tbuckley/cabot-search huggingface dataset:
Abstract 11608: Characteristics of Incident Heart Failure in HIV Disease at an Urban HIV Clinic and Hospital From 2007-2014
Authors: Blake G Daley, David F Miranda, Namo Tetekpor, Jason V Baker, Mengistu Simegn
Journal: Circulation (2015)

Introduction: HIV is an independent risk factor for coronary artery disease and the prevalence of subclinical systolic and diastolic abnormalities are greater than expected for age. However, less is known regarding the incidence and pattern of acute heart failure syndrome (HF) among contemporary HIV-positive patients. Methods: We performed a retrospective analysis of HIV-positive patients presenting with incident HF from 2007-2014. All patients with ICD-9 diagnoses for HIV and HF were selected and further adjudicated for incident HF based on symptoms, physical findings, biomarkers, and imaging studies. Clinical characteristics and echocardiographic findings were described, and subgroup comparisons were explored based on HIV viral suppression. Results: Among 2703 HIV-positive patients, 74 had a diagnosis of HF (prevalence of 2.7%), of which 28 were adjudicated incident HF (annual incidence of 0.15%). Patients with incident HF were younger (median age 50 yr.), predominantly male (75%), and African American (68%). The median duration of HIV infection prior to heart failure was 11 years with the majority (75%) on HAART (39% receiving a protease inhibitor) with a median CD4+ cell count of 295 cells/mm 3 . The major comorbid conditions include hypertension (82%), history of substance abuse (64%), and diabetes (32%). Table-1 presents the transthoracic echocardiographic findings for all incident HF patients. The mean ejection fraction (EF) for virally suppressed (HIV RNA &lt;200 copies/ml) patients was 45.3% as opposed to 31.8 % for those unsuppressed. Conclusion: Incident HF among urban HIV-positive patients occurs at younger age when compared to the rates of the uninfected in the general population, with a significant proportion presenting with preserved EF. Future research should focus on whether HF syndrome in HIV disease shifts from predominantly systolic dysfunction, to a pattern similar in the general population, particularly among the virally suppressed.
Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing
Authors: Matthew B. Lanktree, Amirreza Haghighi, Elsa Guiard, Ioan-Andrei Iliuta, Xuewen Song, Peter C. Harris, Andrew D. Paterson, York Pei
Journal: Journal of the American Society of Nephrology (2018)

Background Estimating the prevalence of autosomal dominant polycystic kidney disease (ADPKD) is challenging because of age-dependent penetrance and incomplete clinical ascertainment. Early studies estimated the lifetime risk of ADPKD to be about one per 1000 in the general population, whereas recent epidemiologic studies report a point prevalence of three to five cases per 10,000 in the general population. Methods To measure the frequency of high-confidence mutations presumed to be causative in ADPKD and autosomal dominant polycystic liver disease (ADPLD) and estimate lifetime ADPKD prevalence, we used two large, population sequencing databases, gnomAD (15,496 whole-genome sequences; 123,136 exome sequences) and BRAVO (62,784 whole-genome sequences). We used stringent criteria for defining rare variants in genes involved in ADPKD ( PKD1 , PKD2 ), ADPLD ( PRKCSH , SEC63 , GANAB , ALG8 , SEC61B , LRP5 ), and potential cystic disease modifiers; evaluated variants for quality and annotation; compared variants with data from an ADPKD mutation database; and used bioinformatic tools to predict pathogenicity. Results Identification of high-confidence pathogenic mutations in whole-genome sequencing provided a lower boundary for lifetime ADPKD prevalence of 9.3 cases per 10,000 sequenced. Estimates from whole-genome and exome data were similar. Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced, respectively. Conclusions Population whole-genome sequencing suggests a higher than expected prevalence of ADPKD-associated mutations. Loss-of-function mutations in ADPLD genes are also more common than expected, suggesting the possibility of unrecognized cases and incomplete penetrance. Substantial rare variation exists in genes with potential for phenotype modification in ADPKD.
Phylogeny Estimation by Integration over Isolation with Migration Models
Authors: Jody Hey, Yujin Chung, Arun Sethuraman, Joseph Lachance, Sarah Tishkoff, Vitor C Sousa, Yong Wang
Journal: Molecular Biology and Evolution (2018)

