tbuckley/cabot-search huggingface dataset:
Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies
Authors: Tadeusz Robak, Jan A. Burger, Alessandra Tedeschi, Paul M. Barr, Carolyn Owen, Osnat Bairey, Peter Hillmen, David Simpson, Sebastian Grosicki, Stephen Devereux, Helen McCarthy, Steven E. Coutre, Hang Quach, Gianluca Gaidano, Zvenyslava Maslyak, Don A. Stevens, Carol Moreno, Devinder S. Gill, Ian W. Flinn, John G. Gribben, Ahmad Mokatrin, Mei Cheng, Lori Styles, Danelle F. James, Thomas J. Kipps, Paolo Ghia
Journal: American Journal of Hematology (2018)

Chemoimmunotherapy (CIT) and targeted therapy with single-agent ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with ibrutinib. Grade ≥ 3 neutropenia was 12% for ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings.
Quiescent Endothelial Cells Upregulate Fatty Acid β-Oxidation for Vasculoprotection via Redox Homeostasis
Authors: Joanna Kalucka, Laura Bierhansl, Nadine Vasconcelos Conchinha, Rindert Missiaen, Ilaria Elia, Ulrike Brüning, Samantha Scheinok, Lucas Treps, Anna Rita Cantelmo, Charlotte Dubois, Pauline de Zeeuw, Jermaine Goveia, Annalisa Zecchin, Federico Taverna, Francisco Morales-Rodriguez, Aleksandra Brajic, Lena-Christin Conradi, Sandra Schoors, Ulrike Harjes, Kim Vriens, Gregor-Alexander Pilz, Rongyuan Chen, Richard Cubbon, Bernard Thienpont, Bert Cruys, Brian W. Wong, Bart Ghesquière, Mieke Dewerchin, Katrien De Bock, Xavier Sagaert, Sebastian Jessberger, Elizabeth A.V. Jones, Bernard Gallez, Diether Lambrechts, Massimiliano Mazzone, Guy Eelen, Xuri Li, Sarah-Maria Fendt, Peter Carmeliet
Journal: Cell Metabolism (2018)
Air pollution may claim 36 000 lives a year in UK
Authors: Jacqui Wise
Journal: BMJ (2018)

Air pollution causes 28 000 to 36 000 deaths a year in the UK, estimates from the Committee on the Medical Effects of Air Pollutants have shown.1

The committee’s previous estimate, made in 2015, was an annual effect equivalent to nearly 29 000 deaths a year. The new figure was arrived at by combining the effects seen in studies of nitrogen dioxide (NO2) and fine particulate matter (PM2.5). The committee found it difficult to separate the effects of particulate air pollution from that of NO2 because of scientific uncertainty.

In May the European Commission announced that it was taking the UK, along with France and Germany, to the European Court of Justice for failing to meet EU …
Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma
Authors: Ryan A. Hlady, Aishwarya Sathyanarayan, Joyce J. Thompson, Dan Zhou, Qunfeng Wu, Kien Pham, Jeong‐Heon Lee, Chen Liu, Keith D. Robertson
Journal: Hepatology (2018)

Disruption of epigenetic mechanisms has been intimately linked to the etiology of human cancer. Understanding how these epigenetic mechanisms (including DNA methylation [5mC], hydroxymethylation [5hmC], and histone post‐translational modifications) work in concert to drive cancer initiation and progression remains unknown. Hepatocellular carcinoma (HCC) is increasing in frequency in Western countries but lacks efficacious treatments. The epigenome of HCC remains understudied. To better understand the epigenetic underpinnings of HCC, we performed a genome‐wide assessment of 5mC, 5hmC, four histone modifications linked to promoter/enhancer function (H3K4me1, H3K27ac, H3K4me3, and H3K27me3), and transcription across normal, cirrhotic, and HCC liver tissue. Implementation of bioinformatic strategies integrated these epigenetic marks with each other and with transcription to provide a comprehensive epigenetic profile of how and when the liver epigenome is perturbed during progression to HCC. Our data demonstrate significant deregulation of epigenetic regulators combined with disruptions in the epigenome hallmarked by profound loss of 5hmC, locus‐specific gains in 5mC and 5hmC, and markedly altered histone modification profiles, particularly remodeling of enhancers. Data integration demonstrates that these marks collaborate to influence transcription (e.g., hyper‐5hmC in HCC‐gained active enhancers is linked to elevated expression) of genes regulating HCC proliferation. Two such putative epigenetic driver loci identified through our integrative approach, COMT and FMO3 , increase apoptosis and decrease cell viability in liver‐derived cancer cell lines when ectopically re‐expressed. Conclusion : Altogether, integration of multiple epigenetic parameters is a powerful tool for identifying epigenetically regulated drivers of HCC and elucidating how epigenome deregulation contributes to liver disease and HCC.
Renal impairment during pemetrexed maintenance in patients with advanced nonsmall cell lung cancer: a cohort study
Authors: Sabine Visser, Jeannine Huisbrink, Nils E. van ‘t Veer, Jermo J. van Toor, Anton J.M. van Boxem, Nico C. van Walree, Bruno H. Stricker, Joachim G.J.V. Aerts
Journal: European Respiratory Journal (2018)

