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1.  Helicobacter pylori colonization and obesity – a Mendelian randomization study 
Scientific Reports  2017;7:14467.
Obesity is associated with substantial morbidity, costs, and decreased life expectancy, and continues to rise worldwide. While etiological understanding is needed for prevention, epidemiological studies indicated that colonization with Helicobacter pylori (H. pylori) may affect body mass index (BMI), but with inconsistent results. Here, we examine the relationship between H. pylori colonization and BMI/obesity. Cross-sectional analyses were performed in two independent population-based cohorts of elderly from the Netherlands and Germany (n = 13,044). Genetic risk scores were conducted based on genetic loci associated with either H. pylori colonization or BMI/obesity. We performed a bi-directional Mendelian randomization. Meta-analysis of cross-sectional data revealed no association between anti-H. pylori IgG titer and BMI, nor of H. pylori positivity and BMI. Anti-H. pylori IgG titer was negatively associated with obesity (OR 0.99972; 95% CI 0.99946-0.99997, p = 0.03) and with obesity classes (Beta −6.91 •10−5; 95% CI −1.38•10−4, −5.49•10−7, p = 0.048), but the magnitude of these effects was limited. Mendelian randomization showed no causal relation between H. pylori genetic risk score and BMI/obesity, nor between BMI or obesity genetic risk scores and H. pylori positivity. This study provides no evidence for a clinically relevant association between H. pylori and BMI/obesity.
doi:10.1038/s41598-017-14106-4
PMCID: PMC5663904  PMID: 29089580
2.  High-density lipoprotein subpopulation profiles in lipoprotein lipase and hepatic lipase deficiency 
Atherosclerosis  2016;253:7-14.
Background and aims
Our aim was to gain insight into the role that lipoprotein lipase (LPL) and hepatic lipase (HL) plays in HDL metabolism and to better understand LPL- and HL-deficiency states.
Methods
We examined the apolipoprotein (apo) A-I-, A-II-, A-IV-, C-I-, C-III-, and E-containing HDL subpopulation profiles, assessed by native 2-dimensional gel-electrophoresis and immunoblotting, in 6 homozygous and 11 heterozygous LPL-deficient, 6 homozygous and 4 heterozygous HL-deficient, and 50 control subjects.
Results
LPL-deficient homozygotes had marked hypertriglyceridemia and significant decreases in LDL-C, HDL-C, and apoA-I. Their apoA-I-containing HDL subpopulation profile was shifted toward small HDL particles compared to controls. HL-deficient homozygotes had moderate hypertriglyceridemia, modest increases in LDL-C and HDL-C level, but normal apoA-I concentration. HL-deficient homozygotes had a unique distribution of apoA-I-containing HDL particles. The normally apoA-I:A-II, intermediate-size (α-2 and α-3) particles were significantly decreased, while the normally apoA-I only (very large α-1, small α-4, and very small preβ-1) particles were significantly elevated. In contrast to control subjects, the very large α-1 particles of HL-deficient homozygotes were enriched in apoA-II. Homozygous LPL- and HL-deficient subjects also had abnormal distributions of apo C-I, C-III, and E in HDL particles. Values for all measured parameters in LPL- and HL-deficient heterozygotes were closer to values measured in controls than in homozygotes.
Conclusions
Our data are consistent with the concept that LPL is important for the maturation of small discoidal HDL particles into large spherical HDL particles, while HL is important for HDL remodeling of very large HDL particles into intermediate-size HDL particles.
doi:10.1016/j.atherosclerosis.2016.08.014
PMCID: PMC5064856  PMID: 27573733
Apolipoproteins; Lipoprotein metabolism; HDL particles; HDL remodeling; Reverse cholesterol transport
3.  11C-choline PET/CT and whole-body MRI including diffusion-weighted imaging for patients with recurrent prostate cancer 
Oncotarget  2017;8(39):66516-66527.
Purpose
To compare the detection efficacy of 11C-choline positron emission tomography and computed tomography (PET/CT) with whole-body magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) in patients with suspected recurrent prostate cancer.
Materials and Methods
Fifty-seven patients (mean age 68, range 54-80 years) underwent 11C-choline PET/CT and MRI using T1-weighted (T1w), short-tau inversion recovery (STIR), and DWI. Two readers visually rated suspicious lesions on a 5-point scale in 20 different regions. Clinical follow-up and histopathology served as the standard of reference (SOR).
Results
Fifty patients (mean PSA 29.9, range 1.0-670 ng/mL) had at least one positive lesion according to the SOR. Twenty-four patients had local recurrence (LR), 27 had lymph node (LN) involvement, and 22 had bone metastases. The overall detection rates for PET/CT and MRI on a patient basis were 94% and 88%, respectively (p = 0.07). The PSA level (>2 ng/mL vs ≤2 ng/mL) significantly influenced the overall performance of PET/CT (p = 0.003) and MRI (p = 0.03). PET/CT was significantly superior to MRI in detecting LR (p = 0.03) and bone metastasis (p = 0.02). We found no difference with respect to the detection of LN metastasis (p = 0.65).
Conclusion
11C-choline PET/CT was superior in the detection of local recurrence and bone metastasis on a regional basis. Whole-body MRI including DWI showed similar diagnostic accuracy only for detecting lymph node metastases. Compared with 11C-choline PET/CT, therefore, whole-body MRI including DWI cannot serve as alternative imaging modality for restaging prostate cancer.
doi:10.18632/oncotarget.16227
PMCID: PMC5630432
prostate cancer; recurrence; 11C-choline; PET/CT; MRI
4.  Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells 
eLife  null;6:e24502.
