tbuckley/cabot-search huggingface dataset:
SAT0100 Fenofibrate reduces serum urate in patients with hyperuricaemia established on allopurinol
Authors: AL Hepburn, MB Hogarth, SG Ball, SA Kaye, MD Feher
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Fenofibrate is an established treatment for various forms of hyperlipidaemia and is unique amongst the fibric acid derivatives due to its ability to lower serum urate. This urate-lowering effect has not, however, been assessed in patients established on allopurinol, the most widely used drug in the prevention of gout. <h3>Objectives</h3> To assess the short-term urate lowering effect of fenofibrate in patients with hyperuricaemia and gout already treated with allopurinol. <h3>Methods</h3> 11 patients (10M:1F), mean age 56.5 (range 38–74) with a history of either chronic tophaceous or interval gout in association with hyperuricaemia were assessed in an open crossover study. Each had been treated with allopurinol 300 mg/day or more for at least 3 months and had been free of acute gout for a minimum of 1 month. Each patient received micronised fenofibrate 200 mg once daily for 3 weeks. Before this was commenced, the following were measured: serum urate and creatinine, 24 hr urinary output of urate and creatinine, liver function tests, creatine kinase and fasting serum lipids These were repeated at the end of fenofibrate therapy and again 3 weeks later. Allopurinol was continued throughout the study period. <h3>Results</h3> Fenofibrate was associated with a 24% reduction in serum urate after 3 weeks of treatment (mean 0.36 ± 0.11 vs 0.29 ± 0.07 mmol/l; p = 0.002). The urate-lowering effect was rapidly reversed on its withdrawal (0.29 ± 0.07 vs 0.37 ± 0.09 mmol/l). There was a rise in urate clearance of 56% (6.7 ± 3.1 vs 10.5 ± 5.6 ml/min NR 6–11; p = 0.005) without any significant change in creatinine clearance. The largest reductions in serum urate occurred in patients with the highest levels at baseline. Both total cholesterol and triglyceride levels in the serum fell, but this was not statistically significant in either case (5.9 ± 1.0 vs 5.3 ± 0.9 mmol/l; p = 0.16 and 2.34 ± 1.11 vs 1.77 ± 0.66 mmol/l; p = 0.15 respectively). Alkaline phosphatase activity was reduced in each patient, confirming compliance with fenofibrate (70 ± 15 vs 53 ± 12U/l). Importantly, none of the group developed acute arthritis whilst taking fenofibrate, and the three who continue to take the drug remain free of gouty attacks. <h3>Conclusion</h3> Fenofibrate rapidly lowers serum urate by a significant degree in patients with hyperuricaemia who are already established on allopurinol prophylaxis. No adverse effects were seen, in particular a flare of gout. Fenofibrate is a potential novel treatment for hyperuricaemia and the prevention of gout. In particular it may have a useful dual role in patients with coexisting hyperuricaemia and hyperlipidaemia. <h3>Reference</h3> Bastow MD, <i>et al</i>. Hypertriglyceridaemia &amp; hyperuricaemia: effects of two fibric acid derivatives (bezafibrate &amp; fenofibrate) in a double-blind, placebo-controlled trial. Metabolism 1988;37:217–20
Immune thrombocytopenia (ITP) World Impact Survey (iWISh): Patient and physician perceptions of diagnosis, signs and symptoms, and treatment
Authors: Nichola Cooper, Alexandra Kruse, Caroline Kruse, Shirley Watson, Mervyn Morgan, Drew Provan, Waleed Ghanima, Donald M. Arnold, Yoshiaki Tomiyama, Cristina Santoro, Marc Michel, Serge Laborde, Barbara Lovrencic, Ming Hou, Tom Bailey, Gavin Taylor‐Stokes, Jens Haenig, James B. Bussel
Journal: American Journal of Hematology (2020)