Optimal survival benefit from different lines of anticancer treatment in advanced nonsmall cell lung cancer (NSCLC) requires conservation of renal function. We evaluated the development of renal impairment during pemetrexed maintenance. In a prospective multicentre cohort study, we evaluated the incidence of acute/chronic kidney disease (AKD/CKD), its related treatment discontinuation frequency and associated clinical variables with AKD in patients with stage IIIB/IV NSCLC treated with pemetrexed maintenance. We validated the findings in an independent cohort. 190 patients received pemetrexed. In the primary cohort, 149 patients started induction, of whom 44 patients (30%) continued maintenance. In the independent cohort, 41 patients received maintenance. During maintenance 13 patients (30%) developed AKD, leading to CKD and treatment discontinuation in eight patients (62%) in the primary cohort. Higher estimated glomerular filtration rate (eGFR) (per unit 5 mL·min −1 per 1.73 m 2 ) before maintenance and induction (OR 0.70, 95% CI 0.54–0.90 and OR 0.78, 95% CI 0.62–0.98, respectively) and relative decline (per 10%) in eGFR during induction (OR 2.54, 95% CI 1.36–4.74) were associated with AKD during maintenance. In the independent cohort, 20 patients (49%) developed AKD, leading to CKD in 11 patients (55%) and treatment discontinuation in six patients (30%). Patients are at risk for renal impairment during pemetrexed maintenance, which may jeopardise further lines of anticancer treatment.
Call for a new national performance assessment body for doctors led by the health secretary
Authors: A R Sooltan
Journal: BMJ (2018)

Performance assessment of hospital doctors and general practitioners is initiated by NHS England. Doctors are referred to the General Medical Council for further assessment and sanctioning, a process that can span over years with a heavy toll. It can destroy the doctor’s career, health, life, and family.1 To the country, the cost of suspension is colossal. Retaining and recruiting doctors …
First results on the DCVax phase III trial: raising more questions than providing answers
Authors: Wolfgang Wick, Martin J van den Bent
Journal: Neuro-Oncology (2018)

Recently, the long-awaited report on efficacy data of the DCVax trial has appeared in the Journal of Translational Medicine.1 Patients and physicians alike are eager to critically evaluate the first results of this important trial, which is one of the earliest major attempts to improve outcome in patients with glioblastoma using immunotherapy based on an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax). It is not only one of the first randomized phase III trials of its kind, but in light of recent successes with cancer immunotherapies outside neuro-oncology, there is a huge interest in any form of immune treatment for glioma patients.
The use of social features in mobile health interventions to promote physical activity: a systematic review
Authors: Huong Ly Tong, Liliana Laranjo
Journal: npj Digital Medicine (2018)

