tbuckley/cabot-search huggingface dataset:
Bipartite Network Analysis of Gene Sharings in the Microbial World
Authors: Eduardo Corel, Raphaël Méheust, Andrew K Watson, James O Mcinerney, Philippe Lopez, Eric Bapteste
Journal: Molecular Biology and Evolution (2018)

Extensive microbial gene flows affect how we understand virology, microbiology, medical sciences, genetic modification, and evolutionary biology. Phylogenies only provide a narrow view of these gene flows: plasmids and viruses, lacking core genes, cannot be attached to cellular life on phylogenetic trees. Yet viruses and plasmids have a major impact on cellular evolution, affecting both the gene content and the dynamics of microbial communities. Using bipartite graphs that connect up to 149,000 clusters of homologous genes with 8,217 related and unrelated genomes, we can in particular show patterns of gene sharing that do not map neatly with the organismal phylogeny. Homologous genes are recycled by lateral gene transfer, and multiple copies of homologous genes are carried by otherwise completely unrelated (and possibly nested) genomes, that is, viruses, plasmids and prokaryotes. When a homologous gene is present on at least one plasmid or virus and at least one chromosome, a process of "gene externalization," affected by a postprocessed selected functional bias, takes place, especially in Bacteria. Bipartite graphs give us a view of vertical and horizontal gene flow beyond classic taxonomy on a single very large, analytically tractable, graph that goes beyond the cellular Web of Life.
Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism
Authors: Wilbur M. Song, Satoru Joshita, Yingyue Zhou, Tyler K. Ulland, Susan Gilfillan, Marco Colonna
Journal: The Journal of Experimental Medicine (2018)

Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β-induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction.
Recommendation of the Advisory Committee on Immunization Practices for Use of a Third Dose of Mumps Virus–Containing Vaccine in Persons at Increased Risk for Mumps During an Outbreak
Authors: Mona Marin, Mariel Marlow, Kelly L. Moore, Manisha Patel
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

A substantial increase in the number of mumps outbreaks and outbreak-associated cases has occurred in the United States since late 2015 (1,2). To address this public health problem, the Advisory Committee on Immunization Practices (ACIP) reviewed the available evidence and determined that a third dose of measles, mumps, rubella (MMR) vaccine is safe and effective at preventing mumps. During its October 2017 meeting, ACIP recommended a third dose of a mumps virus-containing vaccine* for persons previously vaccinated with 2 doses who are identified by public health authorities as being part of a group or population at increased risk for acquiring mumps because of an outbreak. The purpose of the recommendation is to improve protection of persons in outbreak settings against mumps disease and mumps-related complications. This recommendation supplements the existing ACIP recommendations for mumps vaccination (3).
Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9)
Authors: Thomas Aparicio, Francois Ghiringhelli, Valérie Boige, Karine Le Malicot, Julien Taieb, Olivier Bouché, Jean-Marc Phelip, Eric François, Christian Borel, Roger Faroux, Laetitia Dahan, Stéphane Jacquot, Dominique Genet, Faiza Khemissa, Etienne Suc, Françoise Desseigne, Patrick Texereau, Come Lepage, Jaafar Bennouna
Journal: Journal of Clinical Oncology (2018)

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.
Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines
Authors: Francis K L Chan, Khean-Lee Goh, Nageshwar Reddy, Kazuma Fujimoto, Khek Yu Ho, Seiji Hokimoto, Young-Hoon Jeong, Takanari Kitazono, Hong Sik Lee, Varocha Mahachai, Kelvin K F Tsoi, Ming-Shiang Wu, Bryan P Yan, Kentaro Sugano
Journal: Gut (2018)

This Guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society for Digestive Endoscopy (APSDE). It was developed in response to the increasing use of antithrombotic agents (antiplatelet agents and anticoagulants) in patients undergoing gastrointestinal (GI) endoscopy in Asia. After reviewing current practice guidelines in Europe and the USA, the joint committee identified unmet needs, noticed inconsistencies, raised doubts about certain recommendations and recognised significant discrepancies in clinical practice between different regions. We developed this joint official statement based on a systematic review of the literature, critical appraisal of existing guidelines and expert consensus using a two-stage modified Delphi process. This joint APAGE-APSDE Practice Guideline is intended to be an educational tool that assists clinicians in improving care for patients on antithrombotics who require emergency or elective GI endoscopy in the Asian Pacific region.
Natural killer cells from epithelial ovarian cancer patients exhibit an altered phenotype and bind to MUC16
Authors: Jennifer Belisle, Jennifer Gubbels, Joseph Connor, Ellen Hartenbach, David Kushner, Manish Patankar
Journal: Cancer Research (2007)