Abstract Immune thrombocytopenia (ITP) is now well‐known to reduce patients' health‐related quality of life. However, data describing which signs and symptoms patients and physicians perceive as having the greatest impact are limited, as is understanding the full effects of ITP treatments. I‐WISh (ITP World Impact Survey) was an exploratory, cross‐sectional survey designed to establish the multifaceted impact of ITP, and its treatments, on patients' lives. It focused on perceptions of 1507 patients and 472 physicians from 13 countries regarding diagnostic pathway, frequency and severity of signs and symptoms, and treatment use. Twenty‐two percent of patients experienced delayed diagnosis (caused by several factors), 73% of whom felt anxious as a result. Patients rated fatigue among the most frequent, severe symptom associated with ITP at diagnosis (58% most frequent; 73% most severe), although physicians assigned it lower priority (30%). Fatigue was one of the few symptoms persisting at survey completion (50% and 65%, respectively) and was the top symptom patients wanted resolved (46%). Participating physicians were experienced at treating ITP, thereby recognizing the need to limit corticosteroid use to newly‐diagnosed or first‐relapse patients and espoused increased use of thrombopoietin receptor agonists and anti‐CD20 after relapse in patients with persistent/chronic disease. Patient and physicians were largely aligned on diagnosis, symptoms, and treatment use. I‐WISh demonstrated that patients and physicians largely align on overall ITP symptom burden, with certain differences, for example, fatigue. Understanding the emotional and clinical toll of ITP on the patient will facilitate shared decision‐management, setting and establishment of treatment goals and disease stage‐appropriate treatment selection.
Abstract 14693: Rheumatic Heart Disease and Deprivation in the United States: A Retrospective Review
Authors: Sarah R De Loizaga, Lindsay Arthur, Bhawna Arya, Andrew F Beck, Brian Beckman, Wubishet Belay, Cole Brokamp, Tom Choi, Sean Connolly, Soham Dasgupta, Tavenner Dibert, Marylou M Dryer, Lakshmi Gokanapudy, Elizabeth Anne Greene, Daphney Kernizan, Omar Khalid, Jennifer Klein, Ryan Kobayashi, subhrajit lahiri, Raymond P Lorenzoni, Andrea Otero Luna, Jennifer Marshall, Theodore Millette, Lily Moore, Babu Muhamed, Meghna Murali, Kinjal Parikh, Amy S Sanyahumbi, Divya Shakti, Elizabeth Stein, Sanket S Shah, Hannah Wilkins, McAllister Windom, Scott Wirth, Meghan Zimmerman, Craig A SABLE, Nicholas Ollberding, Andrea Z Beaton
Journal: Circulation (2020)

Introduction: Rheumatic heart disease (RHD) tracks with other cardiovascular health inequities in the US; however, RHD mortality captures a fraction of those affected and lags behind diagnosis by decades. There is little contemporary data on children living with acute rheumatic fever (ARF) and RHD within the US. This study describes recent pediatric ARF/RHD in the US and examines the association with community deprivation. Methods: Sixty US institutions were invited to participate in a 10-year review (2008-2018). Geocoding was used to determine a census tract-based socioeconomic deprivation index (DI) ranging from 0-1 (1 being most deprived). Independent sample t-test was used to compare DI means. Odds ratios (OR) with 95% confidence intervals were obtained from multivariable logistic regression. The DI was scaled to provide ORs for a one standard deviation increase. Results: Data for 947 cases from 22 institutions showed median age at diagnosis of 9 years, with half identifying as male (51%) and non-white (52%), and three-quarters (74%) identifying as non-Hispanic. Most identified English as their primary language, had health insurance, and were first diagnosed in the US (84%, 89%, and 82%, respectively). Of the 157 (17%) with travel exposure, Pacific Islands (38%) and Africa (21%) were most commonly identified. Nearly three-quarters (73%) were diagnosed with ARF and most (98%) had an echocardiogram at diagnosis. While 96% of patients were prescribed secondary prophylaxis, only half (58%) were prescribed intramuscular Benzathine penicillin (BPG), the gold standard. The mean DI was 0.39±0.15. Higher deprivation was associated with RHD as opposed to ARF at diagnosis (DI 0.42 vs. 0.38, p&lt;0.001). Additionally, higher deprivation was associated with increased risk of severe RHD (OR 1.34; 95% CI 1.11-1.62) and increased use of BPG vs enteral penicillin for secondary prevention (OR 0.67; 95% CI 0.56-0.8). Conclusions: Recent pediatric cases of ARF and RHD in the US are endemic, rather than from foreign exposure and children who live in more deprived communities are at risk for more severe disease. Additional research is needed into why intramuscular penicillin, which has superior efficacy compared to oral penicillin, is prescribed in only half of cases.
Abstract 15416: Longitudinal Assessment of Electrical-Mechanical Interactions in Children and Young Adults With Repaired Tetralogy of Fallot
Authors: Suellen M Yin, Laura M Mercer-rosa, Jungwon Min, Elizabeth Goldmuntz, Victoria L Vetter
Journal: Circulation (2020)

