HTTP 200 OK
Allow: GET, HEAD, OPTIONS
Content-Type: application/json
Vary: Accept
{
"count": 127182,
"next": "https://api-test.medunigraz.at/v1/research/search/publication/?format=api&limit=20&offset=127080",
"previous": "https://api-test.medunigraz.at/v1/research/search/publication/?format=api&limit=20&offset=127040",
"results": [
{
"text": "\n160763\nRelations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.\n\nZewinger, S\n\nKleber, ME\n\nTragante, V\n\nMcCubrey, RO\n\nSchmidt, AF\n\nDirek, K\n\nLaufs, U\n\nWerner, C\n\nKoenig, W\n\nRothenbacher, D\n\nMons, U\n\nBreitling, LP\n\nBrenner, H\n\nJennings, RT\n\nPetrakis, I\n\nTriem, S\n\nKlug, M\n\nFilips, A\n\nBlankenberg, S\n\nWaldeyer, C\n\nSinning, C\n\nSchnabel, RB\n\nLackner, KJ\n\nVlachopoulou, E\n\nNygård, O\n\nSvingen, GFT\n\nPedersen, ER\n\nTell, GS\n\nSinisalo, J\n\nNieminen, MS\n\nLaaksonen, R\n\nTrompet, S\n\nSmit, RAJ\n\nSattar, N\n\nJukema, JW\n\nGroesdonk, HV\n\nDelgado, G\n\nStojakovic, T\n\nPilbrow, AP\n\nCameron, VA\n\nRichards, AM\n\nDoughty, RN\n\nGong, Y\n\nCooper-DeHoff, R\n\nJohnson, J\n\nScholz, M\n\nBeutner, F\n\nThiery, J\n\nSmith, JG\n\nVilmundarson, RO\n\nMcPherson, R\n\nStewart, AFR\n\nCresci, S\n\nLenzini, PA\n\nSpertus, JA\n\nOlivieri, O\n\nGirelli, D\n\nMartinelli, NI\n\nLeiherer, A\n\nSaely, CH\n\nDrexel, H\n\nMündlein, A\n\nBraund, PS\n\nNelson, CP\n\nSamani, NJ\n\nKofink, D\n\nHoefer, IE\n\nPasterkamp, G\n\nQuyyumi, AA\n\nKo, YA\n\nHartiala, JA\n\nAllayee, H\n\nTang, WHW\n\nHazen, SL\n\nEriksson, N\n\nHeld, C\n\nHagström, E\n\nWallentin, L\n\nÅkerblom, A\n\nSiegbahn, A\n\nKarp, I\n\nLabos, C\n\nPilote, L\n\nEngert, JC\n\nBrophy, JM\n\nThanassoulis, G\n\nBogaty, P\n\nSzczeklik, W\n\nKaczor, M\n\nSanak, M\n\nVirani, SS\n\nBallantyne, CM\n\nLee, VV\n\nBoerwinkle, E\n\nHolmes, MV\n\nHorne, BD\n\nHingorani, A\n\nAsselbergs, FW\n\nPatel, RS\n\nGENIUS-CHD consortium\n\nKrämer, BK\n\nScharnagl, H\n\nFliser, D\n\nMärz, W\n\nSpeer, T\n\nBeiträge in Fachzeitschriften\nISI:000403672400019\n28566218.0\n10.1016/S2213-8587(17)30096-7\nPMC5651679\nLipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.\n We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.\n The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies.\n In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.\n Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.\n Copyright © 2017 Elsevier Ltd. All rights reserved.\n\nMärz, Winfried\n\nScharnagl, Hubert\n\n\n"
},
{
"text": "\n169166\nMulti-ethnic genome-wide association study for atrial fibrillation.\n\nRoselli, C\n\nChaffin, MD\n\nWeng, LC\n\nAeschbacher, S\n\nAhlberg, G\n\nAlbert, CM\n\nAlmgren, P\n\nAlonso, A\n\nAnderson, CD\n\nAragam, KG\n\nArking, DE\n\nBarnard, J\n\nBartz, TM\n\nBenjamin, EJ\n\nBihlmeyer, NA\n\nBis, JC\n\nBloom, HL\n\nBoerwinkle, E\n\nBottinger, EB\n\nBrody, JA\n\nCalkins, H\n\nCampbell, A\n\nCappola, TP\n\nCarlquist, J\n\nChasman, DI\n\nChen, LY\n\nChen, YI\n\nChoi, EK\n\nChoi, SH\n\nChristophersen, IE\n\nChung, MK\n\nCole, JW\n\nConen, D\n\nCook, J\n\nCrijns, HJ\n\nCutler, MJ\n\nDamrauer, SM\n\nDaniels, BR\n\nDarbar, D\n\nDelgado, G\n\nDenny, JC\n\nDichgans, M\n\nDörr, M\n\nDudink, EA\n\nDudley, SC\n\nEsa, N\n\nEsko, T\n\nEskola, M\n\nFatkin, D\n\nFelix, SB\n\nFord, I\n\nFranco, OH\n\nGeelhoed, B\n\nGrewal, RP\n\nGudnason, V\n\nGuo, X\n\nGupta, N\n\nGustafsson, S\n\nGutmann, R\n\nHamsten, A\n\nHarris, TB\n\nHayward, C\n\nHeckbert, SR\n\nHernesniemi, J\n\nHocking, LJ\n\nHofman, A\n\nHorimoto, ARVR\n\nHuang, J\n\nHuang, PL\n\nHuffman, J\n\nIngelsson, E\n\nIpek, EG\n\nIto, K\n\nJimenez-Conde, J\n\nJohnson, R\n\nJukema, JW\n\nKääb, S\n\nKähönen, M\n\nKamatani, Y\n\nKane, JP\n\nKastrati, A\n\nKathiresan, S\n\nKatschnig-Winter, P\n\nKavousi, M\n\nKessler, T\n\nKietselaer, BL\n\nKirchhof, P\n\nKleber, ME\n\nKnight, S\n\nKrieger, JE\n\nKubo, M\n\nLauner, LJ\n\nLaurikka, J\n\nLehtimäki, T\n\nLeineweber, K\n\nLemaitre, RN\n\nLi, M\n\nLim, HE\n\nLin, HJ\n\nLin, H\n\nLind, L\n\nLindgren, CM\n\nLokki, ML\n\nLondon, B\n\nLoos, RJF\n\nLow, SK\n\nLu, Y\n\nLyytikäinen, LP\n\nMacfarlane, PW\n\nMagnusson, PK\n\nMahajan, A\n\nMalik, R\n\nMansur, AJ\n\nMarcus, GM\n\nMargolin, L\n\nMargulies, KB\n\nMärz, W\n\nMcManus, DD\n\nMelander, O\n\nMohanty, S\n\nMontgomery, JA\n\nMorley, MP\n\nMorris, AP\n\nMüller-Nurasyid, M\n\nNatale, A\n\nNazarian, S\n\nNeumann, B\n\nNewton-Cheh, C\n\nNiemeijer, MN\n\nNikus, K\n\nNilsson, P\n\nNoordam, R\n\nOellers, H\n\nOlesen, MS\n\nOrho-Melander, M\n\nPadmanabhan, S\n\nPak, HN\n\nParé, G\n\nPedersen, NL\n\nPera, J\n\nPereira, A\n\nPorteous, D\n\nPsaty, BM\n\nPulit, SL\n\nPullinger, CR\n\nRader, DJ\n\nRefsgaard, L\n\nRibasés, M\n\nRidker, PM\n\nRienstra, M\n\nRisch, L\n\nRoden, DM\n\nRosand, J\n\nRosenberg, MA\n\nRost, N\n\nRotter, JI\n\nSaba, S\n\nSandhu, RK\n\nSchnabel, RB\n\nSchramm, K\n\nSchunkert, H\n\nSchurman, C\n\nScott, SA\n\nSeppälä, I\n\nShaffer, C\n\nShah, S\n\nShalaby, AA\n\nShim, J\n\nShoemaker, MB\n\nSiland, JE\n\nSinisalo, J\n\nSinner, MF\n\nSlowik, A\n\nSmith, AV\n\nSmith, BH\n\nSmith, JG\n\nSmith, JD\n\nSmith, NL\n\nSoliman, EZ\n\nSotoodehnia, N\n\nStricker, BH\n\nSun, A\n\nSun, H\n\nSvendsen, JH\n\nTanaka, T\n\nTanriverdi, K\n\nTaylor, KD\n\nTeder-Laving, M\n\nTeumer, A\n\nThériault, S\n\nTrompet, S\n\nTucker, NR\n\nTveit, A\n\nUitterlinden, AG\n\nVan Der Harst, P\n\nVan Gelder, IC\n\nVan Wagoner, DR\n\nVerweij, N\n\nVlachopoulou, E\n\nVölker, U\n\nWang, B\n\nWeeke, PE\n\nWeijs, B\n\nWeiss, R\n\nWeiss, S\n\nWells, QS\n\nWiggins, KL\n\nWong, JA\n\nWoo, D\n\nWorrall, BB\n\nYang, PS\n\nYao, J\n\nYoneda, ZT\n\nZeller, T\n\nZeng, L\n\nLubitz, SA\n\nLunetta, KL\n\nEllinor, PT\n\nBeiträge in Fachzeitschriften\nISI:000443151300012\n29892015.0\n10.1038/s41588-018-0133-9\nPMC6136836\nAtrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65, 46 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.\n\nKatschnig-Winter, Petra\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n131553\nMultiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.