tbuckley/cabot-search huggingface dataset:
Phase Ib/II trial of lenvatinib plus pembrolizumab in advanced melanoma.
Authors: Matthew H. Taylor, Nicholas J. Vogelzang, Allen Lee Cohn, Daniel E. Stepan, Robert Charles Shumaker, Corina E. Dutcus, Matthew Guo, Emmett V. Schmidt, Drew W. Rasco
Journal: Journal of Clinical Oncology (2019)

15 Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is approved for first-line treatment of advanced melanoma (objective response rates [ORR], 21–34%). In preclinical studies, LEN decreased tumor-associated macrophage populations, increased CD8 + T cell infiltration, and augmented PD-1 inhibitor activity; thus, LEN is a rational combination partner for PEM. We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in solid tumors, focusing on advanced melanoma. Methods: In this multicenter, open-label study, patients (pts) with measurable, confirmed, metastatic melanoma and ECOG PS ≤1 received oral LEN (20 mg/day) + PEM (200 mg Q3W, IV). Pts were not preselected for PD-L1 status. Tumor assessments were by investigator per immune-related RECIST (irRECIST). Phase 2 primary end point was ORR at 24 weeks (ORR WK24 ). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 14 (67%) were PD-L1+, 4 (19%) were PD-L1-; 3 (14%) not tested. 38% had ≥1 prior anticancer therapy. ORR WK24 was 47.6% (95% CI, 25.7–70.2). All pts had ≥1 treatment-related adverse event (TRAE). Grade 3 and 4 TRAEs occurred in 13 (62%) and 1 (5%; adrenal insufficiency) pts respectively. There were no fatal TRAEs. Most common any-grade TRAEs were fatigue (52%), decreased appetite (48%), diarrhea (48%), hypertension (48%), dysphonia (43%), and nausea (43%). Dose reduction and interruption due to TRAEs occurred in 13 (62%) and 10 (48%) pts, respectively. Conclusions: LEN + PEM was well-tolerated and had encouraging clinical activity. The combination may potentially improve on the antitumor activity of anti-PD-1 monotherapies, supporting further evaluation in advanced melanoma. Clinical trial information: NCT02501096. [Table: see text]
Keep calm and carry on testing: a substantive reanalysis and critique of ‘what is the evidence for and validity of return-to-sport testing after anterior cruciate ligament reconstruction surgery? A systematic review and meta-analysis’
Authors: Jacob John Capin, Lynn Snyder-Mackler, May Arna Risberg, Hege Grindem
Journal: British Journal of Sports Medicine (2019)

Clinicians rely on rigorous systematic reviews to guide practice. We therefore suspect many clinicians will note the results of the 2019 systematic review and meta-analysis by Webster and Hewett, ‘What is the Evidence for and Validity of Return-to-Sport Testing after Anterior Cruciate Ligament Reconstruction Surgery? A Systematic Review and Meta-Analysis’.1 We agree that it is important to evaluate the association between return-to-sport (RTS) test batteries and outcomes after ACL reconstruction. The third review question in Webster and Hewett (2019) is particularly pertinent: ‘Is passing RTS test batteries associated with reduced rates of subsequent knee injury (all knee injuries and ACL injury)?’1 We are authors of several of the original data papers cited in the systematic review, and we are concerned about the study methodology and its conclusions. We highlight major problems with including two studies and present revised analyses that demonstrate the impact these studies had on the conclusions.

First, we question the validity of pooling studies with substantial clinical and methodological diversity.2 The meta-analysis combined studies where only some athletes returned to sport3 4 and studies where all, or mostly all, returned to sport;5–7 studies with skeletally immature patients7 and studies with elite athletes;6 and studies where substantially different RTS test batteries were used. Our second concern is that Webster and Hewett1 did not assess risk of bias, a fundamental precept of systematic review methodology clearly stated in the PRISMA reporting guideline.8–10 Assessment of study quality (as performed by Webster and Hewett1) does not quantify risk of bias.11 A risk of bias assessment identifies factors within studies that can skew results, and these factors must be considered carefully in the decision to pool data and in the conclusion. Important bias domains for review questions 2 and 3 include …
Implications of Gestational Weight Gain in Studies of Gestational Diabetes—Reply
Authors: Linghua Kong, Mika Gissler, Catharina Lavebratt
Journal: JAMA Pediatrics (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Abstract 14612: Influence of Donor Transmitted and Acquired Intimal Hyperplasia on Mid Term Outcomes After Heart Transplant
Authors: Mohamed A Omer, David Safley, Andrew Kao, Hunter Brandt, Kevin F Kennedy, A Michael Borkon, Bethany A Austin
Journal: Circulation (2017)