Genetic analysis has revealed that the dual specificity protein kinase DYRK1A has multiple roles in the development of the central nervous system. Increased DYRK1A gene dosage, such as occurs in Down syndrome, is known to affect neural progenitor cell differentiation, while haploinsufficiency of DYRK1A is associated with severe microcephaly. Using a set of known and newly synthesized DYRK1A inhibitors, along with CRISPR-mediated gene activation and shRNA knockdown of DYRK1A, we show here that chemical inhibition or genetic knockdown of DYRK1A interferes with neural specification of human pluripotent stem cells, a process equating to the earliest stage of human brain development. Specifically, DYRK1A inhibition insulates the self-renewing subpopulation of human pluripotent stem cells from powerful signals that drive neural induction. Our results suggest a novel mechanism for the disruptive effects of the absence or haploinsufficiency of DYRK1A on early mammalian development, and reveal a requirement for DYRK1A in the acquisition of competence for differentiation in human pluripotent stem cells.
doi:10.7554/eLife.24502
PMCID: PMC5656431  PMID: 28884684
Homo sapiens; pluripotent; stem cell; None
5.  Diagnosis and Treatment of High Density Lipoprotein Deficiency 
Low serum high density lipoprotein cholesterol level (HDL-C) < 40 mg/dL in men and < 50 mg/dL in women are a significant independent risk factor for cardiovascular disease (CVD), and are often observed in patients with hypertriglyceridemia, obesity, insulin resistance, and diabetes. Patients with marked deficiency of HDL-C (< 20 mg/dL) in the absence of secondary causes are much less common (< 1% of the population). These patients may have homozygous, compound heterozygous, or heterozygous defects involving the apolipoprotein (APO)AI, ABCA1, or lecithin:cholesterol acyl transferase genes, associated with Apo A-I Deficiency, ApoA-I Variants, Tangier Disease, Familial Lecithin:Cholesteryl Ester Acyltransferase Deficiency, and Fish Eye Disease. There is marked variability in laboratory and clinical presentation, and DNA analysis is necessary for diagnosis. These patients can develop premature CVD, neuropathy, kidney failure, neuropathy, hepatosplenomegaly and anemia. Treatment should be directed at optimizing all non-HDL risk factors.
doi:10.1016/j.pcad.2016.08.006
PMCID: PMC5331615  PMID: 27565770
Lipoproteins; HDL; high-density lipoproteins; HDL-C; genetic dyslipidemias
6.  Randomized supplementation of 4000 IU vitamin D3 daily vs placebo on the prevalence of anemia in advanced heart failure: the EVITA trial 
Nutrition Journal  2017;16:49.
Background
Low 25-hydroxyvitamin D (25OHD) levels (< 75 nmol/l) are inversely associated with anemia prevalence. Since anemia and low 25OHD levels are common in patients with heart failure (HF), we aimed to investigate whether vitamin D supplementation can reduce anemia prevalence in advanced HF.
Methods
EVITA (Effect of Vitamin D on Mortality in Heart Failure) is a randomized, placebo-controlled clinical trial in patients with initial 25OHD levels < 75 nmol/l. Participants received either 4000 IU vitamin D3 daily or a matching placebo for 36 months. A total of 172 patients (vitamin D group: n = 85; placebo group: n = 87) were investigated in this pre-specified secondary data analysis. Hemoglobin (Hb) and other hematological parameters were measured at baseline and study termination. Assessment of between-group differences in anemia prevalence and Hb concentrations was performed at study termination, while adjusting for baseline differences.
Results
In the vitamin D and placebo group, baseline proportions of patients with anemia (Hb < 12.0 g/dL in females and < 13.0 g/dL in males) were 17.2% and 10.6%, respectively (P = 0.19). At study termination, the proportion of patients with anemia in the vitamin D and placebo groups was 32.2% and 31.8%, respectively (P > 0.99). There was no between-group difference in change in the Hb concentrations (− 0.04 g/dL [95%CI:-0.53 to 0.45 g/dL]; P = 0.87). Results regarding anemia risk and Hb concentrations were similar in the subgroup of patients with chronic kidney disease (vitamin D group: n = 26; placebo group: n = 23). Moreover, results did not differ substantially when data analysis was restricted to patients with deficient baseline 25OHD levels.
Conclusions
A daily vitamin D supplement of 4000 IU did not reduce anemia prevalence in patients with advanced HF. Data challenge the clinical relevance of vitamin D supplementation to increase Hb levels.
Trial registration
The study was registered at EudraCT (No. 2010–020793-42) and clinicaltrials.gov (NCT01326650).