\n\nSabater-Lleal, M\n\nHuang, J\n\nChasman, D\n\nNaitza, S\n\nDehghan, A\n\nJohnson, AD\n\nTeumer, A\n\nReiner, AP\n\nFolkersen, L\n\nBasu, S\n\nRudnicka, AR\n\nTrompet, S\n\nMälarstig, A\n\nBaumert, J\n\nBis, JC\n\nGuo, X\n\nHottenga, JJ\n\nShin, SY\n\nLopez, LM\n\nLahti, J\n\nTanaka, T\n\nYanek, LR\n\nOudot-Mellakh, T\n\nWilson, JF\n\nNavarro, P\n\nHuffman, JE\n\nZemunik, T\n\nRedline, S\n\nMehra, R\n\nPulanic, D\n\nRudan, I\n\nWright, AF\n\nKolcic, I\n\nPolasek, O\n\nWild, SH\n\nCampbell, H\n\nCurb, JD\n\nWallace, R\n\nLiu, S\n\nEaton, CB\n\nBecker, DM\n\nBecker, LC\n\nBandinelli, S\n\nRäikkönen, K\n\nWiden, E\n\nPalotie, A\n\nFornage, M\n\nGreen, D\n\nGross, M\n\nDavies, G\n\nHarris, SE\n\nLiewald, DC\n\nStarr, JM\n\nWilliams, FM\n\nGrant, PJ\n\nSpector, TD\n\nStrawbridge, RJ\n\nSilveira, A\n\nSennblad, B\n\nRivadeneira, F\n\nUitterlinden, AG\n\nFranco, OH\n\nHofman, A\n\nvan Dongen, J\n\nWillemsen, G\n\nBoomsma, DI\n\nYao, J\n\nSwords Jenny, N\n\nHaritunians, T\n\nMcKnight, B\n\nLumley, T\n\nTaylor, KD\n\nRotter, JI\n\nPsaty, BM\n\nPeters, A\n\nGieger, C\n\nIllig, T\n\nGrotevendt, A\n\nHomuth, G\n\nVölzke, H\n\nKocher, T\n\nGoel, A\n\nFranzosi, MG\n\nSeedorf, U\n\nClarke, R\n\nSteri, M\n\nTarasov, KV\n\nSanna, S\n\nSchlessinger, D\n\nStott, DJ\n\nSattar, N\n\nBuckley, BM\n\nRumley, A\n\nLowe, GD\n\nMcArdle, WL\n\nChen, MH\n\nTofler, GH\n\nSong, J\n\nBoerwinkle, E\n\nFolsom, AR\n\nRose, LM\n\nFranco-Cereceda, A\n\nTeichert, M\n\nIkram, MA\n\nMosley, TH\n\nBevan, S\n\nDichgans, M\n\nRothwell, PM\n\nSudlow, CL\n\nHopewell, JC\n\nChambers, JC\n\nSaleheen, D\n\nKooner, JS\n\nDanesh, J\n\nNelson, CP\n\nErdmann, J\n\nReilly, MP\n\nKathiresan, S\n\nSchunkert, H\n\nMorange, PE\n\nFerrucci, L\n\nEriksson, JG\n\nJacobs, D\n\nDeary, IJ\n\nSoranzo, N\n\nWitteman, JC\n\nde Geus, EJ\n\nTracy, RP\n\nHayward, C\n\nKoenig, W\n\nCucca, F\n\nJukema, JW\n\nEriksson, P\n\nSeshadri, S\n\nMarkus, HS\n\nWatkins, H\n\nSamani, NJ\n\nVTE Consortium\n\nSTROKE Consortium\n\nWellcome Trust Case Control Consortium 2 (WTCCC2)\n\nC4D Consortium\n\nCARDIoGRAM Consortium\n\nWallaschofski, H\n\nSmith, NL\n\nTregouet, D\n\nRidker, PM\n\nTang, W\n\nStrachan, DP\n\nHamsten, A\n\nO'Donnell, CJ\n\nBeiträge in Fachzeitschriften\nISI:000324477900015\n23969696.0\n10.1161/CIRCULATIONAHA.113.002251\nPMC3842025\nBackground Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. Methods and Results We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5x10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.\n\n\n"
},
{
"text": "\n182219\nAccuracy of mobile digital teledermoscopy for skin self-examinations in adults at high risk of skin cancer: an open-label, randomised controlled trial.\n\nJanda, M\n\nHorsham, C\n\nVagenas, D\n\nLoescher, LJ\n\nGillespie, N\n\nKoh, U\n\nCuriel-Lewandrowski, C\n\nHofmann-Wellenhof, R\n\nHalpern, A\n\nWhiteman, DC\n\nWhitty, JA\n\nSmithers, BM\n\nSoyer, HP\n\nBeiträge in Fachzeitschriften\nISI:000525882100010\nNone\n10.1016/S2589-7500(20)30001-7\nNone\nBackground Skin self-examinations supplemented with mobile teledermoscopy might improve early detection of skin cancers compared with naked-eye skin self-examinations. We aimed to assess whether mobile teledermoscopy-enhanced skin self-examination can improve sensitivity and specificity of self-detection of skin cancers when compared with naked-eye skin self-examination. Methods This randomised, controlled trial was done in Brisbane (QLD, Australia). Eligible participants (aged >= 18 years) had at least two skin cancer risk factors as self-reported in the eligibility survey and had to own or have access to an iPhone compatible with a dermatoscope attachment (iPhone versions 5-8). Participants were randomly assigned (1:1), via a computer-generated randomisation procedure, to the intervention group (mobile dermoscopy-enhanced self-skin examination) or the control group (naked-eye skin self-examination). Control group and intervention group participants received web-based instructions on how to complete a whole body skin self-examination. All participants completed skin examinations at baseline, 1 month, and 2 months; intervention group participants submitted photographs of suspicious lesions to a dermatologist for telediagnosis after each skin examination and control group participants noted lesions on a body chart that was sent to the research team after each skin examination. All participants had an in-person whole-body clinical skin examination within 3 months of their last skin self-examination. Primary outcomes were sensitivity and specificity of skin self-examination, patient selection of clinically atypical lesions suspicious for melanoma or keratinocyte skin cancers (body sites examined, number of lesions photographed, types of lesions, and lesions missed), and diagnostic concordance of telediagnosis versus in-person whole-body clinical skin examination diagnosis. All primary outcomes were analysed in the modified intention-to-treat population, which included all patients who had a clinical skin examination within 3 months of their last skin self-examination. This trial was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12616000989448. Findings Between March 6, 2017, and June 7, 2018, 234 participants consented to enrol in the study, of whom 116 (50%) were assigned to the intervention group and 118 (50%) were assigned to the control group. 