Introduction: Intravascular Ultrasound (IVUS) detection of cardiac allograft vasculopathy (CAV) defined by maximal intimal thickness (MIT) has been associated with reduced survival rates post ortho...
Vena cava backflow and right ventricular stiffness in pulmonary arterial hypertension
Authors: J. Tim Marcus, Berend E. Westerhof, Joanne A. Groeneveldt, Harm Jan Bogaard, Frances S. de Man, Anton Vonk Noordegraaf
Journal: European Respiratory Journal (2019)

Vena cava backflow is a well-recognised clinical hallmark of right ventricular failure in pulmonary arterial hypertension (PAH). Backflow may result from tricuspid regurgitation during right ventricular systole or from impaired right ventricular diastolic filling during atrial contraction. Our aim was to quantify the forward and backward flow in the vena cava and to establish the main cause in PAH. In 62 PAH patients, cardiac magnetic resonance measurements provided volumetric flows (mL·s −1 ) in the superior and inferior vena cava; time integration of flow gave volume. The “backward fraction” was defined as the ratio of the backward and forward volumes in the vena cava, expressed as a percentage. Time of maximum vena cava backflow was expressed as a percentage of the cardiac cycle. Right ventricular volumes and aortic stroke volume were determined. Right heart catheterisation gave right ventricular and right atrial pressures. Right ventricular end-diastolic stiffness was determined with the single-beat method. The median (interquartile range) backward fraction was 12% (3–24%) and it was &gt;20% in 21 patients. Maximum backflow occurred at near 90% of the cardiac cycle, coinciding with atrial contraction. The backward fraction was associated with maximal right atrial pressure (Spearman's r=0.77), right ventricular end-diastolic stiffness (r=0.65) and right ventricular end-diastolic pressure (r=0.77), and was negatively associated with stroke volume (r= –0.61) (all p&lt;0.001). Significant backward flow in the vena cava was observed in a large group of PAH patients and occurred mostly during atrial contraction as a consequence of impaired right ventricular filling due to right ventricular diastolic stiffness. The backward flow due to tricuspid regurgitation was of significance in only a small minority of patients.
CCR2/CCR5-mediated macrophage–smooth muscle cell crosstalk in pulmonary hypertension
Authors: Shariq Abid, Elisabeth Marcos, Aurélien Parpaleix, Valérie Amsellem, Marielle Breau, Amal Houssaini, Nora Vienney, Marine Lefevre, Genevieve Derumeaux, Steven Evans, Cedric Hubeau, Marion Delcroix, Rozenn Quarck, Serge Adnot, Larissa Lipskaia
Journal: European Respiratory Journal (2019)