Abstract Mobile health (mHealth) technologies have increasingly been used in interventions to promote physical activity (PA), yet, they often have high attrition rates. Integrating social features into mHealth has the potential to engage users; however, little is known about the efficacy and user engagement of such interventions. Thus, the aim of this systematic review was to characterize and evaluate the impact of interventions integrating social features in mHealth interventions to promote PA. During database screening, studies were included if they involved people who were exposed to a mHealth intervention with social features, to promote PA. We conducted a narrative synthesis of included studies and a meta-analysis of randomized controlled trials (RCTs). Nineteen studies were included: 4 RCTs, 10 quasi-experimental, and 5 non-experimental studies. Most experimental studies had retention rates above 80%, except two. Social features were often used to provide social support or comparison. The meta-analysis found a non-significant effect on PA outcomes [standardized difference in means = 0.957, 95% confidence interval −1.09 to 3.00]. Users’ preferences of social features were mixed: some felt more motivated by social support and competition, while others expressed concerns about comparison, indicating that a one-size-fits-all approach is insufficient. In summary, this is an emerging area of research, with limited evidence suggesting that social features may increase user engagement. However, due to the quasi-experimental and multi-component nature of most studies, it is difficult to determine the specific impact of social features, suggesting the need for more robust studies to assess the impact of different intervention components.
Abstract P179: Systolic Blood Pressure and Risk for Cardiovascular Disease Among Adults 60 Years and Older without Diabetes or Chronic Kidney Disease
Authors: Samantha G Bromfield, Lisandro D Colantonio, George Howard, Monika M Safford, Daniel Lackland, Olugbenga Ogedegbe, Maciej Banach, C. Barrett Bowling, Maria-Corina Serban, Daichi Shimbo, Paul Muntner
Journal: Circulation (2016)

The 2014 Evidence-based Guideline for the Management of High Blood Pressure in Adults: Report from the Panel Members Appointed to the Eighth Joint National Committee (JNC 8) raised the systolic blood pressure (SBP) threshold for treatment initiation and goal attainment to 150 mmHg in adults 60 years and older without a history of diabetes or chronic kidney disease (CKD). Using data from the nationwide Reasons for Geographic and Racial Difference in Stroke (REGARDS) study, we examined the association between SBP levels and cardiovascular disease (CVD), coronary heart disease (CHD), and stroke among adults ≥60 years of age. We excluded participants with a history of diabetes, CKD, and diastolic blood pressure (DBP) ≥90 mmHg. Baseline REGARDS data were collected during telephone interviews and in-home study visits in 2003 through 2007 and included two blood pressure measurements following a standardized protocol. SBP was categorized as &lt;140 mmHg, 140-149 mmHg, and ≥150 mmHg. Outcomes were identified through December 31, 2012 using primary data collection. Of the 4,618 REGARDS participants taking antihypertensive medication, 593 (12.8%) had SBP 140-149 mmHg and 343 (7.4%) had SBP ≥150 mmHg. After multivariable adjustment, SBP of 140-149 mmHg versus SBP &lt;140 mmHg was not associated with any of the outcomes (Table 1) whereas SBP ≥150 mmHg was associated with an increased risk for CVD and CHD, but not stroke. Of the 5,601 participants not taking antihypertensive medication, 417 (7.5%) had SBP 140-149 mmHg and 181 (3.2%) had SBP ≥150 mmHg. Compared with SBP &lt;140 mmHg, SBP140-149 mmHg but not SBP ≥150 mmHg was associated with an increased risk for CVD, CHD, and stroke. In summary, SBP between 140-149 mmHg was associated with CVD-related outcomes in untreated, but not treated individuals. These data suggest using different thresholds for antihypertensive treatment initiation and goal attainment among individuals ≥60 years of age without a history of diabetes or CKD, with DBP ≥90 mmHg may be safe.
Effect of Achieving Minimal Disease Activity on the Progression of Subclinical Atherosclerosis and Arterial Stiffness: A Prospective Cohort Study in Psoriatic Arthritis
Authors: Isaac T. Cheng, Qing Shang, Edmund K. Li, Priscilla C. Wong, Emily W. Kun, Mei Yan Law, Ronald M. Yip, Isaac C. Yim, Billy T. Lai, Shirley K. Ying, Kitty Y. Kwok, Martin Li, Tena K. Li, Tracy Y. Zhu, Jack J. Lee, Mimi M. Chang, Cheuk‐Chun Szeto, Bryan P. Yan, Alex P. Lee, Lai‐Shan Tam
Journal: Arthritis & Rheumatology (2018)