199 participants (98 participants in the intervention group and 101 participants in the control group) attended the clinical skin examination and thus were eligible for analyses. Participants in the intervention group submitted 615 lesions (median 6.0 per person; range 1-24) for telediagnosis and participants in the control group identified and recorded 673 lesions (median 6.0 per person; range 1-16). At the lesion level, sensitivity for lesions clinically suspicious for skin cancer was 75% (95% CI 63-84) in the intervention group and 88% (95% CI 80-91) in the control group (p=0.04). Specificity was 87% (95% CI 85-90) in the intervention group and 89% (95% CI 87-91) in the control group (p=0.42). At the individual level, the intervention group had a sensitivity of 87% (95% CI 76-99) compared with 97% (95% CI 91-100) in the control group (p=0.26), and a specificity of 95% (95% CI 90-100) compared with 96% (95% CI 91-100) in the control group. The overall diagnostic concordance between the telediagnosis and in-person clinical skin examination was 88%. Interpretation The use of mobile teledermoscopy did not increase sensitivity for the detection of skin cancers compared with naked-eye skin self-examination; thus, further evidence is necessary for inclusion of skin self-examination technology for public health benefit. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.\n\nHofmann-Wellenhof, Rainer\n\n\n"
},
{
"text": "\n90182\nPharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation.\n\nPetrides, PE\n\nGisslinger, H\n\nSteurer, M\n\nLinkesch, W\n\nKrumpl, G\n\nSchuller, A\n\nWidmann, R\n\nBeiträge in Fachzeitschriften\nISI:000264310400016\n19302911.0\n10.1016/j.clinthera.2009.02.008\nNone\nBackground: Anagrelide hydrochloride is an \nanti-thrombotic agent indicated for the treatment of essential thrombocythemia (ET). In various previously published clinical trials of 2 branded formulations of anagrelide in patients with \nET at high risk for thrombohemorrhagic events, the rates of adverse events and discontinuation were strikingly divergent between brands. Because the formulations and manufacturers differed, \nthe differences in tolerability, as well as platelet counts, might have been related to differences in pharmacokinetic properties between the 2 formulations. Objectives: The present series of \ninvestigations (1) determined the pharmacokinetic profile of anagrelide and its metabolites; (2) compared the pharmacokinetic profiles of the test and reference formulations of anagrelide; (3) \ninvestigated the in vitro release of anagrelide as a marker of intragastric anagrelide release of the test and reference formulations; and (4) compared the platelet-reducing effects of the test \nand reference formulations in patients with thrombocythemia in 2 longitudinal studies over 4 weeks. Methods: A series of 4 in vivo studies and 1 in vitro study were conducted. In a pilot, \nprospective, single-dose study in healthy volunteers, the pharmacokinetic properties (C-max, T-max, and AUC(0-infinity)) of a test formulation of anagrelide were assessed using high-performance \nliquid chromatography analysis of plasma samples. Based on the results from that study, a single-dose, randomized, double-blind, 2-period crossover study in healthy volunteers was conducted to \ndetermine bioequivalence of 2 formulations of anagrelide 2 mg/d (taken as 4 capsules). In vitro dissolution properties of the test or reference formulation containing 0.5 mg anagrelide as the \nactive ingredient were studied in an assay mimicking gastrointestinal release. To test for effects on platelet counts of switching from the reference formulation (previous treatment on stable \ndose for 3 months) to the test formulation, two 4-week longitudinal trials were conducted: one in patients with ET (in Germany), and one in patients with thrombocythemia associated with \nchronic myeloproliferative disorders (CMPDs) (in Austria). Results: The pilot pharmacokinetic study of the test formulation in 1.6 volunteers (10 women, 6 men; mean [SD] age, 20.5 [1.5] years; \nweight, 69.0 [10.0 kg) suggested that anagrelide was metabolized to 3-hydroxyanagreide (AUC(0-infinity) 50% compared with anagrelide) and the inactive metabolite 2-amino-5, -dichloro-, \n4-dihydroquinazolone. The subsequent bioequivalence study in 24 volunteers found that the test formulation was associated with a significantly lower C-max and AUC(0-infinity). Values for \nanagrelide and 3-hydroxyanagrelide were 1 hour longer with the rest formulation compared with the reference formulation. The total number of adverse events with the reference formulation was 46; \nthe test formulation, 29 (P = 0.05). In vitro, anagrelide from the reference formulation was immediately released, whereas there was a delayed release from the test formulation (P < 0.05). \nIn the last 2 studies, 2 cohorts of white patients who had received treatment for >= 3 months with the reference formulation were switched to the same dose of the test formulation and maintained on this dose for 4 weeks. Platelet Counts did not change significantly from baseline over 4 weeks and stayed within a predefined margin of 150 x 10(3) cells/mu L Conclusions: The pharmacokinetic properties, adverse event rates, and in vitro dissolution profile differed between the test and reference anagrelide formulations in these healthy volunteers. In patients with ET or thrombocythemia associated with CMPD, platelet counts did not differ significantly from baseline at 4 weeks when Subjects were switched from the reference to the test anagrelide formulation. (Clin Ther. 2009;31:386-398) (C) 2009 Excerpta Medica Inc.\n\n\n"
},
{