Introduction: Electrical-mechanical interactions contribute to arrhythmias, sudden cardiac death, and right ventricular remodeling in repaired tetralogy of Fallot (TOF). Hypothesis: There are significant changes in electrocardiographic properties and electrical-mechanical interactions that occur over time after complete TOF repair and with pulmonary valve replacement (PVR). Methods: This retrospective cohort study of 177 patients, initially recruited for a cross-sectional research protocol, underwent complete TOF repair at 0.3±0.9 years with 21.5±4.2 years of clinical follow-up. We assessed ECG, Holter, cardiopulmonary exercise testing (CPET), and MRI data. We used linear mixed effects models to examine QRS duration (QRSd) and its rate of change over time, associations between comparable ECG and MRI, Holter and MRI, ECG and Holter, ECG and CPET, and pre-PVR and post-PVR results. Results: QRSd increased after TOF repair, but the rate of change decreased from 5.2 ms/year 1 year post-operatively to 1.7 ms/year 20 years post-operatively. Twenty years from TOF repair, post-operative arrhythmias included ventricular ectopy: ventricular tachycardia (4 of 20 patients) on Holter and premature ventricular contractions (14 of 19 patients) on CPET. QRSd was positively associated with right ventricular (RV) volumes, RV:left ventricular (LV) end-diastolic volume ratio, and complex ventricular ectopy on Holter; and negatively associated with RV ejection fraction (EF). The association between QRSd and RV volumes was weaker post-PVR. QRSd and its rate of change were associated with increased LV volume post-PVR. Complex ventricular ectopy was associated with lower LV EF, and significant atrial ectopy was associated with higher LV mass-to-volume ratio. Conclusions: Substantial ventricular ectopy occurs in adolescents and young adults after repair of TOF. Electrophysiologic changes included QRSd prolongation that progressively slowed. QRSd and its rate of change were associated with published risk factors for arrhythmia and sudden cardiac death, and with indications for PVR. Our ongoing research aims to identify an optimal threshold of pre-PVR QRSd and its rate of change that preserves bi-ventricular electrical-mechanical coupling post-PVR.
Abstract 15228: Role of Sympathetic Innervation in the Pathogenesis of Abdominal Aortic Aneurysm
Authors: Bin JIANG, Yugang Liu, Guillermo A Ameer
Journal: Circulation (2020)

Introduction: The objective of this study is to understand the role of neurological factors, specifically those from the perivascular sympathetic nervous system (SNS), on the initiation and development of Abdominal Aortic Aneurysm (AAA). Hypothesis: We hypothesize that the formation of AAA is associated with the loss of perivascular SNS-induced vasoconstriction specific to the aneurysm region. Methods: We developed a rat Abdominal Aortic Denervation (AAD) model, where the infrarenal aorta of Spauge Dawley rats was denervated with surgical removal of nerve fibers and chemical denervation with 10% phenol ( Figure. A ). A sham control group was included where the infrarenal aorta was treated with PBS. The arteries were harvested at 1 month after the surgeries for histological assessment. Results: The denervated aortas exhibited significant thinning of the aortic wall including the media and the adventitia, compared to the sham controls ( Figure. B ). Moreover, degradation of elastin, demonstrated by the fragmentation of elastic fibers and the decreased number of lamellar units, was also observed in the dennervated aortas in comparison to the sham controls. While the control aortas were well innervated with perivascular nerve bundles adjacent to the adventitia, no nerves were found surrounding the denervated aortas, suggesting successful denervation. Conclusions: We generated an AAD model that could be used for mechanistic understanding and therapeutic development of AAA. The preliminary data suggest a direct link between the lack of aortic sympathetic innervation and AAA formation. Long-term studies are currently underway to further characterize changes in the aortic walls after sympathetic denervation. Figure. (A) Illustration of the denervated region on the rat infrarenal aorta. ( B ) Histological staining of control and denervated rat abdominal aortas at 1 month after surgery. Yellow stars: para-aortic nerve bundles. Scale bar = 200 μm.
Abstract 15432: Observation of Aortic Dilatation in Congenital Conotruncal Anomalies - Tetralogy of Fallot, Double Outlet Right Ventricle and Truncus Arteriosus
Authors: Woojung Kim, Jae Gun Kwak
Journal: Circulation (2020)