Electronic supplementary material
The online version of this article (doi:10.1186/s12937-017-0270-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12937-017-0270-5
PMCID: PMC5569566  PMID: 28835271
Vitamin D supplementation; Hemoglobin; Anemia; 25-Hydroxyvitamin D; 1,25-Dihydroxyvitamin D; Chronic heart failure
7.  Fiducial, total and differential cross-section measurements of t-channel single top-quark production in pp collisions at 8 TeV using data collected by the ATLAS detector 
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M. | Blackburn, D. | Blair, R. E. | Blazek, T. | Bloch, I. | Blocker, C. | Blue, A. | Blum, W. | Blumenschein, U. | Blunier, S. | Bobbink, G. J. | Bobrovnikov, V. S. | Bocchetta, S. S. | Bocci, A. | Bock, C. | Boehler, M. | Boerner, D. | Bogaerts, J. A. | Bogavac, D. | Bogdanchikov, A. G. | Bohm, C. | Boisvert, V. | Bokan, P. | Bold, T. | Boldyrev, A. S. | Bomben, M. | Bona, M. | Boonekamp, M. | Borisov, A. | Borissov, G. | Bortfeldt, J. | Bortoletto, D. | Bortolotto, V. | Bos, K. | Boscherini, D. | Bosman, M. | Sola, J. D. Bossio | Boudreau, J. | Bouffard, J. | Bouhova-Thacker, E. V. | Boumediene, D. | Bourdarios, C. | Boutle, S. K. | Boveia, A. | Boyd, J. | Boyko, I. R. | Bracinik, J. | Brandt, A. | Brandt, G. | Brandt, O. | Bratzler, U. | Brau, B. | Brau, J. E. | Madden, W. D. Breaden | Brendlinger, K. | Brennan, A. J. | Brenner, L. | Brenner, R. | Bressler, S. | Bristow, T. M. | Britton, D. | Britzger, D. | Brochu, F. M. | Brock, I. | Brock, R. | Brooijmans, G. | Brooks, T. | Brooks, W. K. | Brosamer, J. | Brost, E. | Broughton, J. H | de Renstrom, P. A. Bruckman | Bruncko, D. | Bruneliere, R. | Bruni, A. | Bruni, G. | Bruni, L. S. | Brunt, BH | Bruschi, M. | Bruscino, N. | Bryant, P. | Bryngemark, L. | Buanes, T. | Buat, Q. | Buchholz, P. | Buckley, A. G. | Budagov, I. A. | Buehrer, F. | Bugge, M. K. | Bulekov, O. | Bullock, D. | Burckhart, H. | Burdin, S. | Burgard, C. D. | Burger, A. M. | Burghgrave, B. | Burka, K. | Burke, S. | Burmeister, I. | Burr, J. T. P. | Busato, E. | Büscher, D. | Büscher, V. | Bussey, P. | Butler, J. M. | Buttar, C. M. | Butterworth, J. M. | Butti, P. | Buttinger, W. | Buzatu, A. | Buzykaev, A. R. | Urbán, S. Cabrera | Caforio, D. | Cairo, V. M. | Cakir, O. | Calace, N. | Calafiura, P. | Calandri, A. | Calderini, G. | Calfayan, P. | Callea, G. | Caloba, L. P. | Lopez, S. Calvente | Calvet, D. | Calvet, S. | Calvet, T. P. | Toro, R. Camacho | Camarda, S. | Camarri, P. | Cameron, D. | Armadans, R. Caminal | Camincher, C. | Campana, S. | Campanelli, M. | Camplani, A. | Campoverde, A. | Canale, V. | Canepa, A. | Bret, M. Cano | Cantero, J. | Cao, T. | Garrido, M. D. M. Capeans | Caprini, I. | Caprini, M. | Capua, M. | Carbone, R. M. | Cardarelli, R. | Cardillo, F. | Carli, I. | Carli, T. | Carlino, G. | Carlson, B. T. | Carminati, L. | Carney, R. M. D. | Caron, S. | Carquin, E. | Carrillo-Montoya, G. D. | Carter, J. R. | Carvalho, J. | Casadei, D. | Casado, M. P. | Casolino, M. | Casper, D. W. | Castaneda-Miranda, E. | Castelijn, R. | Castelli, A. | Gimenez, V. Castillo | Castro, N. F. | Catinaccio, A. | Catmore, J. R. | Cattai, A. | Caudron, J. | Cavaliere, V. | Cavallaro, E. | Cavalli, D. | Cavalli-Sforza, M. | Cavasinni, V. | Ceradini, F. | Alberich, L. Cerda | Cerqueira, A. S. | Cerri, A. | Cerrito, L. | Cerutti, F. | Cervelli, A. | Cetin, S. A. | Chafaq, A. | Chakraborty, D. | Chan, S. K. | Chan, Y. L. | Chang, P. | Chapman, J. D. | Charlton, D. G. | Chatterjee, A. | Chau, C. C. | Barajas, C. A. Chavez | Che, S. | Cheatham, S. | Chegwidden, A. | Chekanov, S. | Chekulaev, S. V. | Chelkov, G. A. | Chelstowska, M. A. | Chen, C. | Chen, H. | Chen, S. | Chen, S. | Chen, X. | Chen, Y. | Cheng, H. C. | Cheng, H. J | Cheng, Y. | Cheplakov, A. | Cheremushkina, E. | Moursli, R. Cherkaoui El | Chernyatin, V. | Cheu, E. | Chevalier, L. | Chiarella, V. | Chiarelli, G. | Chiodini, G. | Chisholm, A. S. | Chitan, A. | Chizhov, M. V. | Choi, K. | Chomont, A. R. | Chouridou, S. | Chow, B. K. B. | Christodoulou, V. | Chromek-Burckhart, D. | Chudoba, J. | Chuinard, A. J. | Chwastowski, J. J. | Chytka, L. | Ciapetti, G. | Ciftci, A. K. | Cinca, D. | Cindro, V. | Cioara, I. A. | Ciocca, C. | Ciocio, A. | Cirotto, F. | Citron, Z. H. | Citterio, M. | Ciubancan, M. | Clark, A. | Clark, B. L. | Clark, M. R. | Clark, P. J. | Clarke, R. 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Detailed measurements of t-channel single top-quark production are presented. They use 20.2 fb\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{-1}$$\end{document}-1 of data collected by the ATLAS experiment in proton–proton collisions at a centre-of-mass energy of 8 TeV at the LHC. Total, fiducial and differential cross-sections are measured for both top-quark and top-antiquark production. The fiducial cross-section is measured with a precision of 5.8% (top quark) and 7.8% (top antiquark), respectively. The total cross-sections are measured to be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sigma _{\text {tot}} (tq) = 56.7^{+4.3}_{-3.8}\;\mathrm{pb}$$\end{document}σtot(tq)=56.7-3.8+4.3pb for top-quark production and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sigma _{\text {tot}} (\bar{t} q) = 32.9^{+3.0}_{-2.7}\;\mathrm{pb}$$\end{document}σtot(t¯q)=32.9-2.7+3.0pb for top-antiquark production, in agreement with the Standard Model prediction. In addition, the ratio of top-quark to top-antiquark production cross-sections is determined to be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R_t=1.72 \pm 0.09$$\end{document}Rt=1.72±0.09. The differential cross-sections as a function of the transverse momentum and rapidity of both the top quark and the top antiquark are measured at both the parton and particle levels. The transverse momentum and rapidity differential cross-sections of the accompanying jet from the t-channel scattering are measured at particle level. All measurements are compared to various Monte Carlo predictions as well as to fixed-order QCD calculations where available.