Macrophages are major players in the pathogenesis of pulmonary arterial hypertension (PAH). To investigate whether lung macrophages and pulmonary-artery smooth muscle cells (PASMCs) collaborate to stimulate PASMC growth and whether the CCL2-CCR2 and CCL5-CCR5 pathways inhibited macrophage–PASMC interactions and PAH development, we used human CCR5-knock-in mice and PASMCs from patients with PAH and controls. Conditioned media from murine M1 or M2 macrophages stimulated PASMC growth. This effect was markedly amplified with conditioned media from M2 macrophage/PASMC co-cultures. CCR2, CCR5, CCL2 and CCL5 were upregulated in macrophage/PASMC co-cultures. Compared to inhibiting either receptor, dual CCR2 and CCR5 inhibition more strongly attenuated the growth-promoting effect of conditioned media from M2-macrophage/PASMC co-cultures. Deleting either CCR2 or CCR5 in macrophages or PASMCs attenuated the growth response. In mice with hypoxia- or SUGEN/hypoxia-induced PH, targeting both CCR2 and CCR5 prevented or reversed PH more efficiently than targeting either receptor alone. Patients with PAH exhibited CCR2 and CCR5 upregulation in PASMCs and perivascular macrophages compared to controls. The PASMC growth-promoting effect of conditioned media from M2-macrophage/PASMC co-cultures was greater when PASMCs from PAH patients were used in the co-cultures or as the target cells and was dependent on CCR2 and CCR5. PASMC migration toward M2-macrophages was greater with PASMCs from PAH patients and was attenuated by blocking CCR2 and CCR5. CCR2 and CCR5 are required for collaboration between macrophages and PASMCs to initiate and amplify PASMC migration and proliferation during PAH development. Dual targeting of CCR2 and CCR5 may hold promise for treating human PAH.
Time trends in diagnostic testing for primary ciliary dyskinesia in Europe
Authors: Florian S. Halbeisen, Amelia Shoemark, Angelo Barbato, Mieke Boon, Siobhan Carr, Suzanne Crowley, Rob Hirst, Bulent Karadag, Cordula Koerner-Rettberg, Michael R. Loebinger, Jane S. Lucas, Bernard Maitre, Henryk Mazurek, Uğur Özçelik, Vendula Martinů, Nicolaus Schwerk, Guillaume Thouvenin, Stefan A. Tschanz, Panayiotis Yiallouros, Myrofora Goutaki, Claudia E. Kuehni
Journal: European Respiratory Journal (2019)

<b>Adherence to the 2009 ERS task force diagnostic recommendations was low. To further improve PCD diagnosis, we must be more diligent and engaging in implementing the new evidence-based guidelines published in 2017.</b>http://bit.ly/2zvjpBh
ECG predictors of outcome in non-left bundle branch block cardiac resynchronization therapy patients
Authors: A. M. W. Antonius Martinus Wilhelmus Van Stipdonk, M. Dural, F. C. W. M. Salden, I. A. H. Ter Horst, H. J. G. Crijns, F. W. Prinzen, M. Meine, A. H. Maass, K. Vernooy
Journal: European Journal of Heart Failure (2019)
Abstract 16412: Lower Educational Level is Associated With Higher 1-Year Mortality After First Hospitalization for Atrial Fibrillation and Flutter - A Nationwide Register-Based Study
Authors: Louise Hagengaard, Peter Søgaard, Mogens L Larsen, Regitze K Skals, Steen M Hansen, Jacob M Larsen, Sam Riahi, Christian Torp-Pedersen, Kristian Kragholm
Journal: Circulation (2017)

Introduction: Atrial fibrillation and flutter (AF) are the most common supraventricular arrhythmias with influence on patient morbidity and healthcare costs. Little is known about the impact of pat...
In CVD, continuing vs interrupting clopidogrel before colonoscopy did not differ for delayed postpolypectomy bleeding
Authors: David Lichtenstein, Abhinav Vemula
Journal: Annals of Internal Medicine (2019)

Source Citation Chan FK, Kyaw MH, Hsiang JC, et al. Risk of postpolypectomy bleeding with uninterrupted clopidogrel therapy in an industry-independent, double-blind, randomized trial. Gastroenterology. 2019;156:918-25.e1. 30518511
How to become an anaesthetist
Authors: Jacqui Wise
Journal: BMJ (2019)

A career in anaesthesia is rewarding and challenging.Anaesthetists form the largest specialty group of doctors in the NHS and their skills are used in all aspects of patient care.They provide care to patients across all age ranges and a spectrum of comorbidities, and work in many different areas of the hospital.The first step to becoming an anaesthetist is completing five years of undergraduate medical training, followed by two years of foundation training.During the second year of foundation training, trainees can apply for postgraduate training in anaesthesia.There are two options for postgraduate training.One is the direct route through core training, which takes a total of seven years.The other is an eight year anaesthesia programme, which includes two years of the acute care common stem (ACCS) programme.
Sex-Ratio Meiotic Drive Shapes the Evolution of the Y Chromosome in Drosophila simulans
Authors: Quentin Helleu, Cécile Courret, David Ogereau, Katie L Burnham, Nicole Chaminade, Mohamed Chakir, Sylvie Aulard, Catherine Montchamp-Moreau
Journal: Molecular Biology and Evolution (2019)

