tbuckley/cabot-search huggingface dataset:
Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study
Authors: Marie Warny, Jens Helby, Børge Grønne Nordestgaard, Henrik Birgens, Stig Egil Bojesen
Journal: PLoS Medicine (2018)

Background Neutropenia increases the risk of infection, but it is unknown if this also applies to lymphopenia. We therefore tested the hypotheses that lymphopenia is associated with increased risk of infection and infection-related death in the general population. Methods and findings Of the invited 220,424 individuals, 99,191 attended examination. We analyzed 98,344 individuals from the Copenhagen General Population Study (Denmark), examined from November 25, 2003, to July 9, 2013, and with available blood lymphocyte count at date of examination. During a median of 6 years of follow-up, they developed 8,401 infections and experienced 1,045 infection-related deaths. Due to the completeness of the Danish civil and health registries, none of the 98,344 individuals were lost to follow-up, and those emigrating (n = 385) or dying (n = 5,636) had their follow-up truncated at the day of emigration or death. At date of examination, mean age was 58 years, and 44,181 (44.9%) were men. Individuals with lymphopenia (lymphocyte count < 1.1 × 109/l, n = 2,352) compared to those with lymphocytes in the reference range (1.1–3.7 × 109/l, n = 93,538) had multivariable-adjusted hazard ratios of 1.41 (95% CI 1.28–1.56) for any infection, 1.31 (1.14–1.52) for pneumonia, 1.44 (1.15–1.79) for skin infection, 1.26 (1.02–1.56) for urinary tract infection, 1.51 (1.21–1.89) for sepsis, 1.38 (1.01–1.88) for diarrheal disease, 2.15 (1.16–3.98) for endocarditis, and 2.26 (1.21–4.24) for other infections. The corresponding hazard ratio for infection-related death was 1.70 (95% CI 1.37–2.10). Analyses were adjusted for age, sex, smoking status, cumulative smoking, alcohol intake, body mass index, plasma C-reactive protein, blood neutrophil count, recent infection, Charlson comorbidity index, autoimmune diseases, medication use, and immunodeficiency/hematologic disease. The findings were robust in all stratified analyses and also when including only events later than 2 years after first examination. However, due to the observational design, the study cannot address questions of causality, and our analyses might theoretically have been affected by residual confounding and reverse causation. In principle, fluctuating lymphocyte counts over time might also have influenced analyses, but lymphocyte counts in 5,181 individuals measured 10 years after first examination showed a regression dilution ratio of 0.68. Conclusions Lymphopenia was associated with increased risk of hospitalization with infection and increased risk of infection-related death in the general population. Notably, causality cannot be deduced from our data.
FRI0254 Clinical features and risk factors for developing gout attacks during anti-tuberculosis medication: a case-control study in south korea
Authors: Y.-J. Ha, S.W. Chung, J. Lee, E.H. Kang, Y.J. Lee, Y.W. Song
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Gout is a form of inflammatory arthritis that develops in some people with hyperuricemia. Several drugs may induce hyperuricemia and gout attack. Some anti-tuberculosis (TB) medications are also known to increase uric acid level and trigger acute gout attack. However, there have been no well-described studies for gout during anti-TB therapy. <h3>Objectives</h3> To investigate the clinical features and risk factors of gout attacks following anti-TB treatment in South Korea. <h3>Methods</h3> We conducted the case-control study including 49 patients who developed gout attack following anti-TB medications and 147 age- and sex- matched TB controls without gout attack. Demographic, clinical features and laboratory findings of patients with gout attacks following anti-TB medication were analysed and compared to those of controls in order to establish risk factors associated with gout attack during anti-TB treatment. <h3>Results</h3> The mean age was 67.7±13.2 years and 39 patients (79.6%) were male. Twenty-four patients (49.0%) had a previous history of gout. The mean time interval to develop gout attack from the initiation of anti-TB therapy was 4.13±4.49 months. The attacks tended to involve lower extremity joints (43/49, 87.8%), especially the ankle and the first metatarsophalangeal joint. Factors associated with experiencing gout attack during anti-TB medication were higher body mass index (BMI, 23.7±3.6 vs 21.8±3.6, p<i>=</i>0.003), higher pre-treatment uric acid level (7.2±2.5 vs 6.2±1.7 mg/dL, p<i>&lt;</i>0.001), previous history of gout (49.0% vs 1.4%, p<i>&lt;</i>0.001), absence of dyslipidemia (4.1% vs 16.3%, p<i>=</i>0.008), and decreased renal function (eGFR 63.6±27.5 vs 82.6±29.9, p<i>=</i>0.003). In multivariate model, higher BMI, chronic kidney disease (CKD, eGFR &lt;60 ml/min/1.73m<sup>2</sup>), previous history of gout, and pre-treatment hyperuricemia (uric acid ≥6.8 mg/dL) were found to be independent risk factors for gout attack following anti-TB medication (table 1). <h3>Conclusions</h3> TB patients with obesity, history of gout, pre-treatment hyperuricemia, and CKD have higher risk for having gout attack following anti-TB medication. When starting anti-TB therapy in TB patients with these risk factors, physicians should pay attention to the development of gout attack and educate the patients. <h3>References</h3> [1] Gerdan G, Nurullah A, Ucan ES, et al. Paradoxical increase in uric acid level with allopurinol use in pyrazinamide-induced hyperuricemia. Singapore Med J. 2013;54(6):e125–128. [2] Postlethwaite AE, Bartel AG, Kelley WN. Hyperuricemia due to ethambutol. N Engl J Med. 1972;286(14):761–762. [3] Ben Salem C, Slim R, Fathallah N, Hmouda H. Drug-induced hyperuricaemia and gout. Rheumatology (Oxford)2017;56(5):679–688. <h3>Disclosure of Interest</h3> None declared
Deficiency of Lsh, a regulator of genomic methylation in mice, impairs hematopoiesis and promotes erythroleukemia development.
Authors: Kathrin Muegge, Anja Schmidtman, Tao Fan, John Goyaa, Jonathan Keller, Sandra Ruscetti, Miriam Anver
Journal: Cancer Research (2006)