doi:10.1140/epjc/s10052-017-5061-9
PMCID: PMC5589447
8.  Grating-based phase-contrast and dark-field computed tomography: a single-shot method 
Scientific Reports  2017;7:7476.
Grating-based X-ray interferometry offers vast potential for imaging materials and tissues that are not easily visualised using conventional X-ray imaging. Tomographic reconstruction based on X-ray interferometric data provides not only access to the attenuation coefficient of an object, but also the refractive index and information about ultra-small-angle scattering. This improved functionality comes at the cost of longer measurement times because existing projection-based signal extraction algorithms require not only a single measurement per projection angle but several with precise grating movements in between. This obstacle hinders the adaptation of grating-based interferometry into a continuously rotating gantry. Several solutions to this problem have been proposed but all suffer from major drawbacks. We present results using an iterative reconstruction algorithm working directly on the interferograms. The suggested direct approach enables improved image quality, since interpolations and unnecessary assumptions about the object are circumvented. Our results demonstrate that it is possible to successfully reconstruct the linear attenuation coefficient, the refractive index and the linear diffusion coefficient, which is a measure related to ultra-small-angle scattering, using a single measurement per projection angle and without any grating movements. This is a milestone for future clinical implementation of grating-based phase-contrast and dark-field contrast X-ray computed tomography.
doi:10.1038/s41598-017-06729-4
PMCID: PMC5547164  PMID: 28785015
9.  Analysis of SHIP1 expression and activity in Crohn’s disease patients 
PLoS ONE  2017;12(8):e0182308.
Background
SH2 domain containing inositol-5-phosphatase (SHIP1) is an important modulator of innate and adaptive immunity. In mice, loss of SHIP1 provokes severe ileitis resembling Crohn’s disease (CD), as a result of deregulated immune responses, altered cytokine production and intestinal fibrosis. Recently, SHIP1 activity was shown to be correlated to the presence of a CD-associated single nucleotide polymorphism in ATG16L1. Here, we studied SHIP1 activity and expression in an adult cohort of CD patients.
Methods
SHIP1 activity, protein and mRNA expression in peripheral blood mononuclear cells from CD patients in clinical remission were determined by Malachite green assay, Western blotting and qRT-PCR respectively. Genomic DNA was genotyped for ATG16L1 rs2241880.
Results
SHIP1 protein levels are profoundly diminished in a subset of patients; however, SHIP1 activity and expression are not correlated to ATG16L1 SNP status in this adult cohort.
Conclusions
Aberrant SHIP1 activity can contribute to disease in a subset of adult CD patients, and warrants further investigation.
doi:10.1371/journal.pone.0182308
PMCID: PMC5540589  PMID: 28767696
10.  Gas Phase Sensing of Alcohols by Metal Organic Framework–Polymer Composite Materials 
ACS Applied Materials & Interfaces  2017;9(29):24926-24935.
Affinity layers play a crucial role in chemical sensors for the selective and sensitive detection of analytes. Here, we report the use of composite affinity layers containing Metal Organic Frameworks (MOFs) in a polymeric matrix for sensing purposes. Nanoparticles of NH2-MIL-53(Al) were dispersed in a Matrimid polymer matrix with different weight ratios (0–100 wt %) and drop-casted on planar capacitive transducer devices. These coated devices were electrically analyzed using impedance spectroscopy and investigated for their sensing properties toward the detection of a series of alcohols and water in the gas phase. The measurements indicated a reversible and reproducible response in all devices. Sensor devices containing 40 wt % NH2-MIL-53(Al) in Matrimid showed a maximum response for methanol and water. The sensor response time slowed down with increasing MOF concentration until 40 wt %. The half time of saturation response (τ0.5) increased by ∼1.75 times for the 40 wt % composition compared to devices coated with Matrimid only. This is attributed to polymer rigidification near the MOF/polymer interface. Higher MOF loadings (≥50 wt %) resulted in brittle coatings with a response similar to the 100 wt % MOF coating. Cross-sensitivity studies showed the ability to kinetically distinguish between the different alcohols with a faster response for methanol and water compared to ethanol and 2-propanol. The observed higher affinity of the pure Matrimid polymer toward methanol compared to water allows also for a higher uptake of methanol in the composite matrices. Also, as indicated by the sensing studies with a mixture of water and methanol, the methanol uptake is independent of the presence of water up to 6000 ppm of water. The NH2-MIL-53(Al) MOFs dispersed in the Matrimid matrix show a sensitive and reversible capacitive response, even in the presence of water. By tuning the precise compositions, the affinity kinetics and overall affinity can be tuned, showing the promise of this type of chemical sensors.