The recent emergence and spread of X-linked segregation distorters-called "Paris" system-in the worldwide species Drosophila simulans has elicited the selection of drive-resistant Y chromosomes. Here, we investigate the evolutionary history of 386 Y chromosomes originating from 29 population samples collected over a period of 20 years, showing a wide continuum of phenotypes when tested against the Paris distorters, from high sensitivity to complete resistance (males sire ∼95% to ∼40% female progeny). Analyzing around 13 kb of Y-linked gene sequences in a representative subset of nine Y chromosomes, we identified only three polymorphic sites resulting in three haplotypes. Remarkably, one of the haplotypes is associated with resistance. This haplotype is fixed in all samples from Sub-Saharan Africa, the region of origin of the drivers. Exceptionally, with the spread of the drivers in Egypt and Morocco, we were able to record the replacement of the sensitive lineage by the resistant haplotype in real time, within only a few years. In addition, we performed in situ hybridization, using satellite DNA probes, on a subset of 21 Y chromosomes from six locations. In contrast to the low molecular polymorphism, this revealed extensive structural variation suggestive of rapid evolution, either neutral or adaptive. Moreover, our results show that intragenomic conflicts can drive astonishingly rapid replacement of Y chromosomes and suggest that the emergence of Paris segregation distorters in East Africa occurred less than half a century ago.
Abstract 15449: Modulation of Coronary Plaque Composition by Specific Lipoprotein(a) Apheresis
Authors: Maya Safarova, Marat Ezhov, Olga Afanasieva, Yuriy Matchin, Irina Adamova, Gennadiy Konovalov, Sergei Pokrovsky
Journal: Circulation (2012)

Background. No imaging studies have shown that targeted lipoprotein(a) [Lp(a)] reduction has a favorable effect on coronary disease progression. Following the hypothesis that Lp(a) excess has a det...
Comparative global epidemiology of influenza, respiratory syncytial and parainfluenza viruses, 2010–2015
Authors: Tommy T Lam, Julian W Tang, Florence Y Lai, Hassan Zaraket, Ghassan Dbaibo, Seweryn Bialasiewicz, Sarah Tozer, Jean-Michel Heraud, Steven J Drews, Todd Hachette, Paul KS Chan, Evelyn SC Koay, Hong Kai Lee, Kok Keng Tee, Yang Liu, Pieter LA Fraaij, Lance Jennings, Matti Waris, Mel Krajden, André Corriveau, Hamid Jalal, Hidekazu Nishimura, Pagbajabyn Nymadawa, Darmaa Badarch, Aripuana Watanabe, Alice Kabanda, Theo Sloots, Jen Kok, Dominic E Dwyer, Marion Koopmans
Journal: Journal of Infection (2019)

ObjectivesTo improve our understanding of the global epidemiology of common respiratory viruses by analysing their contemporaneous incidence at multiple sites.Methods2010–2015 incidence data for influenza A (IAV), influenza B (IBV), respiratory syncytial (RSV) and parainfluenza (PIV) virus infections were collected from 18 sites (14 countries), consisting of local (n = 6), regional (n = 9) and national (n = 3) laboratories using molecular diagnostic methods. Each site submitted monthly virus incidence data, together with details of their patient populations tested and diagnostic assays used.ResultsFor the Northern Hemisphere temperate countries, the IAV, IBV and RSV incidence peaks were 2–6 months out of phase with those in the Southern Hemisphere, with IAV having a sharp out-of-phase difference at 6 months, whereas IBV and RSV showed more variable out-of-phase differences of 2–6 months. The tropical sites Singapore and Kuala Lumpur showed fluctuating incidence of these viruses throughout the year, whereas subtropical sites such as Hong Kong, Brisbane and Sydney showed distinctive biannual peaks for IAV but not for RSV and PIV.ConclusionsThere was a notable pattern of synchrony of IAV, IBV and RSV incidence peaks globally, and within countries with multiple sampling sites (Canada, UK, Australia), despite significant distances between these sites.
SiRNA knockdown of CYR61 inhibits proliferation of breast cancer cell lines.
Authors: Naoki Komatsu, Carl W. Miller, Linda Ford, Wen Wen Chien, James O’Kelly, Phillip H. Koeffler
Journal: Cancer Research (2004)