5065   Alterations in DNA methylation are thought to play a role in tumorigenesis. Lsh belongs to the chromatin remodeling family of SNF2 proteins and is a crucial regulator of DNA methylation in mice. Here we addressed the question whether genomic hypomethylation plays a role in hematopoiesis and the formation of hematopoietic tumors. Using radiation chimera that received Lsh deficient hematopoietic precursor cells, we found a greatly reduced survival rate of Lsh-/- recipients. Death was in part due to an impaired grafting of Lsh deficient precursor cells suggesting a crucial role for Lsh in hematopoiesis. A subset of Lsh-/- mice and Lsh-/-p53-/- mice succumbed to erythroleukemia. Lsh-/- tumor tissues showed activation of endogenous retroviral elements and a slight elevation of the transcription factor PU.1 involved in Friend virus-induced erythroleukemia. Thus DNA hypomethylation caused by Lsh deficiency may promote tumor formation through de-repression of genes such as PU.1.
Differential Burden of Rare and Common Variants on Tumor Characteristics, Survival, and Mode of Detection in Breast Cancer
Authors: Jingmei Li, Emilio Ugalde-Morales, Wei Xiong Wen, Brennan Decker, Mikael Eriksson, Astrid Torstensson, Helene Nordahl Christensen, Alison M. Dunning, Jamie Allen, Craig Luccarini, Karen A. Pooley, Jacques Simard, Leila Dorling, Douglas F. Easton, Soo Hwang Teo, Per Hall, Kamila Czene
Journal: Cancer Research (2018)

Abstract Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes—or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer–specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16–2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21–2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (&amp;lt;25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12–3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64–0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection. Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329–38. ©2018 AACR.
Characterisation of HIV-1 transmission clusters and drug-resistant mutations in Denmark, 2004 to 2016
Authors: Andreas Petersen, Susan A Cowan, Jens Nielsen, Thea K Fischer, Jannik Fonager
Journal: Eurosurveillance (2018)