5120  Natural killer (NK) cells are important components of innate immunity and are vital in anti-tumor responses. They are regulated through a delicate balance of cell-surface activating and inhibitory receptors. NK cells in epithelial ovarian cancer (EOC) have not been exhaustively studied. In our previous studies, we have shown that MUC16, a high molecular weight mucin overexpressed by ovarian tumors, inhibits NK cell cytolytic function and downregulates CD16, an activating receptor present on NK cells. We hypothesized, therefore, that MUC16 and other factors could be affecting the phenotype of NK cells in cancer patients. In order to study this further, we obtained peritoneal fluid (PF) and peripheral blood (PB) from nine cancer patients and PB from three healthy donors. Lymphocytes were isolated from these three sample types and stained with a panel of antibodies against numerous activating and inhibitory NK cell receptors. Multi-color flow cytometry was performed on the LSR II (Beckton Dickenson), and the data was analyzed using FlowJo (TreeStar) software. Normally, the majority of circulating peripheral blood (PB) human NK cells carry the CD56dim/CD16bright phenotype, which is capable of cytolytic activity. Small numbers of PBNK cells in healthy donors have a CD56bright/CD16dim phenotype, which do not exhibit high cytolytic responses. PBNK cells from EOC patients also carry the normal CD56dim/CD16bright phenotype. However, we have found that a subset of NK cells in the PF of patients with EOC show a 28% increase (p
Hematopoietic Stem Cell Transplantation at Home
Authors: Anthony D. Sung, Krista R. Nichols, Julia A. Messina, Kristi Romero, Tara Dalton, Amy Bush, Megan Covington, Rebecca Shelby, Jennifer Frith, Cristina J. Gasparetto, Mitchell E. Horwitz, Gwynn D. Long, Richard Lopez, David A. Rizzieri, Stefanie Sarantopoulos, Keith M. Sullivan, Nelson J. Chao
Journal: Blood (2017)
Authors’ reply to Sharvill and Beales
Authors: Hasnain M Dalal, Manish M Gandhi, Christos Voukalis, Fatima Dalal
Journal: BMJ (2018)

We thank Sharvill and Beales for drawing attention to gastroprotection for dyspepsia associated with dual antiplatelet therapy and a higher bleeding risk in elderly people, which we referred to in our article.123 We agree that a proton pump inhibitor or H2 receptor antagonist should be used to reduce the risk of bleeding in patients with a history of bleeding in the upper gastrointestinal tract and should …
Reciprocal Spatiotemporally Controlled Apoptosis Regulates Wolffian Duct Cloaca Fusion
Authors: Masato Hoshi, Antoine Reginensi, Matthew S. Joens, James A. J. Fitzpatrick, Helen McNeill, Sanjay Jain
Journal: Journal of the American Society of Nephrology (2018)

The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT.
Abstract 17355: Obesity is Strongly Associated With New Onset Atrial Fibrillation/Flutter in Middle-Aged Adults
Authors: Andrew Foy, John Mandrola, Gerald Naccarelli
Journal: Circulation (2016)

Introduction:  Obesity has been found to be associated with new onset atrial fibrillation/flutter (AF) in several prospective cohort and case control studies. However, the strength of association is not well established, especially in middle-aged and younger adults.   Hypothesis:  Obesity will be independently associated with new onset AF in a national cohort of middle-aged, privately-insured individuals.   Methods:  We performed a longitudinal cohort study from January 1, 2006 through December 31, 2013 using a national claims database that tracks all inpatient, outpatient and pharmacy claims data. Obese and non-obese individuals without a diagnosis of AF were recruited 1:1 during an observation period from January 1, 2005 through December 31, 2005 if they maintained continuous enrollment over the duration of the study period. The primary endpoint was new diagnosis of AF. Logistic regression was used to determine the strength of association between obesity and new onset AF controlling for age, gender, hypertension and diabetes.   Results:  A total of 67,278 individuals were included in the cohort, divided evenly between those with and without a diagnosis of obesity. The average age and sex of each cohort was 43.8 years and 76.9% female. Obese individuals were significantly more likely to have hypertension (29.5% vs 14.6%) and diabetes (12.7% vs 5.2%) at study onset. Over 8 years of follow up a new diagnosis of AF was recorded in 1,511 (2.2%) individuals. Obesity was strongly associated with a new diagnosis of AF after controlling for age, gender, hypertension and diabetes (OR 1.4; 95% CI: 1.3-1.6).   Conclusions:  Obesity is strongly associated with new onset AF in middle-aged adults. This information contributes to the growing evidence supporting the causal relationship between obesity and AF and could promote novel strategies for AF prevention and treatment.
Novel Approach for In Vivo Detection of Vulnerable Coronary Plaques Using Molecular 3-T CMR Imaging With an Albumin-Binding Probe
Authors: Leif-Christopher Engel, Ulf Landmesser, Kevin Gigengack, Thomas Wurster, Constantina Manes, Georg Girke, Milosz Jaguszewski, Carsten Skurk, David M. Leistner, Alexander Lauten, Andreas Schuster, Bernd Hamm, Rene M. Botnar, Marcus R. Makowski, Boris Bigalke
Journal: JACC. Cardiovascular imaging (2018)
Abstract 16987: Simulation Modeling to Inform Future Population Health Interventions to Decrease the Burden of Cardiovascular Disease in the United States
Authors: Matthew D Ritchey, Pamela Coxson, Quanhe Yang, Robert Merritt, Briana Lucido, Yuling Hong
Journal: Circulation (2016)