Phylogeny estimation is difficult for closely related populations and species, especially if they have been exchanging genes. We present a hierarchical Bayesian, Markov-chain Monte Carlo method with a state space that includes all possible phylogenies in a full Isolation-with-Migration model framework. The method is based on a new type of genealogy augmentation called a "hidden genealogy" that enables efficient updating of the phylogeny. This is the first likelihood-based method to fully incorporate directional gene flow and genetic drift for estimation of a species or population phylogeny. Application to human hunter-gatherer populations from Africa revealed a clear phylogenetic history, with strong support for gene exchange with an unsampled ghost population, and relatively ancient divergence between a ghost population and modern human populations, consistent with human/archaic divergence. In contrast, a study of five chimpanzee populations reveals a clear phylogeny with several pairs of populations having exchanged DNA, but does not support a history with an unsampled ghost population.
The innate immune receptor TREM-1 promotes liver injury and fibrosis
Authors: Anh Thu Nguyen-Lefebvre, Ashwin Ajith, Vera Portik-Dobos, Daniel David Horuzsko, Ali Syed Arbab, Amiran Dzutsev, Ramses Sadek, Giorgio Trinchieri, Anatolij Horuzsko
Journal: Journal of Clinical Investigation (2018)

Inflammation occurs in all tissues in response to injury or stress and is the key process underlying hepatic fibrogenesis. Targeting chronic and uncontrolled inflammation is one strategy to prevent liver injury and fibrosis progression. Here, we demonstrate that triggering receptor expressed on myeloid cells 1 (TREM-1), an amplifier of inflammation, promotes liver disease by intensifying hepatic inflammation and fibrosis. In the liver, TREM-1 expression was limited to liver macrophages and monocytes and was highly upregulated on Kupffer cells, circulating monocytes, and monocyte-derived macrophages in a mouse model of chronic liver injury and fibrosis induced by carbon tetrachloride (CCl4) administration. TREM-1 signaling promoted proinflammatory cytokine production and mobilization of inflammatory cells to the site of injury. Deletion of Trem1 reduced liver injury, inflammatory cell infiltration, and fibrogenesis. Reconstitution of Trem1-deficient mice with Trem1-sufficient Kupffer cells restored the recruitment of inflammatory monocytes and the severity of liver injury. Markedly increased infiltration of liver fibrotic areas with TREM-1-positive Kupffer cells and monocytes/macrophages was found in patients with hepatic fibrosis. Our data support a role of TREM-1 in liver injury and hepatic fibrogenesis and suggest that TREM-1 is a master regulator of Kupffer cell activation, which escalates chronic liver inflammatory responses, activates hepatic stellate cells, and reveals a mechanism of promotion of liver fibrosis.
Air pollution exposure and lung function until age 16 years: the PIAMA birth cohort study
Authors: Edith B. Milanzi, Gerard H. Koppelman, Henriette A. Smit, Alet H. Wijga, Marieke Oldenwening, Judith M. Vonk, Bert Brunekreef, Ulrike Gehring
Journal: European Respiratory Journal (2018)

Evidence for the effects of air pollution exposure on lung function growth into adolescence is scarce. We investigated associations of air pollution exposure with lung function and lung function growth until age 16. We conducted both longitudinal (n=915) and cross-sectional (n=721) analyses of associations of air pollution exposure with forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) growth from ages eight to 16 and FEV 1 and FVC at age 16. We estimated residential concentrations of nitrogen dioxide (NO 2 ), “soot” and particulate matter (PM x , where x is the 50% cut-off aerodynamic diameter in µm) with diameters of &lt;2.5 µm (PM 2.5 ), &lt;10 µm (PM 10 ) and 2.5–10 µm (PM coarse ) during the preschool, primary school and secondary school time windows by land use regression models. Associations with (growth in) FEV 1 and FVC were analysed by linear (mixed effects) regression. Higher air pollution exposure was associated with reduced FEV 1 growth ( e.g. adjusted difference −0.26% (95% CI −0.49 to −0.03%) per interquartile range increase in secondary school PM 2.5 ) and lower FEV 1 (adjusted difference −2.36% (95% CI −3.76 to −0.94%)), but was not adversely associated with FVC. Associations with FEV 1 were stronger in boys than girls and were not modified by asthma status. Higher air pollution exposure may lead to increased airway obstruction, but not reduced lung volume in adolescence.
Comparison of the ‘11+ Kids’ injury prevention programme and a regular warmup in children’s football (soccer): a cost effectiveness analysis
Authors: Roland Rössler, Evert Verhagen, Nikki Rommers, Jiri Dvorak, Astrid Junge, Eric Lichtenstein, Lars Donath, Oliver Faude
Journal: British Journal of Sports Medicine (2018)