To investigate the effects of achieving minimal disease activity (MDA) on the progression of subclinical atherosclerosis and arterial stiffness in patients with psoriatic arthritis (PsA).A total of 101 consecutive patients with PsA were recruited for this prospective cohort study. All patients received protocolized treatment targeting MDA for a period of 2 years. High-resolution carotid ultrasound and arterial stiffness markers were assessed annually. The primary outcome measure was the effect of achieving MDA at 12 months (MDA group) on the progression of subclinical atherosclerosis over a period of 24 months. Secondary objectives were to compare the changes in arterial stiffness markers over 24 months between the MDA and non-MDA groups, as well as the changes in subclinical atherosclerosis and arterial stiffness markers in patients who achieved MDA at each visit from month 12 through month 24 (sustained MDA [sMDA]).Ninety PsA patients (mean ± SD age 50 ± 11 years, 58% male [n = 52]) who completed 24 months of follow-up were included in this analysis. Fifty-seven patients (63%) had achieved MDA at 12 months. Subclinical atherosclerosis and arterial stiffness outcomes were similar between the MDA and non-MDA groups. Forty-one patients (46%) achieved sMDA. As shown by multivariate analysis, achieving sMDA had a protective effect on plaque progression (odds ratio 0.273 [95% confidence interval 0.088-0.846], P = 0.024), and less of an increase in total plaque area, mean intima-media thickness, and augmentation index values after adjustment for covariates.Our results support the recommendation that once MDA is achieved, it should ideally be maintained for a prolonged period in order to prevent progression of carotid atherosclerosis and arterial stiffness in patients with PsA.
Skin Self-examination for Skin Cancer Prevention—Reply
Authors: Susan J. Curry, Alex H. Krist, Douglas K. Owens
Journal: JAMA (2018)

In Reply The USPSTF shares the frustration of Dr Svoboda and colleagues that there is insufficient evidence to recommend for or against counseling adults to perform routine self-skin examination. Skin cancer is the most common cancer, and melanoma will result in 9320 deaths in 2018.1
Subretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degeneration
Authors: Haihan Jiao, Matt Rutar, Nilisha Fernando, Ted Yednock, Sethu Sankaranarayanan, Riemke Aggio-Bruce, Jan Provis, Riccardo Natoli
Journal: Molecular Neurodegeneration (2018)

The role of the alternative complement pathway and its mediation by retinal microglia and macrophages, is well-established in the pathogenesis of Age-Related Macular Degeneration (AMD). However, the contribution of the classical complement pathway towards the progression of retinal degenerations is not fully understood, including the role of complement component 1q (C1q) as a critical activator molecule of the classical pathway. Here, we investigated the contribution of C1q to progressive photoreceptor loss and neuroinflammation in retinal degenerations.Wild-type (WT), C1qa knockout (C1qa-/-) and mice treated with a C1q inhibitor (ANX-M1; Annexon Biosciences), were exposed to photo-oxidative damage (PD) and were observed for progressive lesion development. Retinal function was assessed by electroretinography, followed by histological analyses to assess photoreceptor degeneration. Retinal inflammation was investigated through complement activation, macrophage recruitment and inflammasome expression using western blotting, qPCR and immunofluorescence. C1q was localised in human AMD donor retinas using immunohistochemistry.PD mice had increased levels of C1qa which correlated with increasing photoreceptor cell death and macrophage recruitment. C1qa-/- mice did not show any differences in photoreceptor loss or inflammation at 7 days compared to WT, however at 14 days after the onset of damage, C1qa-/- retinas displayed less photoreceptor cell death, reduced microglia/macrophage recruitment to the photoreceptor lesion, and higher visual function. C1qa-/- mice displayed reduced inflammasome and IL-1β expression in microglia and macrophages in the degenerating retina. Retinal neutralisation of C1q, using an intravitreally-delivered anti-C1q antibody, reduced the progression of retinal degeneration following PD, while systemic delivery had no effect. Finally, retinal C1q was found to be expressed by subretinal microglia/macrophages located in the outer retina of early AMD donor eyes, and in mouse PD retinas.Our data implicate subretinal macrophages, C1q and the classical pathway in progressive retinal degeneration. We demonstrate a role of local C1q produced by microglia/macrophages as an instigator of inflammasome activation and inflammation. Crucially, we have shown that retinal C1q neutralisation during disease progression may slow retinal atrophy, providing a novel strategy for the treatment of complement-mediated retinal degenerations including AMD.
Abstract 11431: Critical Role of miR-181 Family During Oxidative Stress in Heart
Authors: Samarjit Das, Mark Kohr, Brittany Dunkerly, Oliver A Kent, Anthony K Leung, Jorge Henao-Mejia, Richard A Flavell, Charles Steenbergen
Journal: Circulation (2014)