"text": "\n892\nEvidence for the participation of glutamate in reflexes involving afferent, substance P-containing nerve fibres in the rat.\n\nJuránek, I\n\nLembeck, F\n\nBeiträge in Fachzeitschriften\nISI:A1996TY67400011\n8825345.0\n10.1111/j.1476-5381.1996.tb15156.x\nPMC1909381\n1. Responses mediated, either peripherally or centrally, by substance P-containing primary afferent C-fibres were investigated in the rat following impairment of axonal transport by colchicine (120 micrograms kg-1, i.p., daily for 3 days), and after treatment with the tachykinin antagonist SR-140333 (10-100 micrograms kg-1, i.v.) or the N-methyl-D-aspartate (NMDA) antagonist MK-801 (100 micrograms kg-1). 2. Peripheral effects mediated by afferent C-fibres were measured by plasma protein extravasation (Evans blue method), following antidromic stimulation of the sciatic nerve, topical application of mustard oil and, as control, i.v. injection of substance P. SR-140333 (100 micrograms kg-1) reduced the effects by 86%, 75% and 74%, respectively. Colchicine reduced the effects of the first two stimuli by 31% and 33% and, as expected not the effect of substance P. The increase of paw skin temperature following capsaicin i.v. was inhibited by SR-140333, but not by colchicine. MK-801 had no effect on the plasma protein extravasation following antidromic sciatic nerve stimulation or on the rise of paw skin temperature induced by capsaicin i.v., thus excluding an effect of MK-801 on peripheral terminals of afferent neurones. 3. Depressor reflexes, which are known to be mediated by capsaicin-sensitive afferent neuones, such as those elicited (A) by a stimulating dose of 30 ng capsaicin i.a., (B) by distension of the ascending colon or (C) by afferent sciatic nerve stimulation were studied. Colchicine significantly reduced depressor reflexes A and B, but had no effect on reflex C. None of the reflexes was affected by SR-140333. MK-801 significantly inhibited all three reflexes. 4. Capsaicin, injected either i.v. (200 micrograms kg-1) or into the nucleus caudatus/putamen (i.c., 30 micrograms), induced an increase in paw skin temperature and a decrease in colon temperature. The rise in fore paw skin temperature (delta t = 2.3 +/- 0.4 degrees C) evoked by capsaicin i.v. was almost completely blocked by SR-140333 (100 micrograms kg-1, i.v.), but no inhibition was observed with MK-801, indicating that capsaicin had brought about a release of substance P from peripheral nerve terminals. Colchicine did not influence heat dissipation induced by i.v. capsaicin. 5. When capsaicin was injected i.c., the rise in paw skin temperature in colchicine- and SR-140333-pretreated groups did not differ from that of the control group. MK-801 totally prevented the heat loss reaction to i.c. capsaicin administration. Colchicine did not change the effects of i.v. or i.c. injected capsaicin: this excludes the involvement of a mechanism dependent on axonal transport of neurotransmitters. 6. The reduction of axonal transport by colchicine reduced plasma extravasation induced by mustard oil and antidromic sciatic nerve stimulation (peripheral functions) and depressor reflexes evoked by i.a. capsaicin and colon distension (central functions). It can be argued that afferent stimulation of the sciatic nerve includes the stimulation of A-fibres, which might be less sensitive to colchicine. SR-140333 was effective only on peripherally mediated responses. 7. The recent evidence for the concomitant release of glutamate and substance P from central terminals of afferent C-fibres, known to mediate reflexes abolished after capsaicin treatment allows the following conclusions: (a) the inhibition by MK-801 indicates an essential role for glutamate in the central transmission of these reflexes; (b) tachykinin antagonists such as SR-140333 do not affect these responses when administered systemically. Centrally released substance P could be involved in functions of the CNS other than those investigated here unless the access of neurokinin antagonists to their receptors in the CNS is insufficient.\n\n\n"
},
{
"text": "\n174809\nSurgical outcomes of patients with diffuse-type tenosynovial giant-cell tumours: an international, retrospective, cohort study.\n\nMastboom, MJL\n\nPalmerini, E\n\nVerspoor, FGM\n\nRueten-Budde, AJ\n\nStacchiotti, S\n\nStaals, EL\n\nSchaap, GR\n\nJutte, PC\n\nAston, W\n\nGelderblom, H\n\nLeithner, A\n\nDammerer, D\n\nTakeuchi, A\n\nThio, Q\n\nNiu, X\n\nWunder, JS\n\nTGCT Study Group\n\nvan de Sande, MAJ\n\nBeiträge in Fachzeitschriften\nISI:000469336000055\n31029509.0\n10.1016/S1470-2045(19)30100-7\nNone\nDiffuse-type tenosynovial giant-cell tumour is a rare, locally aggressive, and difficult-to-treat soft tissue tumour. Clinical and surgical outcomes depend on multiple factors, including preoperative diagnostic assessment, the localisation and extent of disease, and possibly the choice of treatment modalities by orthopaedic surgeons. We did a retrospective cohort study to characterise global surgical treatment protocols, and assess surgical outcomes, complications, and functional results in patients with diffuse-type tenosynovial giant-cell tumours.\n In this international, multicentre, retrospective cohort study, we included consecutive patients treated in 31 sarcoma reference centres between Jan 1, 1990, and Dec 31, 2017. Eligible patients were of any age and had histologically proven diffuse-type tenosynovial giant-cell tumour of large joints. Patient data were retrieved from the local databases of participating centres. Patients with localised-type tenosynovial giant-cell tumour were excluded. In the analysis, we only included patients with complete core criteria data regarding admission status, date of treatment, type of treatment at participating centre, and first local recurrence after treatment. We used a non-parametric method to estimate recurrence-free survival at 3, 5, and 10 years after initial surgical resection in a tertiary centre. We used a multivariate Cox regression model to estimate the effect of risk factors. We also present subgroup analyses of disease status at presentation (primary vs recurrent disease) and recurrence-free survival by surgery type (open surgery vs arthroscopic synovectomy), and prespecified risk factors were tested in a univariate and multivariable analyses, with an endpoint of first local recurrence after treatment in a tertiary centre.\n Data collection for these analyses occurred between January, 2016, and May, 2018. We received the records of 1192 patients, of which 966 (81%) were surgically treated and had complete information on core criteria. 