Objective To evaluate a potential reduction in injury related healthcare costs when using the ‘11+ Kids’ injury prevention programme compared with a usual warmup in children’s football. Methods This cost effectiveness analysis was based on data collected in a cluster randomised controlled trial over one season from football teams (under-9 to under-13 age groups) in Switzerland. The intervention group (INT) replaced their usual warmup with ‘11+ Kids’, while the control group (CON) warmed up as usual. Injuries, healthcare resource use and football exposure (in hours) were collected prospectively. We calculated the mean injury related costs in Swiss Francs (CHF) per 1000 hours of football. We calculated the cost effectiveness (the direct net healthcare costs divided by the net health effects of the ‘11+ Kids’ intervention) based on the actual data in our study (trial based) and for a countrywide implementation scenario (model based). Results Costs per 1000 hours of exposure were CHF228.34 (95% CI 137.45, 335.77) in the INT group and CHF469.00 (95% CI 273.30, 691.11) in the CON group. The cost difference per 1000 hours of exposure was CHF−240.66 (95%CI −406.89, −74.32). A countrywide implementation would reduce healthcare costs in Switzerland by CHF1.48 million per year. 1002 players with a mean age of 10.9 (SD 1.2) years participated. During 76 373 hours of football, 99 injuries occurred. Conclusion The ‘11+ Kids’ programme reduced the healthcare costs by 51% and was dominant (ie, the INT group had lower costs and a lower injury risk) compared with a usual warmup. This provides a compelling case for widespread implementation.
Colorectal premalignancy is associated with consensus molecular subtypes 1 and 2
Authors: K. Chang, J.A. Willis, J. Reumers, M.W. Taggart, F.A. San Lucas, S. Thirumurthi, P. Kanth, D.A. Delker, C.H. Hagedorn, P.M. Lynch, L.M. Ellis, E.T. Hawk, P.A. Scheet, S. Kopetz, J. Arts, J. Guinney, R. Dienstmann, E. Vilar
Journal: Annals of Oncology (2018)

Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown.We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier.Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-β activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations.Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.
Biallelic inactivation of the retinoblastoma gene results in transformation of chronic myelomonocytic leukemia to a blastic plasmacytoid dendritic cell neoplasm: shared clonal origins of two aggressive neoplasms
Authors: Mrinal M. Patnaik, Terra Lasho, Matthew Howard, Christy Finke, Rhett L. Ketterling, Aref Al-Kali, Animesh Pardanani, Nathalie Droin, Naseema Gangat, Ayalew Tefferi, Eric Solary
Journal: Blood Cancer Journal (2018)