The role of oxidative stress in cardiac injury has been extensively studied. Mitochondria are the major source of ROS and a target for ROS damage. Recently, we have identified a mi(cro)RNA, miR-181...
Is Mini-Dose Glucagon the Answer to Preventing Exercise-Related Dysglycemia?
Authors: Jessica R. Castle
Journal: Diabetes Care (2018)

Hypoglycemia is a potentially fatal complication of insulin therapy. In normal physiology, glucagon acts as a counterregulatory hormone to raise circulating glucose, defending against hypoglycemia. This defense is lost early in type 1 diabetes (1,2). The absence of normal counterregulation in patients with type 1 diabetes, combined with the slow offset of subcutaneous insulin therapy, results in a significant risk of hypoglycemia in this population. Mild hypoglycemia can be treated with the ingestion of simple carbohydrates, but frequent treatments may lead to unwanted weight gain. Frequent hypoglycemic episodes also put a patient at risk for hypoglycemia unawareness, which significantly increases a person’s risk of severe hypoglycemia (3).

For decades, the use of glucagon has been largely limited to a rescue treatment for severe hypoglycemia. The available rescue kits require the user to reconstitute glucagon from a lyophilized powder. After reconstitution into an aqueous solution, native glucagon quickly forms fibrils and degrades (4). For this reason, rescue glucagon kits are currently designed to be used immediately after reconstitution and then discarded.

To address this …
Enrollment of Older Patients, Women, and Racial and Ethnic Minorities in Contemporary Heart Failure Clinical Trials
Authors: Ayman Samman Tahhan, Muthiah Vaduganathan, Stephen J. Greene, Gregg C. Fonarow, Mona Fiuzat, Mariell Jessup, JoAnn Lindenfeld, Christopher M. O’Connor, Javed Butler
Journal: JAMA Cardiology (2018)

Despite the importance of age, sex, and race/ethnicity representativeness in clinical trials, limited data exist regarding the enrollment trends of these groups in contemporary heart failure (HF) trials.To characterize the representation of older patients, women, and racial and ethnic minorities in HF trials.We performed a systematic search of HF trials enrolling more than 400 participants published between January 2001 and December 2016 using PubMed/Medline and ClinicalTrials.gov. A total of 118 trials enrolling a cumulative 215 508 patients were included. Trial findings were compared with large epidemiologic studies indexed to hospitalization status and ejection fraction.Median number of participants per trial was 994 (interquartile range [IQR], 543-1899), enrolled from a median of 82 (IQR, 28-171) study sites. Overall, 94 trials (80%) enrolled patients with HF with reduced ejection fraction (HFrEF) exclusively. Mean (SD) age of trial participants was 65 (11) years (from 64 years in 2001 to 2004 to 65 years in 2013 to 2016), and 58 873 of 215 508 were women (27%; from 26% in 2001 to 2004 to 29% in 2013 to 2016); no significant temporal trends were observed (P ≥ .60 for both). Chronic HF with preserved ejection fraction (HFpEF) trials enrolled older participants (mean [SD] age, 71 [7] years compared with 65 [11] years for HFrEF and 66 [12] years for acute HF [AHF] trials; P = .01). Corresponding mean ages in US epidemiologic studies were 69 years for HFrEF and 73 years for both patients with HFpEF and patients with AHF. The HFpEF trials had a higher proportion of women (n = 4940 of 8845 [56%]) compared with HFrEF (n = 34 397 of 143 538 [24%]) or AHF (n = 11 013 of 34 633 [32%]) (P < .001). Corresponding weighted proportions of women in HFpEF, HFrEF, and AHF trials in epidemiologic studies were 62%, 29%, and 50%, respectively. Distribution of racial/ethnic groups was reported in 55% (47%) of the trials; 22% of the participants were not white (n = 27 463 of 124 980), with significant increase over time from 13% in 2001 to 2004 (n = 5606 of 44 616) to 30% in 2013 to 2016 (8421 of 28 073) (P = .01).In contemporary HF trials, older patients and women are consistently underrepresented. Race/ethnicity data are reported in less than half of trials; when reported, such data show that enrollment of nonwhite patients increased over time.