doi:10.1021/acsami.7b02630
PMCID: PMC5532685  PMID: 28440621
metal organic frameworks; composites; mixed matrix membranes; impedance spectroscopy; capacitive detection; gas sensors
11.  Topological cell clustering in the ATLAS calorimeters and its performance in LHC Run 1 
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P. | Gadatsch, S. | Gadomski, S. | Gagliardi, G. | Gagnon, P. | Galea, C. | Galhardo, B. | Gallas, E. J. | Gallop, B. J. | Gallus, P. | Galster, G. | Gan, K. K. | Gao, J. | Gao, Y. | Gao, Y. S. | Walls, F. M. Garay | Garberson, F. | García, C. | Navarro, J. E. García | Garcia-Sciveres, M. | Gardner, R. W. | Garelli, N. | Garonne, V. | Gatti, C. | Gaudiello, A. | Gaudio, G. | Gaur, B. | Gauthier, L. | Gauzzi, P. | Gavrilenko, I. L. | Gay, C. | Gaycken, G. | Gazis, E. N. | Ge, P. | Gecse, Z. | Gee, C. N. P. | Geich-Gimbel, Ch. | Geisler, M. P. | Gemme, C. | Genest, M. H. | Geng, C. | Gentile, S. | George, M. | George, S. | Gerbaudo, D. | Gershon, A. | Ghasemi, S. | Ghazlane, H. | Giacobbe, B. | Giagu, S. | Giangiobbe, V. | Giannetti, P. | Gibbard, B. | Gibson, S. M. | Gignac, M. | Gilchriese, M. | Gillam, T. P. S. | Gillberg, D. | Gilles, G. | Gingrich, D. M. | Giokaris, N. | Giordani, M. P. | Giorgi, F. M. | Giorgi, F. M. | Giraud, P. F. | Giromini, P. | Giugni, D. | Giuliani, C. | Giulini, M. | Gjelsten, B. K. | Gkaitatzis, S. | Gkialas, I. | Gkougkousis, E. L. | Gladilin, L. K. | Glasman, C. | Glatzer, J. | Glaysher, P. C. F. | Glazov, A. | Goblirsch-Kolb, M. | Goddard, J. R. | Godlewski, J. | Goldfarb, S. | Golling, T. | Golubkov, D. | Gomes, A. | Gonçalo, R. | Costa, J. Goncalves Pinto Firmino Da | Gonella, L. | de la Hoz, S. González | Parra, G. Gonzalez | Gonzalez-Sevilla, S. | Goossens, L. | Gorbounov, P. A. | Gordon, H. A. | Gorelov, I. | Gorini, B. | Gorini, E. | Gorišek, A. | Gornicki, E. | Goshaw, A. T. | Gössling, C. | Gostkin, M. I. | Goujdami, D. | Goussiou, A. G. | Govender, N. | Gozani, E. | Grabas, H. M. X. | Graber, L. | Grabowska-Bold, I. | Gradin, P. O. J. | Grafström, P. | Gramling, J. | Gramstad, E. | Grancagnolo, S. | Gratchev, V. | Gray, H. M. | Graziani, E. | Greenwood, Z. D. | Grefe, C. | Gregersen, K. | Gregor, I. M. | Grenier, P. | Griffiths, J. | Grillo, A. A. | Grimm, K. | Grinstein, S. | Gris, Ph. | Grivaz, J.-F. | Groh, S. | Grohs, J. P. | Grohsjean, A. | Gross, E. | Grosse-Knetter, J. | Grossi, G. C. | Grout, Z. J. | Guan, L. | Guenther, J. | Guescini, F. | Guest, D. | Gueta, O. | Guido, E. | Guillemin, T. | Guindon, S. | Gul, U. | Gumpert, C. | Guo, J. | Guo, Y. | Gupta, S. | Gustavino, G. | Gutierrez, P. | Ortiz, N. G. Gutierrez | Gutschow, C. | Guyot, C. | Gwenlan, C. | Gwilliam, C. B. | Haas, A. | Haber, C. | Hadavand, H. K. | Haddad, N. | Haefner, P. | Hageböck, S. | Hajduk, Z. | Hakobyan, H. | Haleem, M. | Haley, J. | Hall, D. | Halladjian, G. | Hallewell, G. D. | Hamacher, K. | Hamal, P. | Hamano, K. | Hamilton, A. | Hamity, G. N. | Hamnett, P. G. | Han, L. | Hanagaki, K. | Hanawa, K. | Hance, M. | Haney, B. | Hanke, P. | Hanna, R. | Hansen, J. B. | Hansen, J. D. | Hansen, M. C. | Hansen, P. H. | Hara, K.
The reconstruction of the signal from hadrons and jets emerging from the proton–proton collisions at the Large Hadron Collider (LHC) and entering the ATLAS calorimeters is based on a three-dimensional topological clustering of individual calorimeter cell signals. The cluster formation follows cell signal-significance patterns generated by electromagnetic and hadronic showers. In this, the clustering algorithm implicitly performs a topological noise suppression by removing cells with insignificant signals which are not in close proximity to cells with significant signals. The resulting topological cell clusters have shape and location information, which is exploited to apply a local energy calibration and corrections depending on the nature of the cluster. Topological cell clustering is established as a well-performing calorimeter signal definition for jet and missing transverse momentum reconstruction in ATLAS.
doi:10.1140/epjc/s10052-017-5004-5
PMCID: PMC5586976
12.  In-vivo X-ray Dark-Field Chest Radiography of a Pig 
Scientific Reports  2017;7:4807.