3496   CYR61 is a cysteine-rich secreted protein that binds to the extracellular matrix and has autocrine and paracrine effects on integrin receptors. In breast cancer, we and others have shown that CYR61 has oncogenic properties. Ectopic over-expression of CYR61 in the MCF7 breast cancer cell line increases its cancer-related characteristics including increased growth in soft agar and when implanted in immunodeficient mice. We have examined the effect of siRNA knockdown of CYR61 on transformed properties of the MDA-MB-231 breast cancer cell line, which constitutionally has high expression of CYR61. Four vectors expressing siRNA (shRNA) under control of the U6 promoter were made, including a control with a disrupted stem. One of the four, CYR352, was found to reduce accumulation of CYR61 by 80%, while the three others had no detectable effect on growth or Cyr61 expression. Stable integration of CYR352 into MDA-MB-231 showed that CYR61 knockdown (80%) caused a marked decrease in clonal recovery (90 % ↓) and in liquid culture (75 % ↓). These cells are also morphologically distinct from wild-type MDA-MB-231with fibroblastic morphology. Cell cycle analysis showed on accumulation of cells in G0/G1 (64 % vs. 47 % in wild type control MDA-MB-231 cells). These studies demonstrated that CYR61 is intrinsic to the rapid and malignant growth of MDA-MB-231 and is an excellent therapeutic target in breast cancer.
Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older
Authors: Richard G. Bach, Christopher P. Cannon, Robert P. Giugliano, Jennifer A. White, Yuliya Lokhnygina, Erin A. Bohula, Robert M. Califf, Eugene Braunwald, Michael A. Blazing
Journal: JAMA Cardiology (2019)

Limited evidence is available regarding the benefit and hazard of higher-intensity treatment to lower lipid levels among patients 75 years or older. As a result, guideline recommendations differ for this age group compared with younger patients.To determine the effect on outcomes and risks of combination ezetimibe and simvastatin compared with simvastatin monotherapy to lower lipid levels among patients 75 years or older with stabilized acute coronary syndrome (ACS).In this prespecified secondary analysis of the global, multicenter, prospective clinical randomized Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), outcomes and risks were compared by age among patients 50 years or older after a hospitalization for ACS. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed May 29, 2015, through March 13, 2018, using Kaplan-Meier curves and Cox proportional hazards models.Double-blind randomized assignment to combined simvastatin and ezetimibe or simvastatin and placebo with follow-up for a median of 6 years (interquartile range, 4.3-7.1 years).The primary composite end point consisted of death due to cardiovascular disease, myocardial infarction (MI), stroke, unstable angina requiring hospitalization, and coronary revascularization after 30 days. Individual adverse ischemic and safety end points and lipid variables were also analyzed.Of 18 144 patients enrolled (13 728 men [75.7%]; mean [SD] age, 64.1 [9.8] years), 5173 (28.5%) were 65 to 74 years old, and 2798 (15.4%) were 75 years or older at randomization. Treatment with simvastatin-ezetimibe resulted in lower rates of the primary end point than simvastatin-placebo, including 0.9% for patients younger than 65 years (HR, 0.97; 95% CI, 0.90-1.05) and 0.8% for patients 65 to 74 years of age (hazard ratio [HR], 0.96; 95% CI, 0.87-1.06), with the greatest absolute risk reduction of 8.7% for patients 75 years or older (HR, 0.80; 95% CI, 0.70-0.90) (P = .02 for interaction). The rate of adverse events did not increase with simvastatin-ezetimibe vs simvastatin-placebo among younger or older patients.In IMPROVE-IT, patients hospitalized for ACS derived benefit from higher-intensity therapy to lower lipid levels with simvastatin-ezetimibe compared with simvastatin monotherapy, with the greatest absolute risk reduction among patients 75 years or older. Addition of ezetimibe to simvastatin was not associated with any significant increase in safety issues among older patients. These results may have implications for guideline recommendations regarding lowering of lipid levels in the elderly.ClinicalTrials.gov identifier: NCT00202878.