Rearrangements Frequently Arise from Pre-Existing Clonal Haematopoiesis
Authors: Richard Dillon, Jelena Jovanovic, Nicola Potter, Nicola Foot, Matthew J Ahearne, Sandrine Jayne, Michael Dennis, Ann E. Hunter, Martin J.S. Dyer, Paresh Vyas, Lynn Quek, Nigel H. Russell, Robert K. Hills, Ellen Solomon, David Grimwade
Journal: Blood (2018)
Chromatin Accessibility Profiling Reveals Cis-Regulatory Heterogeneity and Novel Transcription Factor Dependencies in Multiple Myeloma
Authors: Christopher J. Ott, Raphael Szalat, Matthew Lawlor, Mehmet Kemal Samur, Yan Xu, Charles B Epstein, Charles Y Lin, Rao Prabhala, Nina Farrell, Lauren D Walter, Logan Schwartz, Kenneth Wen, Yu-Tzu Tai, Mariateresa Fulciniti, Jinhua Wang, Nathanael Gray, Kenneth Anderson, Richard A. Young, Nikhil Munshi
Journal: Blood (2018)
Diabetes: precision approach will improve outcomes, says research director
Authors: Susan Mayor
Journal: BMJ (2019)

A precision approach that is based on greater understanding of different subtypes of diabetes and responses to treatment is needed to improve outcomes in diabetes, the research director of Diabetes UK told a meeting this week.

“Precision medicine is talked about a lot in relation to cancer. But we need to think about precision medicine from a diabetes perspective as a real potential for the future,” said Elizabeth Robertson.

She added, “Diabetes is complex so needs a personalised approach to prevention, diagnosis, treatment, and care. There is still a lot we don’t understand about diabetes. The more research we do into diabetes the more we understand that it’s an individual condition.”

She explained that evidence was now emerging that diabetes was very heterogeneous. A recent Swedish study classified adult onset diabetes into five different groups.1 “One of these …