Backgrounds: Dilatation of aortic root or ascending aorta is often seen in the patients with conotruncal anomalies (CA). How fast these structures dilate and how we manage this phenomenon are not clear. Methods: We reviewed medical records of patients who underwent biventricular repair of CA such as tetralogy of Fallot (TOF), double outlet right ventricle (DORV) and truncus arteriosus (TA) from 2004 to 2018. We included 99 patients who had follow-up cardiac computed tomography angiography (CT) images at least 5 years since initial CT in this study. We analyzed changes of diameters of aortic root structures and ascending aorta between initial and follow-up CT images. Results: Median follow-up duration was 16.1 years (interquartile range (IQR): 11.8~26.2 years) after operation. Median interval between initial and follow-up CT examination was 9.4 years (IQR: 7.1~11.5 years). Median age of initial and follow-up CT was 4.3 years (IQR: 0.3~12.3 years) and 14.4 years (IQR: 9.2~22.9 years). The median z-scores (with IQR) of sinus of Valsalva (SV, 2.0 (0.8~3.3) → 2.4 (1.4~3.3), p=0.006) and sinotubular junction (STJ, 1.3 (-0.2~2.6) → 2.2 (0.4~3.3), p=0.001) were significantly changed, whereas aortic annulus (AA, 2.4 (0.9~3.4) → 2.3 (0.8~3.3), p=0.21) and ascending aorta (AsA, 1.6 (0.4~2.9) → 1.6 (0.03~2.6), p=0.27) did not show significant changes in CT images. Median increasing rate of diameter of AA, SV, STJ and AsA was 0.72, 0.93, 0.83 and 0.51 mm/year, respectively. Dilatation rate of AA (0.69 in TOF vs. 0.99 in TA, p=0.042) and SV (0.81 in TOF vs. 1.53 in TA, p=0.008) of TA was significantly higher than of TOF. Conclusions: In TOF, DORV and TA, SV and STJ significantly dilated, whereas AsA and AA did not significantly dilated for 9 years of follow-up. Although chance of surgical intervention for dilatation of aortic structures was rare, it might be necessary to observe closely aortic valvular function associated with structural deterioration of SV or STJ.
Abstract 14344: Prognostic Factors of Atrial Fibrillation Patients With Coronary Artery Disease: The Fushimi Af Registry
Authors: Nobutoyo Masunaga, Hisashi Ogawa, Yuya Aono, Syuhei Ikeda, KOSUKE DOI, Yasuhiro Hamatani, Akiko Fujino, Yoshimori An, MITSURU ISHII, Moritake Iguchi, Masahiro Esato, Hikari Tsuji, Hiromichi Wada, Koji Hasegawa, Mitsuru Abe, Masaharu Akao
Journal: Circulation (2020)

Background: Atrial fibrillation (AF) patients are likely to have concomitant coronary artery disease (CAD). A new strategy of antithrombotic therapy in AF patients with stable CAD was demonstrated in recent randomized clinical trials. Now that antithrombotic therapy for AF patients with CAD has reached a major turning point, it is important to know the prognostic factors in those patients. Purpose: In this study, we investigated clinical characteristics, cardiovascular events and prognostic factors in AF patients with CAD. Methods: The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all of the AF patients who visited the participating medical institutions in Fushimi-ku, Kyoto, Japan. Follow up data including prescription status were available in 4,441 patients from March 2011 to November 2019. Of 4,441 patients, 645 patients had a history of CAD at enrollment. Results: The mean age was 76.4±8.6 and 65.9% were male. Averages of CHA 2 DS 2 -VASc score and HAS-BLED score were 4.41 and 2.35, respectively. Oral anticoagulant (OAC) was prescribed in 52.9% of those patients and antiplatelet drug (APD) was prescribed in 70.4%. The combination of OAC and APD was prescribed in 36.0%. During follow-up period (median 1,495 days), cardiac death occurred in 51 patients, composite of cardiac death, myocardial infarction (MI) and stroke in 136, and major bleeding in 77 (1.8, 5.1 and 2.9 per 100 person-years, respectively). In multivariate analysis, factors associated with composite of cardiac death, MI and stroke in AF patients with CAD were low body weight (&lt;=50kg) (hazard ratio [95% confidence interval]; 1.62 [1.07-2.47]), previous stroke (1.69 [1.13-2.52]), heart failure (1.47 [1.02-2.11]), hypertension (0.60 [0.41-0.87]) and diabetes mellitus (1.62 [1.13-2.32]). Furthermore, factors associated with major bleeding in AF patients with CAD were anemia (male: hemoglobin&lt;12 g/dl, female: hemoglobin&lt;11 g/dl) (1.82 [1.09-3.04]) and thrombocytopenia (&lt;150,000 /μL) (3.02 [1.29-7.03]). Conclusion: In Japanese AF patients with CAD, low body weight, previous stroke, heart failure, hypertension and diabetes mellitus were associated with cardiovascular events, and anemia and thrombocytopenia were associated with major bleeding.
Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression?
Authors: Colin G. Nichols, Nathaniel W. York, Maria S. Remedi
Journal: Journal of Clinical Investigation (2020)