This study describes the prevalence of human immunodeficiency virus (HIV) drug resistance mutations among 1,815 patients in Denmark from 2004 to 2016 and characterises transmission clusters. POL sequences were analysed for subtype, drug resistance mutations and phylogenetic relationship. The prevalence of surveillance drug resistance mutations (SDRM) was 6.7%, while the prevalence of drug resistance mutations (DRM) with a clinical impact was 12.3%. We identified 197 transmission clusters with 706 patients. Patients 40 years or older were less likely to be members of a transmission cluster and patients in transmission clusters were less likely to be infected abroad. The proportion of late presenters (LP) was lower in active compared with inactive clusters. Large active clusters consisted of more men who have sex with men (MSM), had members more frequently infected in Denmark and contained a significantly lower proportion of LP and significantly fewer patients with DRM than small active clusters. Subtyping demonstrated that the Danish HIV epidemic is gradually becoming more composed of non-B subtypes/circulating recombinant forms. This study shows that active HIV-1 transmission has become increasingly MSM-dominated and that the recent increase in SDRM and DRM prevalence is not associated with more sustained transmission within identified transmission networks or clusters.
Abstract 12956: Monoclonal Antibody to Domain I of β2-glycoprotein I Prevents the Thrombotic Diathesis Associated With the Antiphospholipid Syndrome
Authors: Lane Lanier, Victoria Ulrich, Cristina Tarango, Ivan Yuhanna, Craig N Morrell, Yu-Min Shen, Philip W Shaul, Chieko Mineo
Journal: Circulation (2013)

Patients with antiphospholipid syndrome (APS) have exaggerated thrombosis caused by antiphospholipid antibodies (aPL). Current therapy with anticoagulation is sometimes ineffective and can lead to ...
Abstract 17137: High-Intensity Statin Therapy Masks the Beneficial Effect of Omega-3 Fatty Acid Supplementation on Progression of Coronary Plaque in Patients With Coronary Artery Disease
Authors: Mohamad Saleh, Abdulhamied Alfaddagh, Tarec K Elajami, Hasan Ashfaque, Francine K Welty
Journal: Circulation (2017)

Introduction: Early clinical trials of omega-3 fatty acids (FAs) conducted prior to the wide use of statins showed benefit on cardiovascular events whereas more recent trials have shown variable re...
Creating a web-based electronic tool to aid tuberculosis (TB) cluster investigation: data integration in TB surveillance activities in the United Kingdom, 2013 to 2016
Authors: Jennifer A Davidson, Laura F Anderson, Victoria Adebisi, Leonardo de Jongh, Andy Burkitt, Maeve K Lalor
Journal: Eurosurveillance (2018)

Molecular technology to identify relatedness between Mycobacterium tuberculosis complex isolates, representative of possible tuberculosis (TB) transmission between individuals, continues to evolve. At the same time, tools to utilise this information for public health action to improve TB control should also be implemented. Public Health England developed the Strain Typing Module (STM) as an integral part of the web-based surveillance system used in the United Kingdom following the roll-out of prospective 24 loci mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) strain typing. The creation of such a system required data integration and linkage, bringing together laboratory results and patient notification information. The STM facilitated widespread access to patient strain typing and clustering results for the public health community working in TB control. In addition, the system provided a log of cluster review and investigation decision making and results. Automated real-time data linkage between laboratory and notification data are essential to allow routine use of genotyping results in TB surveillance and control. Outputs must be accessible by those working in TB control at a local level to have any impact in ongoing public health activity.
Image Gallery: Severe combined immunodeficiency presenting with disseminated bacille Calmette-Guérin
Authors: C. C. Xu, H. Chen, J. F. Sun
Journal: British Journal of Dermatology (2018)