445 patients were admitted with therapy-naive disease of the knee and were primarily treated in a tertiary centre. Since patients with wait and see treatment do not have a starting date of treatment, these patients were excluded in the calculation of median follow-up time for all patients. For this calculation we used time of surgery as a starting date. 758 (64%) of 1192 patients had knee involvement and 628 (54%) of 1163 patients with complete data on type of surgery had one-staged open synovectomy. At a median follow-up of 54 months (IQR 27-97), recurrent disease developed in 425 (44%) of all 966 surgically treated cases, and recurrence-free survival was 62% (95% CI 59-65) at 3 years, 55% (51-58) at 5 years, and 40% (35-45) at 10 years. Surgical complications were reported in 105 (12%) of 906 patients who had complete data on surgical complications. Pain improved after surgical treatment in 255 (59%) of 434 patients and swelling improved in 328 (72%) of 453 patients who had complete data.\n This study of patients with diffuse-type tenosynovial giant-cell tumour provides a comprehensive and up-to-date disease overview, assessing the clinical profile and management of the disease in multiple specialised referral centres. Surgical treatment of diffuse-type tenosynovial giant cell tumours is not a definitive treatment for every patient because it involves a high risk for local recurrent disease and a relatively high risk for postoperative complications. After surgical treatment in treatment-naive patients, risk factors for recurrent disease in individual patients were not identified in what we believe is the largest cohort to date.\n Daiichi Sankyo.\n Copyright © 2019 Elsevier Ltd. All rights reserved.\n\nLeithner, Andreas\n\n\n"
},
{
"text": "\n186471\nLong-term effects of weight-reducing diets in people with hypertension.\n\nSemlitsch, T\n\nKrenn, C\n\nJeitler, K\n\nBerghold, A\n\nHorvath, K\n\nSiebenhofer, A\n\nBeiträge in Fachzeitschriften\nISI:000624575100038\n33555049.0\n10.1002/14651858.CD008274.pub4\nNone\nAll major guidelines for antihypertensive therapy recommend weight loss. Dietary interventions that aim to reduce body weight might therefore be a useful intervention to reduce blood pressure and adverse cardiovascular events associated with hypertension.\n Primary objectives To assess the long-term effects of weight-reducing diets in people with hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events). Secondary objectives To assess the long-term effects of weight-reducing diets in people with hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction.\n For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to April 2020: the Cochrane Hypertension Specialised Register, CENTRAL (2020, Issue 3), Ovid MEDLINE, Ovid Embase, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.\n We included randomised controlled trials (RCTs) of at least 24 weeks' duration that compared weight-reducing dietary interventions to no dietary intervention in adults with primary hypertension.\n Two review authors independently assessed risks of bias and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. In case of moderate or larger heterogeneity as measured by Higgins I2, we used a random-effects model.\n This second review update did not reveal any new trials, so the number of included trials remains the same: eight RCTs involving a total of 2100 participants with high blood pressure and a mean age of 45 to 66 years. Mean treatment duration was 6 to 36 months. We judged the risks of bias as unclear or high for all but two trials. No study included mortality as a predefined outcome. One RCT evaluated the effects of dietary weight loss on a combined endpoint consisting of the necessity of reinstating antihypertensive therapy and severe cardiovascular complications. In this RCT, weight-reducing diet lowered the endpoint compared to no diet: hazard ratio 0.70 (95% confidence interval (CI) 0.57 to 0.87). None of the trials evaluated adverse events as designated in our protocol. The certainty of the evidence was low for a blood pressure reduction in participants assigned to weight-loss diets as compared to controls: systolic blood pressure: mean difference (MD) -4.5 mm Hg (95% CI -7.2 to -1.8 mm Hg) (3 studies, 731 participants), and diastolic blood pressure: MD -3.2 mm Hg (95% CI -4.8 to -1.5 mm Hg) (3 studies, 731 participants). We judged the certainty of the evidence to be high for weight reduction in dietary weight loss groups as compared to controls: MD -4.0 kg (95% CI -4.8 to -3.2) (5 trials, 880 participants). Two trials used withdrawal of antihypertensive medication as their primary outcome. Even though we did not consider this a relevant outcome for our review, the results of these RCTs strengthen the finding of a reduction of blood pressure by dietary weight-loss interventions.\n In this second update, the conclusions remain unchanged, as we found no new trials. In people with primary hypertension, weight-loss diets reduced body weight and blood pressure, but the magnitude of the effects are uncertain due to the small number of participants and studies included in the analyses. Whether weight loss reduces mortality and morbidity is unknown. No useful information on adverse effects was reported in the relevant trials.\n Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n\nBerghold, Andrea\n\nHorvath, Karl\n\nJeitler, Klaus\n\nKrenn, Cornelia\n\nSemlitsch, Thomas\n\nSiebenhofer-Kroitzsch, Andrea\n\n\n"
},
{