Patients with type 2 diabetes (T2D) fail to secrete insulin in response to increased glucose levels that occur with eating. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two incretins secreted from gastrointestinal cells that amplify insulin secretion when glucose is high. In this issue of the JCI, Oduori et al. explore the role of ATP-sensitive K+ (KATP) channels in maintaining glucose homeostasis. In persistently depolarized β cells from KATP channel knockout (KO) mice, the researchers revealed a shift in G protein signaling from the Gs family to the Gq family. This shift explains why GLP-1, which signals via Gq, but not GIP, which signals preferentially via Gs, can effectively potentiate secretion in islets from the KATP channel-deficient mice and in other models of KATP deficiency, including diabetic KK-Ay mice. Their results provide one explanation for differential insulinotropic potential of incretins in human T2D and point to a potentially unifying model for T2D progression itself.
Turnover Modulates the Need for a Cost of Resistance in Adaptive Therapy
Authors: Maximilian A.R. Strobl, Jeffrey West, Yannick Viossat, Mehdi Damaghi, Mark Robertson-Tessi, Joel S. Brown, Robert A. Gatenby, Philip K. Maini, Alexander R.A. Anderson
Journal: Cancer Research (2020)

Abstract Adaptive therapy seeks to exploit intratumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer that determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this article, we study a general, but simple, mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka–Volterra model. For tumors close to their environmental carrying capacity, a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost–turnover interplay in data from 67 patients with prostate cancer undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision-making process. Significance: Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy. See related commentary by Strobl et al., p. 811
Notice of addendum to Article reporting Oxford trial of ChAdOx1 nCoV-19 vaccine
Authors: Andrew J Pollard
Journal: The Lancet (2020)

On request, and to aid others doing similar trials, we are publishing the full standard operating procedures (SOPs) for the Oxford University-sponsored trials of the ChAdOx1 nCoV-19 vaccine. Operational details about running clinical trials of COVID-19 vaccines in a pandemic are not generally available as they are contained in SOPs held at trial sites. These SOPs can provide additional insight into study conduct that assist with interpretation of the data. We have provided an additional appendix to our Article reporting the phase 1/2 findings1Folegatti PM Ewer KJ Aley PK et al.Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled.Lancet. 2020; 396: 467-478Summary Full Text Full Text PDF PubMed Scopus (1772) Google Scholar to provide this information about the key processes guiding the Oxford University-sponsored trials of the ChAdOx1 nCoV-19 vaccine. The SOPs were prepared by Susan Jackson, Susanne H Hodgson, and Hazel Morrison. I report grants from the National Institute for Health Research (NIHR), UK Research and Innovation, and CEPI, am Chair of the UK Department of Health and Social Care (DHSC) Joint Committee on Vaccination and Immunisation (JCVI), and am a member of WHO's Strategic Advisory Group of Experts (SAGE) on Immunization. I have not participated in policy discussions or decisions about COVID-19 vaccines. The views expressed in this Comment do not necessarily represent the views of DHSC, JCVI, NIHR, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on COVID-19 vaccine development. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trialChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. Full-Text PDF Open Access