X-ray chest radiography is an inexpensive and broadly available tool for initial assessment of the lung in clinical routine, but typically lacks diagnostic sensitivity for detection of pulmonary diseases in their early stages. Recent X-ray dark-field (XDF) imaging studies on mice have shown significant improvements in imaging-based lung diagnostics. Especially in the case of early diagnosis of chronic obstructive pulmonary disease (COPD), XDF imaging clearly outperforms conventional radiography. However, a translation of this technique towards the investigation of larger mammals and finally humans has not yet been achieved. In this letter, we present the first in-vivo XDF full-field chest radiographs (32 × 35 cm2) of a living pig, acquired with clinically compatible parameters (40 s scan time, approx. 80 µSv dose). For imaging, we developed a novel high-energy XDF system that overcomes the limitations of currently established setups. Our XDF radiographs yield sufficiently high image quality to enable radiographic evaluation of the lungs. We consider this a milestone in the bench-to-bedside translation of XDF imaging and expect XDF imaging to become an invaluable tool in clinical practice, both as a general chest X-ray modality and as a dedicated tool for high-risk patients affected by smoking, industrial work and indoor cooking.
doi:10.1038/s41598-017-05101-w
PMCID: PMC5500502  PMID: 28684858
13.  Population-based colonoscopy screening for colorectal cancer: a European randomized trial 
JAMA internal medicine  2016;176(7):894-902.
Importance
While some countries have implemented widespread colonoscopy screening, most European countries have not introduced it because of uncertainty with regard to participation rates, procedure-related pain and discomfort, endoscopist performance, and effectiveness. No randomized trials on colonoscopy screening exist today.
Objective
To investigate participation rate, yield, performance and adverse events of population-based colonoscopy screening.
Design
Randomized controlled trial in Poland, Norway, the Netherlands, and Sweden
Setting
Average-risk population, population-based.
Participants
94,958 men and women aged 55 to 64 years.
Intervention
Colonoscopy screening or no-screening.
Outcome measures
This paper reports on screening participation, yield, and subject experience. Study outcomes were compared by country and endoscopist.
Results
Of 31,420 eligible subjects randomized to colonoscopy 12,574 (40%) attended screening. Participation rates were 60.7% in Norway, 39·8% in Sweden, 33% in Poland, and 22.9% in the Netherlands (p<0.001). The cecum intubation rate was 97.2%, with 9,726 (77.3%) of subjects not receiving sedation. We observed one perforation (0.01%), two post-polypectomy serosal burns and 18 bleedings due to polypectomy (0.15%). 62 subjects (0.5%) were diagnosed with colorectal cancer and 3,861 (30.7%) had adenomas, of which 1,304 (10.4%) high-risk adenomas. Detection rates were similar in the proximal and distal colon. Performance differed significantly between endoscopists; recommended benchmarks for caecal intubation (95%) and adenoma detection (25%) were not met by 6 (17.1%) and 10 endoscopists (28.6%), respectively. Moderate or severe abdominal pain after colonoscopy was reported by 16.6% examined with standard air insufflation versus 4.0% with carbon dioxide insufflation (p<0.001).
Conclusion and relevance
Colonoscopy screening entails high detection rates in the proximal and distal colon. Participation rates and endoscopist performance screening vary significantly. Post-procedure abdominal pain is common with standard air insufflation and can be significantly reduced by using carbon dioxide.
Trial registration
NCT 00883792.
doi:10.1001/jamainternmed.2016.0960
PMCID: PMC5333856  PMID: 27214731
14.  Editorial Introduction 
Current opinion in lipidology  2014;25(3):159-160.
doi:10.1097/MOL.0000000000000082
PMCID: PMC5489064  PMID: 24785963
15.  Genetic Variation at the PCSK9 Locus Moderately Lowers Low Density Lipoprotein Cholesterol Levels, But Does Not Significantly Lower Vascular Disease Risk in an Elderly Population 
Atherosclerosis  2008;200(1):95-101.
Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus have been reported to have 15% lower low density lipoprotein (LDL) cholesterol (C) levels and 47% lower coronary heart disease (CHD) risk. Our objective was to examine two PCSK9 single nucleotide polymorphisms (SNPs), R46L and E670G, in 5,783 elderly participants in PROSPER (Prospective Study of Pravastatin in the Elderly at Risk), of whom 43% had a history of vascular disease at baseline, and who were randomized to pravastatin or placebo with followup. In this population 3.5% were carriers of the T allele at R46L, and these subjects had significantly (p<0.001) lower levels of LDL C (mean, −10%), no difference in LDL C lowering response to pravastatin, and a non-significant 19% unadjusted and 9% adjusted decreased risk of vascular disease at baseline, with no on trial effect. Moreover 6.0% were carriers of the G allele at E670G with no significant relationships with baseline LDL C, response to pravastatin, or vascular disease risk being observed. Our data support the concept that the rare allele of the R46L SNP at the PCSK9 locus significantly lowers LDL C, but does not greatly reduce CHD risk in an elderly population with a high prevalence of cardiovascular disease.
doi:10.1016/j.atherosclerosis.2007.12.005
PMCID: PMC5489067  PMID: 18262190
Genetics; Statins; Low density lipoproteins (LDL); Coronary Heart Disease (CHD); Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9); Vascular Disease; Elderly
16.  HDL metabolism, composition, function and deficiency 
Current opinion in lipidology  2014;25(3):194-199.