"text": "\n3191\nSpecial aspects of insulin therapy in pregnancies complicated by gestational diabetes mellitus (GDM)\n\nWeiss, PAM\n\nWalcher, W\n\nScholz, HS\n\nBeiträge in Fachzeitschriften\nISI:000088480900005\nNone\n10.1055/s-2000-7386\nNone\nObjective: In pregnancies complicated by gestational diabetes mellitus (GDM) about 10-20% of fetuses develop hyperinsulinism. Aggressive insulin therapy is required to avoid early and late complications for fetal hyperinsulinism in these offspring. There is no universally agreed upon indication for insulin therapy. The indication for insulin can be based on maternal parameters, such as fasting blood glucose, postprandial blood glucose or mean blood glucose (MBG) values. It can also be initiated prophylactically or be based on fetal parameters, such as macrosomia or elevated amniotic fluid insulin.Methods: Suggested maternal glucose limits For the indication of insulin therapy are 95 - 105 mg/dl (5.3 - 5.8 mmol/l) for fasting blood glucose, 120 - 130 mg/dl (6.7 - 7.2 mmol/l) for postprandial blood glucose, and 90 - 108 mg/dl (5 - 6 mmol/l) for MBG. Prophylactic insulin therapy is administered independently of maternal glycemia. Macrosomia has been defined as the 75th percentile of fetal abdominal circumference; the upper limit of normal amniotic fluid insulin is 8 mu U/ml (48 pmol/l). Maternal glycemia correlates poorly with fetal hyperinsulinism because of individual variations in placental transport and the placentas barrier function. Accordingly, the materno-fetal glucose gradient can vary widely. Additionally, the fetal islet organs vary widely in sensitivity to glucose stimuli.Results: After the 31st gestational week hyperinsulinemic fetuses syphon off maternal glucose and thus reduce maternal postprandial glucose levels by 20 mg/dl (1.1 mmol/l) on average. Consequently, it cannot be distinguished whether maternal euglycemia is a result of normal glucose tolerance, adequate treatment, or the fetoplacental glucose steal phenomenon. A policy of prophylactic insulin treatment of all pregnancies complicated by GDM would overtreat the 80 - 90% of fetuses who are normoinsulinemic. A policy based on sonographic criteria of macrosomia would treat only the hyperinsulinemic fetuses who are also macrosomic, as well as large but normoinsulinemic fetuses. Also, hyperinsulinism precedes macrosomia by weeks or months so that insulin treatment is late. Insulin treatment based on measurement of insulin levels in the amniotic fluid avoids undertreatment and overtreatment. Complications of amniocentesis are negligible but patient acceptance is only 80 - 90%. We analyzed the extent of undertreatment and overtreatment with the fetus as a sensor in 542 GDM with known amniotic fluid insulin levels.Conclusions: Assuming that insulin therapy is only necessary in GDM with fetal hyperinsulinism, no undertreatment ensues from prophylactic insulin therapy or from insulin treatment based on amniotic fluid insulin levels. At a MBG of 90 - 108 mg/dl or estimating the 75th weight percentile for indication, undertreatment results in 16 - 58% or 44%, respectively. Insulin treatment based on a MBG of 90 - 108 mg/dl, the 75th weight percentile and prophylactic insulin therapy lead to overtreatment in 75 - 18%, > 25% and 100% of normoinsulinemic cases, respectively. The problem is undertreatment because preventable sequelae, such as premature births, cesarean deliveries and diabetes in the adolescent ensue from untreated fetal hyperinsulinism. Consequently a policy of insulin treatment for patients with a MBG greater than or equal to 108 mg/dl (greater than or equal to 6 mmol/l) leads to costs eight times higher than those of overtreatment with prophylactic insulin. Due to insulin resistance, insulin requirements in GDM are high. Moreover, insulin administration reduces the mother's own insulin secretion by 30 U/24 h. Consequently the insulin requirement needed to overcome insulin resistance, the reduction of maternal insulin synthesis, and fetal hyperinsulinism is 0.8 - 1.2 U/24 h. Because maternal postprandial insulin secretion is delayed in GDM, insulin administration at the main meals is essential to prevent postprandial hyperglycemia. Consequently, a basal-bolus schema is appropriate. Administration of human insulin is preferable in order to prevent development of insulin antibodies.\n\nWalcher, Wolfgang\n\n\n"
},
{
"text": "\n167825\nMechanical response of human subclavian and iliac arteries to extension, inflation and torsion.\n\nSommer, G\n\nBenedikt, C\n\nNiestrawska, JA\n\nHohenberger, G\n\nViertler, C\n\nRegitnig, P\n\nCohnert, TU\n\nHolzapfel, GA\n\nBeiträge in Fachzeitschriften\nISI:000440125600020\n29859367.0\n10.1016/j.actbio.2018.05.043\nNone\nPeripheral vascular trauma due to injuries of the upper and lower limbs are life-threatening, and their treatment require rapid diagnosis and highly-qualified surgical procedures. Experienced surgeons have recognized that subclavian arteries, affected by injuries of the upper limbs, require a more careful handling due to fragility than common iliac arteries, which are may be affected by injures of the lower limbs. We investigated these two artery types with comparable diameter to evaluate the differences in the biomechanical properties between subclavian and iliac arteries. Human subclavian and common iliac arteries of 14 donors either from the right or the left side (age: 63 yrs, SD: 19, female and 5 male) were investigated. Extension-inflation-torsion experiments at different axial strains (0-20%), transmural pressures (0-200 mmHg) and torsion (±25°) on preconditioned arterial tubes were performed. Residual stresses in both circumferential and axial direction were determined. Additionally, the microstructure of the tissues was determined via second-harmonic generation imaging and by histological investigations. At physiological conditions (pi=13.3 kPa, λz=1.1) common iliac arteries revealed higher Cauchy stresses in circumferential and axial directions but a more compliant response in the circumferential direction than subclavian arteries. Both arteries showed distinct stiffer behavior in circumferential than in axial direction. Circumferential stiffness of common iliac arteries at physiological conditions increased significantly with aging (r=-0.67, =0.02). The median inversion stretches, where the