To the Editor, Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by sustained peripheral blood (PB) monocytosis, bone marrow (BM) dysplasia, and an inherent risk for transformation to acute myeloid leukemia (AML); ~20-30% over 3-5 years 1,2 .Patients with CMML have ~10-15 gene mutations in coding DNA regions, with common mutations involving TET2 (~60%), ASXL1 (~40%), SRSF2 (~40%), and the oncogenic RAS pathway (~30%) 3 .Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematodermic malignancy of dendritic cell origin that is known to infiltrate the blood, BM, skin, and lymph nodes; a diagnosis of which is based on a blast immunophenotype characterized by the expression of CD4, CD43, CD56, CD123, BDCA-2/CD303, TCL1, and CTLA 1 .Cytogenetic studies, array-based comparative genomic hybridization, and gene expression profiling have demonstrated recurrent inactivation/losses/decreased expression of RB1 (retinoblastoma 1; 13q13-q21), LATS2, CDKN1B, CDKN2A, and TP53 genes, 4 while nextgeneration sequencing (NGS) studies have demonstrated point mutations involving TET2 (~36%), ASXL1 (~32%), NRAS (~30%), ATM (21%), along with deletions involving RB1 and APC (~6%) 5,6 .In addition, recurrent MYB gene rearrangements have been documented in both children and adults, with fusion oncogenes including MYB-ZFAT, MYB-PLEKHO1, and MYB-DCPS 7 .Common clonal origins for CMML and BPDCN have been suggested based on similar genetic and epigenetic deregulations identified, along with sporadic case reports of CMML transformation to BPDCN 8,9 .We provide the first in-depth wholeexome sequencing (WES) results on a patient with CMML that transformed to BPDCN and provide information with regards to possible mechanisms of transformation.A 61-year-old male was referred to the hematology clinic in 2014 for sustained PB monocytosis.A BM biopsy was suggestive of CMML-0 (World Health Organization 2016 criteria) with normal cytogenetics (Fig. 1).He did have plasmacytoid dendritic cell nodules comprising ~20% of the BM cellularity.NGS at diagnosis identified mutations involving TET2 (variant allele frequency (VAF) 40%) and SRSF2 (43%).He was conservatively managed with routine blood count checks.In 2017, he presented with worsening constitutional symptoms, a generalized skin rash, and progressive cytopenias.A BM biopsy and skin biopsy were suggestive of BPDCN with normal BM metaphase cytogenetics (Fig. 1).He was treated with AML-like induction chemotherapy using idarubicin and
Incomplete Differentiation of Engrafted Bone Marrow Endothelial Progenitor Cells Initiates Hepatic Fibrosis in the Rat
Authors: Ana C. Maretti‐Mira, Xiangdong Wang, Lei Wang, Laurie D. DeLeve
Journal: Hepatology (2018)

Normal liver sinusoidal endothelial cells (LSECs) promote quiescence of hepatic stellate cells (HSCs). Prior to fibrosis, LSECs undergo capillarization, which is permissive for HSC activation, the proximate event in hepatic fibrosis. The aims of this study were to elucidate the nature of and mechanisms leading to capillarization and to determine how LSECs promote HSC quiescence and why “capillarized LSECs” lose control of HSC activation. The contribution of bone marrow (BM) endothelial progenitor cells to capillarization was identified using rats transplanted with transgenic enhanced green fluorescent protein–positive BM. Shotgun proteomics and informatics were used to identify the LSEC mediator that maintains HSC quiescence. The study shows that capillarization is due to repair of injured LSECs by BM endothelial progenitors that engraft but fail to fully mature. Lack of maturation of BM‐derived LSECs is due to cell autonomous pathways that inhibit the nitric oxide pathway. We identify heparin binding epidermal growth factor–like growth factor (HB‐EGF) as the signal that maintains HSC quiescence and show that immature LSECs are unable to shed HB‐EGF from the cytosolic membrane. Conclusion: Chronic liver injury can recruit BM progenitors of LSECs that engraft and fail to fully differentiate, which creates an environment that is permissive for hepatic fibrosis; elucidation of these early events in the fibrotic process will provide targets for treatment of hepatic fibrosis.
Green fluorescent proteins engineered for cartilage-targeted drug delivery: Insights for transport into highly charged avascular tissues
Authors: Yamini Krishnan, Holly A. Rees, Christina P. Rossitto, Si-Eun Kim, Han-Hwa K. Hung, Eliot H. Frank, Bradley D. Olsen, David R. Liu, Paula T. Hammond, Alan J. Grodzinsky
Journal: Biomaterials (2018)
Exposure to Ultraviolet Radiation in the Modulation of Human Diseases
Authors: Prue H. Hart, Mary Norval, Scott N. Byrne, Lesley E. Rhodes
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