Purpose of review
Our purpose was to examine recent advances in our knowledge of high density lipoprotein (HDL) metabolism, composition, function, and coronary heart disease (CHD), as well as marked HDL deficiency states due to mutations at the apolipoprotein (apo) A-I, ATP binding cassette transfer protein A1 (ABCA1), and lecithin cholesterol acyltransferase (LCAT) gene loci.
Recent findings
It has been documented that apoA-I, myeloperoxidase (MPO), and paraoxonase 1 (PON1) form a complex in HDL that is critical for HDL binding and function. MPO has a negative impact on HDL function, while PON1 has a beneficial effect. Patients that lack apoA-I develop markedly premature CHD. Patients that lack ABCA1 transporter function have only very small discoidal preβ-1 HDL, and develop hepatosplenomegaly, intermittent neuropathy and premature CHD, although significant heterogeneity for these disorders has been reported. Patients with LCAT deficiency have abnormal small discoidal low density lipoproteins and HDL particles, and develop kidney failure. Enzyme replacement therapy is being developed for the latter disorder.
Summary
Recent data indicates that proteins other than apoA-I and apoA-II such as MPO and PON1 have important effects on HDL function. There has been considerable recent progress made in our understanding of HDL protein content and function.
doi:10.1097/MOL.0000000000000074
PMCID: PMC5489068  PMID: 24785961
ABCA1; apoA-I; HDL; LCAT; MPO
17.  Effects of Atorvastatin on Human C Reactive Protein Metabolism 
Atherosclerosis  2012;226(2):466-470.
Objective
Statins are known to reduce plasma C-reactive protein (CRP) concentrations. Our goal was to define the mechanisms by which CRP was reduced by maximal dose atorvastatin.
Methods
Eight subjects with combined hyperlipidemia (5 men and 3 postmenopausal women) were enrolled in a randomized, placebo-controlled double-blind, cross over study. Subjects underwent a 15-hour primed-constant infusion with deuterated leucine after 8 weeks of placebo and 80 mg/day of atorvastatin. CRP was isolated from lipoprotein deficient plasma, (density >1.21 g/ml) by affinity chromatography. Isotopic enrichment was determined by gas chromatography/mass spectrometry. Kinetic parameters were determined using compartmental modeling. Paired t test and Wilcoxon signed ranks test were used to compare differences between placebo and atorvastatin.
Results
Compared with placebo, atorvastatin decreased median CRP pool size by 28.4% (13.31±3.78 vs 10.26±3.93 mg; p=0.16), associated with a median CRP fractional catabolic rate increase of 39.9% (0.34±0.06 vs 0.50±0.11 pools/day; p=0.09), with no significant effect on median CRP production rate (0.050±0.01 vs 0.049±0.01 mg/kg/day; p=0.78).
Conclusion
Our data indicate that maximal doses of atorvastatin lower plasma CRP levels by substantially decreasing the median CRP plasma residence time from 2.94 days to 2.0 days, with no significant effect on the median CRP production rate.
doi:10.1016/j.atherosclerosis.2012.11.012
PMCID: PMC5489069  PMID: 23218801
Atorvastatin; C-reactive protein; lipoprotein; metabolism
18.  Electrochemical Amplification in Side-by-Side Attoliter Nanogap Transducers 
ACS Sensors  2017;2(6):724-728.
We report a strategy for the fabrication of a new type of electrochemical nanogap transducer. These nanogap devices are based on signal amplification by redox cycling. Using two steps of electron-beam lithography, vertical gold electrodes are fabricated side by side at a 70 nm distance encompassing a 20 attoliter open nanogap volume. We demonstrate a current amplification factor of 2.5 as well as the possibility to detect the signal of only 60 analyte molecules occupying the detection volume. Experimental voltammetry results are compared to calculations from finite element analysis.
doi:10.1021/acssensors.7b00180
PMCID: PMC5485373
electrochemical sensor; generator-collector electrodes; nanofluidics; nanogap sensor; redox cycling; nanofabrication
19.  ICTV Virus Taxonomy Profile: Polyomaviridae 
The Journal of General Virology  2017;98(6):1159-1160.
The Polyomaviridae is a family of small, non-enveloped viruses with circular dsDNA genomes of approximately 5 kbp. The family includes four genera whose members have restricted host range, infecting mammals and birds. Polyomavirus genomes have also been detected recently in fish. Merkel cell polyomavirus and raccoon polyomavirus are associated with cancer in their host; other members are human and veterinary pathogens. Clinical manifestations are obvious in immunocompromised patients but not in healthy individuals. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Polyomaviridae, which is available at www.ictv.global/report/polyomaviridae.
doi:10.1099/jgv.0.000839
PMCID: PMC5656788  PMID: 28640744
Polyomaviridae; taxonomy; ICTV report; simian virus 40; budgerigar fledgling disease polyomavirus; Merkel cell polyomavirus; BK polyomavirus; JC polyomavirus
20.  Is multidetector CT-based bone mineral density and quantitative bone microstructure assessment at the spine still feasible using ultra-low tube current and sparse sampling? 
European Radiology  2017;27(12):5261-5271.
Objective
Osteoporosis diagnosis using multidetector CT (MDCT) is limited to relatively high radiation exposure. We investigated the effect of simulated ultra-low-dose protocols on in-vivo bone mineral density (BMD) and quantitative trabecular bone assessment.