axial force is basically independent of the transmural pressure, were determined to be 1.05 for subclavian arteries and 1.11 for common iliac arteries. Both arteries exhibited increased torsional stiffness, when either axial prestretch or inflation pressure was increased. Residual stresses in the circumferential direction were significantly lower for subclavian arteries than for common iliac arteries at measurements after 30 min (p=0.05) and 16hrs (p=0.01). Investigations of the collagen microstructure revealed different collagen fiber orientations and dispersions in subclavian and iliac arteries. The difference in the collagen microstructure revealed further that the adventitia seems to contribute significantly to the passive mechanical response of the tested arteries at physiological loadings. Histological investigations indicated pronounced thickened intimal layers in subclavian and common iliac arteries, with a thickness comparable to the adventitial layer. In conclusion, we obtained biomechanical differences between subclavian and common iliac arteries, which possibly resulted from their different mechanical loadings/environments and respective in vivo movements caused by their anatomical locations. The biomechanical differences explored in this study are well reflected by the microstructure of the collagen and the histology of the investigated arteries, and the results can improve trauma patient care and endovascular implant design.\n During surgical interventions surgeons experienced that subclavian arteries (SAs) supplying the upper extremities, appear more fragile and prone to damage during surgical repair than common iliac arteries (CIAs), supplying the lower extremities. To investigate this difference in a systematic way the aim of this study was to compare the biomechanical properties of these two arteries from the same donors in terms of geometry, extension-inflation-torsion behavior, residual stresses, microstructure, and histology. In regard to cardiovascular medicine the material behavior of aged human arteries is of crucial interest. Moreover, the investigation of SA is important as it can help to improve surgical procedures at this challenging location. Over the long-term it might well be of value in the construction of artificial arteries for substituting native arteries. In addition, the analysis of mechanical stresses can improve design and material choice for endovascular implants to optimize long-term implant function.\n Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.\n\nCohnert, Tina Ulrike\n\nHohenberger, Gloria\n\nNiestrawska, Justyna Anna\n\nRegitnig, Peter\n\nViertler, Christian\n\n\n"
},
{
"text": "\n183133\nVariation in antibiotic prescription rates in febrile children presenting to emergency departments across Europe (MOFICHE): A multicentre observational study.\n\nHagedoorn, NN\n\nBorensztajn, DM\n\nNijman, R\n\nBalode, A\n\nvon Both, U\n\nCarrol, ED\n\nEleftheriou, I\n\nEmonts, M\n\nvan der Flier, M\n\nde Groot, R\n\nHerberg, J\n\nKohlmaier, B\n\nLim, E\n\nMaconochie, I\n\nMartinon-Torres, F\n\nNieboer, D\n\nPokorn, M\n\nStrle, F\n\nTsolia, M\n\nYeung, S\n\nZavadska, D\n\nZenz, W\n\nVermont, C\n\nLevin, M\n\nMoll, HA\n\nPERFORM consortium\n\nBeiträge in Fachzeitschriften\nISI:000563931200001\n32813708.0\n10.1371/journal.pmed.1003208\nPMC7444592\nThe prescription rate of antibiotics is high for febrile children visiting the emergency department (ED), contributing to antimicrobial resistance. Large studies at European EDs covering diversity in antibiotic and broad-spectrum prescriptions in all febrile children are lacking. A better understanding of variability in antibiotic prescriptions in EDs and its relation with viral or bacterial disease is essential for the development and implementation of interventions to optimise antibiotic use. As part of the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) project, the MOFICHE (Management and Outcome of Fever in Children in Europe) study aims to investigate variation and appropriateness of antibiotic prescription in febrile children visiting EDs in Europe.\n Between January 2017 and April 2018, data were prospectively collected on febrile children aged 0-18 years presenting to 12 EDs in 8 European countries (Austria, Germany, Greece, Latvia, the Netherlands [n = 3], Spain, Slovenia, United Kingdom [n = 3]). These EDs were based in university hospitals (n = 9) or large teaching hospitals (n = 3). Main outcomes were (1) antibiotic prescription rate; (2) the proportion of antibiotics that were broad-spectrum antibiotics; (3) the proportion of antibiotics of appropriate indication (presumed bacterial), inappropriate indication (presumed viral), or inconclusive indication (unknown bacterial/viral or other); (4) the proportion of oral antibiotics of inappropriate duration; and (5) the proportion of antibiotics that were guideline-concordant in uncomplicated urinary and upper and lower respiratory tract infections (RTIs). We determined variation of antibiotic prescription and broad-spectrum prescription by calculating standardised prescription rates using multilevel logistic regression and adjusted for general characteristics (e.g., age, sex, comorbidity, referral), disease severity (e.g., triage level, fever duration, presence of alarming signs), use and result of diagnostics, and focus and cause of infection. In this analysis of 35, 50 children (median age 2.8 years, 55% male), overall antibiotic prescription rate was 31.9% (range across EDs: 22.4%-41.6%), and among those prescriptions, the broad-spectrum antibiotic prescription rate was 52.1% (range across EDs: 33.0%-90.3%). After standardisation, differences in antibiotic prescriptions ranged from 0.8 to 1.4, and the ratio between broad-spectrum and narrow-spectrum prescriptions ranged from 0.7 to 1.8 across EDs. Standardised antibiotic prescription rates varied for presumed bacterial infections (0.9 to 1.1), presumed viral infections (0.1 to 3.3), and infections of unknown cause (0.1 to 1.8). In all febrile children, antibiotic prescriptions were appropriate in 65.0% of prescriptions, inappropriate in 12.5% (range across EDs: 0.6%-29.3%), and inconclusive in 22.5% (range across EDs: 0.4%-60.8%). Prescriptions were of inappropriate duration in 20% of oral prescriptions (range across EDs: 4.4%-59.0%). Oral prescriptions were not concordant with the local guideline in 22.3% (range across EDs: 11.8%-47.3%) of prescriptions in uncomplicated RTIs and in 45.1% (range across EDs: 11.1%-100%) of prescriptions in uncomplicated urinary tract infections. A limitation of our study is that the included EDs are not representative of all febrile children attending EDs in that country.