Comparison of electron beam computed tomography scanning and conventional risk factor assessment for the prediction of angiographic coronary artery disease

AbstractObjective. To determine whether electron beam computed tomography (CT) adds to conventional risk factor assessment in the prediction of angiographic coronary artery disease.Background. Electron beam CT scanning can be used to predict the severity of coronary atherosclerosis, but whether it does so independently of conventional risk factors is unclear.Methods. Electron beam CT scans were performed and conventional risk factors were measured in 290 men and women undergoing coronary arteriography for clinical indications. The association of the electron beam CT-derived coronary artery calcium score and conventional risk factors with the presence and severity of angiographically defined coronary atherosclerosis was analyzed by logistic regression and receiver-operator characteristics analysis.Results. Age, the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol and the coronary calcium score were significantly and independently associated with the presence of any coronary disease and obstructive coronary disease. In association with any coronary disease, odds ratios for age, the ratio of total cholesterol to HDL cholesterol and calcium score, highest quartile vs. lowest quartile, were 6.01 (95% confidence interval 2.87 to 12.56), 3.14 (1.56 to 6.31) and 94.08 (21.06 to 420.12), respectively. For obstructive coronary disease, highest quartile vs. lowest quartile, the respective odds ratios for age, the ratio of total cholesterol to HDL and calcium score were 3.86 (1.86 to 8.00), 4.11 (1.98 to 8.52) and 34.12 (12.67 to 91.86). Male gender was also significantly associated with any coronary disease (odds ratio 2.19, p = 0.04) and obstructive coronary disease (odds ratio 2.07, p = 0.04). Cigarette smoking was significantly associated with any coronary disease (odds ratio = 2.74, p = 0.004), and diabetes was significantly associated with obstructive disease (odds ratio 3.16, p = 0.01). After adjustment for the coronary calcium score and other risk factors, it was determined that triglycerides, family history and hypertension were not significantly associated with any disease state. A coronary calcium score ≥80 (Agatston method) was associated with an increased likelihood of any coronary disease regardless of the number of risk factors, and a coronary calcium score ≥170 was associated with an increased likelihood of obstructive coronary disease regardless of the number of risk factors (p < 0.001).Conclusion. Electron beam CT scanning offers improved discrimination over conventional risk factors in the identification of persons with any angiographic coronary disease or angiographic obstructive coronary disease

STM observation of electronic wave interference effect in finite-sized graphite with dislocation-network structures

Superperiodic patterns near a step edge were observed by STM on several-layer-thick graphite sheets on a highly oriented pyrolitic graphite substrate, where a dislocation network is generated at the interface between the graphite overlayer and the substrate. Triangular- and rhombic-shaped periodic patterns whose periodicities are around 100 nm were observed on the upper terrace near the step edge. In contrast, only outlines of the patterns similar to those on the upper terrace were observed on the lower terrace. On the upper terrace, their geometrical patterns gradually disappeared and became similar to those on the lower terrace without any changes of their periodicity in increasing a bias voltage. By assuming a periodic scattering potential at the interface due to dislocations, the varying corrugation amplitudes of the patterns can be understood as changes in LDOS as a result of the beat of perturbed and unperturbed waves, i.e. the interference in an overlayer. The observed changes in the image depending on an overlayer height and a bias voltage can be explained by the electronic wave interference in the ultra-thin overlayer distorted under the influence of dislocation-network structures.Comment: 8 pages; 6 figures; Paper which a part of cond-mat/0311068 is disscussed in detai

Simulated Anthrax Attacks and Syndromic Surveillance

Bioterrorism surveillance systems can be assessed using modeling to simulate real-world attacks

Spitzer Follow-up of Extremely Cold Brown Dwarfs Discovered by the Backyard Worlds: Planet 9 Citizen Science Project

We present Spitzer follow-up imaging of 95 candidate extremely cold brown dwarfs discovered by the Backyard Worlds: Planet 9 citizen science project, which uses visually perceived motion in multiepoch Wide-field Infrared Survey Explorer (WISE) images to identify previously unrecognized substellar neighbors to the Sun. We measure Spitzer [3.6]–[4.5] color to phototype our brown dwarf candidates, with an emphasis on pinpointing the coldest and closest Y dwarfs within our sample. The combination of WISE and Spitzer astrometry provides quantitative confirmation of the transverse motion of 75 of our discoveries. Nine of our motion-confirmed objects have best-fit linear motions larger than 1'' yr⁻¹; our fastest-moving discovery is WISEA J155349.96+693355.2 (μ ≈ 2.”15 yr⁻¹), a possible T-type subdwarf. We also report a newly discovered wide-separation (~400 au) T8 comoving companion to the white dwarf LSPM J0055+5948 (the fourth such system to be found), plus a candidate late T companion to the white dwarf LSR J0002+6357 at 5 5 projected separation (~8700 au if associated). Among our motion-confirmed targets, five have Spitzer colors most consistent with spectral type Y. Four of these five have exceptionally red Spitzer colors suggesting types of Y1 or later, adding considerably to the small sample of known objects in this especially valuable low-temperature regime. Our Y dwarf candidates begin bridging the gap between the bulk of the Y dwarf population and the coldest known brown dwarf

Spitzer Follow-up of Extremely Cold Brown Dwarfs Discovered by the Backyard Worlds: Planet 9 Citizen Science Project

We present Spitzer follow-up imaging of 95 candidate extremely cold brown dwarfs discovered by the Backyard Worlds: Planet 9 citizen science project, which uses visually perceived motion in multi-epoch WISE images to identify previously unrecognized substellar neighbors to the Sun. We measure Spitzer [3.6]-[4.5] color to phototype our brown dwarf candidates, with an emphasis on pinpointing the coldest and closest Y dwarfs within our sample. The combination of WISE and Spitzer astrometry provides quantitative confirmation of the transverse motion of 75 of our discoveries. Nine of our motion-confirmed objects have best-fit linear motions larger than 1"/yr; our fastest-moving discovery is WISEA J155349.96+693355.2 (total motion ~2.15"/yr), a possible T type subdwarf. We also report a newly discovered wide-separation (~400 AU) T8 comoving companion to the white dwarf LSPM J0055+5948 (the fourth such system to be found), plus a candidate late T companion to the white dwarf LSR J0002+6357 at 5.5' projected separation (~8,700 AU if associated). Among our motion-confirmed targets, five have Spitzer colors most consistent with spectral type Y. Four of these five have exceptionally red Spitzer colors suggesting types of Y1 or later, adding considerably to the small sample of known objects in this especially valuable low-temperature regime. Our Y dwarf candidates begin bridging the gap between the bulk of the Y dwarf population and the coldest known brown dwarf.Comment: accepted for publication in The Astrophysical Journa

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies

Alliance of Genome Resources Portal: unified model organism research platform

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource

Alliance of Genome Resources Portal: unified model organism research platform

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial

IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02149160