Funding sources: the CAMS Innovation Fund for Medical Sciences (CIFMS‐2017‐12M‐1‐017) and the PUMC Youth Fund (3332017168). Conflicts of interest: none to declare. Dear Editor, A 6‐month‐old male infant presented with a 1‐week history of multiple necrotizing papules on his trunk (a) and limbs, including his bacille Calmette–Guérin (BCG) vaccination site (b). Skin biopsy showed a strong positive response of acid‐fast bacilli (c). The smooth granular colonies grown in tissue culture were identified as Mycobacterium bovis BCG. Marked lymphopenia with significantly few T, B and natural killer lymphocytes and low serum immunoglobulin levels (all three classes) pointed towards a diagnosis of severe combined immunodeficiency (SCID). If SCID or other primary immunodeficiency disorders are diagnosed in a newborn, BCG vaccination should be avoided, and early haematopoietic stem cell transplantation is an effective treatment for this disease.1,2 ...
h-Channels Contribute to Divergent Intrinsic Membrane Properties of Supragranular Pyramidal Neurons in Human versus Mouse Cerebral Cortex
Authors: Brian E. Kalmbach, Anatoly Buchin, Brian Long, Jennie Close, Anirban Nandi, Jeremy A. Miller, Trygve E. Bakken, Rebecca D. Hodge, Peter Chong, Rebecca de Frates, Kael Dai, Zoe Maltzer, Philip R. Nicovich, C. Dirk Keene, Daniel L. Silbergeld, Ryder P. Gwinn, Charles Cobbs, Andrew L. Ko, Jeffrey G. Ojemann, Christof Koch, Costas A. Anastassiou, Ed S. Lein, Jonathan T. Ting
Journal: Neuron (2018)
Abstract 5193: Syndecan-1 is Protective in Atherosclerosis
Authors: Carolyn A Haller, Sumona Smith, Jing Wen, Jiantao Xiao, Elliot L Chaikof
Journal: Circulation (2009)

Background : Syndecan-1 is a cell surface heparan sulfate proteoglycan characterized by highly regulated expression during development, neoplasia, and wound repair. The biological function of syndecan-1 is primarily exerted via pendant glycosaminoglycans that sequester and regulate the activity of heparin-binding growth factors and chemokines. Several studies have documented a protective role for syndecan-1 in inflammatory disease; however, the functional role syndecan-1 in atherosclerotic lesion formation has not been previously investigated. Methods: Standard cross-breeding was used to generate ApoE −/− Sdc-1 −/− double knockout mice which were maintained on a Western diet for 8 weeks to induce atherosclerotic lesion formation, results were compared to ApoE −/− Sdc-1 +/+ mice (n=19 each group). Brachiocephalic lesion area was quantified in 3 consecutive (hematoxylin and eosin stained) tissue sections with a 50 μ m interval distance. Standard immunohistochemistry was used to characterize both murine and human atherosclerotic tissue samples. Serum was collected at 8 weeks via cardiac puncture, circulating levels of syndecan-1 were analyzed using slot blot analysis with mAb against mouse syndecan-1 (281–1). Results: A significant increase in atherosclerotic lesion area was measured in ApoE −/− Sdc-1 −/− mice verses ApoE −/− Sdc-1 +/+ (88.03±8.66 vs. 57.40±8.08, P &lt; 0.05). Atherogenic animals expressed syndecan-1 positive macrophages in early lesions and advanced lipid cores, correlative staining with human carotid plaques revealed infiltration of syndecan-1 positive macrophages in all specimens. Serum syndecan-1 was undetectable in native mouse serum, soluble syndecan-1 was observed in all mice after 8 week enrollment on the Western diet. Conclusions: The expression of syndecan-1 is significantly increased in the vascular wall of atherogenic mice and is present in human carotid plaque specimens. ApoE −/− Sdc-1 +/+ displayed a significant decrease in lesion area verses ApoE −/− Sdc-1 −/− mice, syndecan-1 may be an important endogenous modulator of vascular inflammation.
Abstract 20965: Use of Plasma Ceramides to Predict Major Adverse Cardiovascular Events - A Community-Based Analysis
Authors: Jose R Medina-Inojosa, Jeffrey Meeusen, Jaffe Allan, Leslie Donato, Richard J rodeheffer, Francisco Lopez-Jimenez
Journal: Circulation (2017)