Materials and methods
Institutional review board approval was obtained. Twelve subjects with osteoporotic vertebral fractures and 12 age- and gender-matched controls undergoing routine thoracic and abdominal MDCT were included (average effective dose: 10 mSv). Ultra-low radiation examinations were achieved by simulating lower tube currents and sparse samplings at 50%, 25% and 10% of the original dose. BMD and trabecular bone parameters were extracted in T10–L5.
Results
Except for BMD measurements in sparse sampling data, absolute values of all parameters derived from ultra-low-dose data were significantly different from those derived from original dose images (p<0.05). BMD, apparent bone fraction and trabecular thickness were still consistently lower in subjects with than in those without fractures (p<0.05).
Conclusion
In ultra-low-dose scans, BMD and microstructure parameters were able to differentiate subjects with and without vertebral fractures, suggesting osteoporosis diagnosis is feasible. However, absolute values differed from original values. BMD from sparse sampling appeared to be more robust. This dose-dependency of parameters should be considered for future clinical use.
Key Points
• BMD and quantitative bone parameters are assessable in ultra-low-dose in vivo MDCT scans.
• Bone mineral density does not change significantly when sparse sampling is applied.
• Quantitative trabecular bone microstructure measurements are sensitive to dose reduction.
• Osteoporosis subjects could be differentiated even at 10% of original dose.
• Radiation exposure should be considered when comparing quantitative bone parameters.
Electronic supplementary material
The online version of this article (doi:10.1007/s00330-017-4904-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s00330-017-4904-y
PMCID: PMC5674130  PMID: 28639046
Computed tomography; Radiation dose; Sparse sampling; Osteoporosis; Trabecular microstructure
21.  Validation of a Novel Immunoline Assay for Patient Stratification according to Virulence of the Infecting Helicobacter pylori Strain and Eradication Status 
Journal of Immunology Research  2017;2017:8394593.
Helicobacter pylori infection shows a worldwide prevalence of around 50%. However, only a minority of infected individuals develop clinical symptoms or diseases. The presence of H. pylori virulence factors, such as CagA and VacA, has been associated with disease development, but assessment of virulence factor presence requires gastric biopsies. Here, we evaluate the H. pylori recomLine test for risk stratification of infected patients by comparing the test score and immune recognition of type I or type II strains defined by the virulence factors CagA, VacA, GroEL, UreA, HcpC, and gGT with patient's disease status according to histology. Moreover, the immune responses of eradicated individuals from two different populations were analysed. Their immune response frequencies and intensities against all antigens except CagA declined below the detection limit. CagA was particularly long lasting in both independent populations. An isolated CagA band often represents past eradication with a likelihood of 88.7%. In addition, a high recomLine score was significantly associated with high-grade gastritis, atrophy, intestinal metaplasia, and gastric cancer. Thus, the recomLine is a sensitive and specific noninvasive test for detecting serum responses against H. pylori in actively infected and eradicated individuals. Moreover, it allows stratifying patients according to their disease state.
doi:10.1155/2017/8394593
PMCID: PMC5468576
22.  Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC 
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This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s} = 8$$\end{document}s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$30\;\upmu {\text {m}}$$\end{document}30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$20\;\upmu {\text {m}}$$\end{document}20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing.
doi:10.1140/epjc/s10052-017-4887-5
PMCID: PMC5586242
23.  Performance of the ATLAS trigger system in 2015 
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During 2015 the ATLAS experiment recorded \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$3.8\,{\mathrm{fb}}^{-1}$$\end{document}3.8fb-1 of proton–proton collision data at a centre-of-mass energy of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$13\,{\mathrm{TeV}}$$\end{document}13TeV. The ATLAS trigger system is a crucial component of the experiment, responsible for selecting events of interest at a recording rate of approximately 1 kHz from up to 40 MHz of collisions. This paper presents a short overview of the changes to the trigger and data acquisition systems during the first long shutdown of the LHC and shows the performance of the trigger system and its components based on the 2015 proton–proton collision data.
doi:10.1140/epjc/s10052-017-4852-3
PMCID: PMC5586243
24.  The NordICC Study: Rationale and design of a randomized trial on colonoscopy screening for colorectal cancer 
Endoscopy  2012;44(7):695-702.
Background
While colonoscopy screening is widely used in several European countries and the United States, no randomised trials exist to quantify its benefits. The Nordic-European Initiative on Colorectal Cancer (NordICC) is a multinational, randomized controlled trial aiming at investigating the effect of colonoscopy screening on CRC incidence and mortality. This paper describes the rationale and design of the NordICC trial.
Material and methods
Men and women age 55 to 64 years are drawn from the population registries in the participating countries and randomly assigned to either once-only colonoscopy screening with removal of all detected lesions, or no screening (standard of care in the trial regions). All individuals are followed for 15 years after inclusion using dedicated national registries.
Results
The primary endpoints of the trial are cumulative CRC-specific death and CRC incidence during 15 years of follow up. We hypothesize a 50% CRC mortality-reducing efficacy of the colonoscopy intervention and predict 50% compliance, yielding a 25% mortality reduction among those invited to screening. For 90% power and a two-sided alpha level of 0.05, using a 2:1 randomisation, 45,600 individuals will be randomised to control, and 22,800 individuals to the colonoscopy group. Interim analyses of the effect of colonoscopy on CRC incidence and mortality will be performed at 10 years follow-up.
Conclusions
The aim of the NordICC trial is to quantify the effectiveness of population-based colonoscopy screening. This will allow development of evidence-based guidelines for CRC screening in the general population.
doi:10.1055/s-0032-1306895
PMCID: PMC5435368  PMID: 22723185
colorectal cancer; screening; colonoscopy; mortality; incidence