This review focuses primarily on the beneficial effects for human health of exposure to ultraviolet radiation (UVR). UVR stimulates anti-inflammatory and immunosuppressive pathways in skin that modulate psoriasis, atopic dermatitis, and vitiligo; suppresses cutaneous lesions of graft-versus-host disease; and regulates some infection and vaccination outcomes. While polymorphic light eruption and the cutaneous photosensitivity of systemic lupus erythematosus are triggered by UVR, polymorphic light eruption also frequently benefits from UVR-induced immunomodulation. For systemic diseases such as multiple sclerosis, type 1 diabetes, asthma, schizophrenia, autism, and cardiovascular disease, any positive consequences of UVR exposure are more speculative, but could occur through the actions of UVR-induced regulatory cells and mediators, including 1,25-dihydroxy vitamin D3, interleukin-10, and nitric oxide. Reduced UVR exposure is a risk factor for the development of several inflammatory, allergic, and autoimmune conditions, including diseases initiated in early life. This suggests that UVR-induced molecules can regulate cell maturation in developing organs.
Abstract 20354: Rurality Predicts Long-Term Adherence to Statins but Not Angiotensin Converting Enzyme Inhibitors/Angiotensin Receptor Blockers in High-Risk Patients
Authors: Matthew Peverelle, Rohullah Sultani, Sarang Paleri, Yun Suk Lee, Janaka Lovell, John Garlick, Amy Wilson-O’Brien, Andrew Wilson
Journal: Circulation (2016)

Introduction: Rural populations experience greater cardiovascular morbidity and mortality compared to urban populations. It is unknown whether regional differences in adherence to cardiovascular me...
低用量アスピリンと胃保護剤を摂取している無症状患者における胃十二指腸潰瘍/糜爛の罹患率と独立因子:OITA-GF研究
Authors: Kotoku Munenori, Tamura Akira, Goto Yukie, Kawano Yoshiyuki, Shinozaki Kazuhiro, Watanabe Toru, Aso Nobuko, Torigoe Kumie, Naono Shigeru, Zaizen Hirofumi, Kadota Junichi
Journal: Circulation (2011)
Coronary CT Angiographic and Flow Reserve-Guided Management of Patients With Stable Ischemic Heart Disease
Authors: Bjarne L. Nørgaard, Christian J. Terkelsen, Ole N. Mathiassen, Erik L. Grove, Hans Erik Bøtker, Erik Parner, Jonathon Leipsic, Flemming H. Steffensen, Anders H. Riis, Kamilla Pedersen, Evald H. Christiansen, Michael Mæng, Lars R. Krusell, Steen D. Kristensen, Ashkan Eftekhari, Lars Jakobsen, Jesper M. Jensen
Journal: Journal of the American College of Cardiology (2018)

Clinical outcomes following coronary computed tomography–derived fractional flow reserve (FFRCT) testing in clinical practice are unknown. This study sought to assess real-world clinical outcomes following a diagnostic strategy including first-line coronary computed tomography angiography (CTA) with selective FFRCT testing. The study reviewed the results of 3,674 consecutive patients with stable chest pain evaluated with CTA and FFRCT testing to guide downstream management in patients with intermediate stenosis (30% to 70%). The composite endpoint (all-cause death, myocardial infarction, hospitalization for unstable angina, and unplanned revascularization) was determined in 4 patient groups: 1) CTA stenosis <30%, optimal medical treatment (OMT), and no additional testing; 2) FFRCT >0.80, OMT, no additional testing; 3) FFRCT ≤0.80, OMT, no additional testing; and 4) FFRCT ≤0.80, OMT, and referral to invasive coronary angiography. Patients were followed for a median of 24 (range 8 to 41) months. FFRCT was available in 677 patients, and the test result was negative (>0.80) in 410 (61%) patients. In 75% of the patients with FFRCT >0.80, maximum coronary stenosis was ≥50%. The cumulative incidence proportion (95% confidence interval [CI]) of the composite endpoint at the end of follow-up was comparable in groups 1 (2.8%; 95% CI: 1.4% to 4.9%) and 2 (3.9%; 95% CI: 2.0% to 6.9%) (p = 0.58) but was higher (when compared with group 1) in groups 3 (9.4%; p = 0.04) and 4 (6.6%; p = 0.08). Risk of myocardial infarction was lower in group 4 (1.3%) than in group 3 (8%; p < 0.001). In patients with intermediate-range coronary stenosis, FFRCT is effective in differentiating patients who do not require further diagnostic testing or intervention (FFRCT >0.80) from higher-risk patients (FFRCT ≤0.80) in whom further testing with invasive coronary angiography and possibly intervention may be needed. Further studies assessing the risk and optimal management strategy in patients undergoing first-line CTA with selective FFRCT testing are needed.