Introduction: Plasma ceramides (CER) are sphingolipids associated with adverse events and mortality in patients with established coronary artery disease (CAD) and/or risk factors for CAD. The ability of these same specific ratios of CER to predict major adverse cardiovascular events (MACE) in subjects without CAD in the community is less certain. We tested the hypothesis that CER are associated with MACE in a community-based cohort free of CAD at enrollment. Methods: In a prospective community-based cohort we performed passive follow-up using a record linkage system to ascertain the composite outcome of MACE, defined as acute myocardial infarction, coronary revascularization (coronary artery bypass grafting or percutaneous coronary intervention), stroke or death. CER were analyzed as continuous variables, ratios and quintiles adjusting for potential confounders. Results: We included 1221 subjects, 49% males, mean age ± (SD) 61.1±9.6 years. After a median follow-up of 16 years (IQR 1.7), 297 patients had a MACE: Myocardial infarction (105), coronary artery bypass surgery (53), percutaneous coronary intervention (92), stroke (137) and all-cause death (120). Some had more than one event. Ratios of CER were significantly associated with MACE in unadjusted and adjusted models, see Figure 1-A. This association was independent of LDL-C, total cholesterol, Apo-B and traditional CAD risk factors. Those in the highest quintile of (24:1/24:0) CER ratio had more than two-fold risk of MACE, HR 2.32 (95% CI, 1.59-3.46). There was a dose-response association across quintiles of CER ratios and MACE, Figure 1-B.: Conclusions: Elevated CER plasma ratios are associated with MACE in patients with no CAD in the community. The risk conferred by plasma CER is independent of traditional risk factors, including lipids, and has a dose-response.
ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome
Authors: Li Ou, Russell C. DeKelver, Michelle Rohde, Susan Tom, Robert Radeke, Susan J. St. Martin, Yolanda Santiago, Scott Sproul, Michael J. Przybilla, Brenda L. Koniar, Kelly M. Podetz-Pedersen, Kanut Laoharawee, Renee D. Cooksley, Kathleen E. Meyer, Michael C. Holmes, R. Scott McIvor, Thomas Wechsler, Chester B. Whitley
Journal: Molecular Therapy (2018)

Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases.
Abstract 14071: Early Prosthetic Valve Dysfunction Due to Bioprosthetic Valve Thrombosis: The Role of Echocardiography
Authors: Alexander C Egbe, Arooj Khan, Heidi Connolly
Journal: Circulation (2017)

Background: Bioprosthetic valve thrombosis (BPVT) is an important cause of prosthetic valve dysfunction (PVD). However, the current guidelines do not recommend routine transthoracic echocardiogram ...
Incidence and survival of esophageal and gastric cancers in BC, Canada.
Authors: Morteza Bashash, Amil Shah, Greg Hislop, Angela Brooks-Wilson, Nhu Le, Chris Bajdik
Journal: Cancer Research (2008)

3857   Background:  Geographical variation and temporal trends in the incidence of esophageal and gastric cancers vary according to both tumor morphology and organ subsite. Both diseases are among the deadliest forms of cancer. We describe the incidence and survival of gastric and esophageal carcinoma in British Columbia, Canada (BC) between 1990 and 1999.  Methods:  Incidence data for the period 1990-1999 were obtained from the BC Cancer Registry (BCCR). Age-adjusted incidence and survival rates were computed by anatomic subsite, histological type and gender. All rates were standardized to the 1996 Canadian population. The Estimated Annual Percent Change (EAPC) was used to measure incidence changes over time. Kaplan-Meier curves were used to show survival, and log-rank tests used to test for differences in the curves among various groups.  Results:  Between 1990 and 1999, 1741 esophageal cancer cases and 3431 gastric cancer cases were registered in BC. There was an increase in the incidence for adenocarcinoma of the esophagus over time (EAPC=9.6) among men and for gastric cardia cancer among both women (EAPC=9.2) and men (EAPC=3.8). Proximal gastric (cardia) cancers had significantly better survival than cancers in the lower third of esophagus. Among gastric cancers, distal tumors had a significantly better survival than proximal tumors.  Discussion:  The incidence of proximal gastric cancer and esophageal adenocarcinoma are increasing, and their survival patterns are different. Examining these cancers together might elucidate new etiologic and prognostic factors.