Introduction:  Cardiovascular disease (CVD) is the leading cause of death nationally. The US Dept. of Health and Human Services Million Hearts initiative has called attention to improving a select set of CVD risk factors, with a goal of preventing 1 million heart attacks, strokes, and other CVD events during 2012-2016. This study leverages simulation modeling to determine the key risk factors the nation should continue to focus on or begin targeting in 2017, and the expected range of events prevented through 2026 if those risk factors are addressed.   Methods:  The CVD Policy Model was used to develop preliminary estimates on the 5- and 10-year impact of attaining achievable risk factor reductions on CVD non-fatal and fatal event totals and direct healthcare costs. Improvements in aspirin use for secondary prevention; blood pressure (BP), cholesterol, smoking, and obesity levels; secondhand smoke exposure; sodium intake; and diabetes incidence were assessed individually among adults aged 35-94. Risk factor goals were based on trend data, the reported effects of evidence-based interventions, and national targets.   Results:  During 2017-2021, the largest event decrease is estimated to be accomplished by a 10% reduction in obesity prevalence (143,000 events prevented), which prevents CVD events via decreasing diabetes incidence and improving BP and cholesterol levels. During 2017-2026, the combined effect of achieving a 42% reduction in smoking prevalence and secondhand smoke exposure, realizing the benefits in BP lowering by reducing mean sodium intake to 2300 mg/day, attaining 75% BP control among hypertensives, and meeting the Healthy People 2020 obesity prevalence goal of 30.5% are estimated to have the greatest individual impacts on CVD events and costs, preventing 279,000, 336,000, 364,000 and 578,000 total events, resp., including 77,000, 88,000, 98,000 and 174,000 deaths, resp., and decreasing costs by $17.3, $26.4, $26.6, and $48.1 billion, resp.   Conclusions:  Sizable decreases in CVD event totals, deaths, and direct medical costs would occur if the modeled risk factor reductions are achieved through 2026. This information can guide future national CVD prevention efforts by helping prioritize which risk factors should be targeted for intervention.
Abstract 16734: Thioredoxin-1 Potentiates Mtor Activity Through Direct Reduction In Cardiomyocytes
Authors: Shinichi Oka, Tsuyoshi Hirata, Hiroaki Yaginuma, Dan Shao, Narayani Nagarajan, Junichi Sadoshima
Journal: Circulation (2016)

Thioredoxin 1 (Trx1) is a 12 KDa oxidoreductase, which reduces proteins with disulfide bonds through thiol-disulfide exchange reactions. Trx1 protects cardiomyocytes (CMs) against stress, such as i...
Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease
Authors: Kimberly C. Paul, Jessica Schulz, Jeff M. Bronstein, Christina M. Lill, Beate R. Ritz
Journal: JAMA Neurology (2018)

Genetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance.To assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD.This longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression.The combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring.Of the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01).Susceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.
Severe peri-ictal respiratory dysfunction is common in Dravet syndrome
Authors: YuJaung Kim, Eduardo Bravo, Caitlin K. Thirnbeck, Lori A. Smith-Mellecker, Se Hee Kim, Brian K. Gehlbach, Linda C. Laux, Xiuqiong Zhou, Douglas R. Nordli, George B. Richerson
Journal: Journal of Clinical Investigation (2018)

Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death. We conclude that SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.
Abstract 14859: Potassium Levels and Mortality in Patients With Newly Diagnosed Heart Failure: A Nationwide Study if US Veterans
Authors: Kunihiro Matsushita, Yingying Sang, Shoshana H Ballew, Morgan E Grams, Josef Coresh, Miklos Z Molnar
Journal: Circulation (2016)

Background: Patients with heart failure (HF) are at high risk for hypo- and hyperkalemia. However, their prognostic values in this clinical population have been only investigated in small samples, ...
Diagnosis of Venous Thromboembolism: 20 Years of Progress
Authors: Philip S. Wells, Ryma Ihaddadene, Aoife Reilly, Melissa Anne Forgie
Journal: Annals of Internal Medicine (2018)

Many guidelines suggest incorporating clinical assessment, imaging, and D-dimer testing into diagnostic algorithms in patients with suspected deep venous thrombosis (DVT) and pulmonary embolism (PE). This special article reviews the evidence supporting the use of algorithms and their individual components for diagnosis of upper- and lower-extremity DVT and PE in adults, including pregnant women. The authors identified evidence through several electronic database searches to April 2017, evaluated the robustness of selected evidence, assessed whether diagnostic approaches that do not use algorithms are acceptable, and identified knowledge gaps that require further research.