\n In this study, we observed wide variation between European EDs in prescriptions of antibiotics and broad-spectrum antibiotics in febrile children. Overall, one-third of prescriptions were inappropriate or inconclusive, with marked variation between EDs. Until better diagnostics are available to accurately differentiate between bacterial and viral aetiologies, implementation of antimicrobial stewardship guidelines across Europe is necessary to limit antimicrobial resistance.\n\nKohlmaier, Benno\n\nZenz, Werner\n\n\n"
},
{
"text": "\n178077\nAssociation of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study.\n\nBIRTH-GENE (BIG) Study Working Group\n\nHuang, T\n\nWang, T\n\nZheng, Y\n\nEllervik, C\n\nLi, X\n\nGao, M\n\nFang, Z\n\nChai, JF\n\nAhluwalia, TVS\n\nWang, Y\n\nVoortman, T\n\nNoordam, R\n\nFrazier-Wood, A\n\nScholz, M\n\nSonestedt, E\n\nAkiyama, M\n\nDorajoo, R\n\nZhou, A\n\nKilpeläinen, TO\n\nKleber, ME\n\nCrozier, SR\n\nGodfrey, KM\n\nLemaitre, R\n\nFelix, JF\n\nShi, Y\n\nGupta, P\n\nKhor, CC\n\nLehtimäki, T\n\nWang, CA\n\nTiesler, CMT\n\nThiering, E\n\nStandl, M\n\nRzehak, P\n\nMarouli, E\n\nHe, M\n\nLecoeur, C\n\nCorella, D\n\nLai, CQ\n\nMoreno, LA\n\nPitkänen, N\n\nBoreham, CA\n\nZhang, T\n\nSaw, SM\n\nRidker, PM\n\nGraff, M\n\nvan Rooij, FJA\n\nUitterlinden, AG\n\nHofman, A\n\nvan Heemst, D\n\nRosendaal, FR\n\nde Mutsert, R\n\nBurkhardt, R\n\nSchulz, CA\n\nEricson, U\n\nKamatani, Y\n\nYuan, JM\n\nPower, C\n\nHansen, T\n\nSørensen, TIA\n\nTjønneland, A\n\nOvervad, K\n\nDelgado, G\n\nCooper, C\n\nDjousse, L\n\nRivadeneira, F\n\nJameson, K\n\nZhao, W\n\nLiu, J\n\nLee, NR\n\nRaitakari, O\n\nKähönen, M\n\nViikari, J\n\nGrote, V\n\nLanghendries, JP\n\nKoletzko, B\n\nEscribano, J\n\nVerduci, E\n\nDedoussis, G\n\nYu, C\n\nTham, YC\n\nLim, B\n\nLim, SH\n\nFroguel, P\n\nBalkau, B\n\nFink, NR\n\nVinding, RK\n\nSevelsted, A\n\nBisgaard, H\n\nColtell, O\n\nDallongeville, J\n\nGottrand, F\n\nPahkala, K\n\nNiinikoski, H\n\nHyppönen, E\n\nPedersen, O\n\nMärz, W\n\nInskip, H\n\nJaddoe, VWV\n\nDennison, E\n\nWong, TY\n\nSabanayagam, C\n\nTai, ES\n\nMohlke, KL\n\nMackey, DA\n\nGruszfeld, D\n\nDeloukas, P\n\nTucker, KL\n\nFumeron, F\n\nBønnelykke, K\n\nRossing, P\n\nEstruch, R\n\nOrdovas, JM\n\nArnett, DK\n\nMeirhaeghe, A\n\nAmouyel, P\n\nCheng, CY\n\nSim, X\n\nTeo, YY\n\nvan Dam, RM\n\nKoh, WP\n\nOrho-Melander, M\n\nLoeffler, M\n\nKubo, M\n\nThiery, J\n\nMook-Kanamori, DO\n\nMozaffarian, D\n\nPsaty, BM\n\nFranco, OH\n\nWu, T\n\nNorth, KE\n\nDavey Smith, G\n\nChavarro, JE\n\nChasman, DI\n\nQi, L\n\nBeiträge in Fachzeitschriften\nISI:000488882800019\n31539074.0\n10.1001/jamanetworkopen.2019.10915\nPMC6755534\nObservational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations.\n To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis.\n This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included.\n Type 2 diabetes and glycemic traits.\n This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration.\n In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n157296\nSafety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial.\n\nMir, O\n\nBrodowicz, T\n\nItaliano, A\n\nWallet, J\n\nBlay, JY\n\nBertucci, F\n\nChevreau, C\n\nPiperno-Neumann, S\n\nBompas, E\n\nSalas, S\n\nPerrin, C\n\nDelcambre, C\n\nLiegl-Atzwanger, B\n\nToulmonde, M\n\nDumont, S\n\nRay-Coquard, I\n\nClisant, S\n\nTaieb, S\n\nGuillemet, C\n\nRios, M\n\nCollard, O\n\nBozec, L\n\nCupissol, D\n\nSaada-Bouzid, E\n\nLemaignan, C\n\nEisterer, W\n\nIsambert, N\n\nChaigneau, L\n\nCesne, AL\n\nPenel, N\n\nBeiträge in Fachzeitschriften\nISI:000389537700041\n27751846.0\n10.1016/S1470-2045(16)30507-1\nNone\nRegorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline.\n In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov, NCT01900743.\n From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9-2·3) with regorafenib versus 1·7 months (0·9-1·8) with placebo (HR 0·89 [95% CI 0·48-1·64] p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5-5·0) with regorafenib versus 1·8 (1·0-2·8) months with placebo (HR 0·46 [95% CI 0·46-0·80] p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4-11·6) with regorafenib versus 1·0 (0·8-1·4) with placebo (HR 0·10 [95% CI 0·03-0·35] p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0-7·8) with regorafenib versus 1·0 (0·9-1·9) with placebo (HR 0·46 [95% CI 0·25-0·81] p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 [19%] events in the 89 patients in the regorafenib group vs two [2%] events in the 92 patients in the placebo group), hand and foot skin reaction (14 [15%] vs no events) and asthenia (12 [13%] vs six [6%]). One treatment-related death occurred in the regorafenib group due to liver failure.\n Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib.\n Bayer HealthCare.\n Copyright © 2016 Elsevier Ltd. All rights reserved.\n\nLiegl-Atzwanger, Bernadette\n\n\n"
},
{
"text": "\n148179\nProspective documentation and analysis of the pre- and early clinical management in severe head injury in southern Bavaria at a population based level.\n\nWirth, A\n\nBaethmann, A\n\nSchlesinger-Raab, A\n\nAssal, J\n\nAydemir, S\n\nBayeff-Filloff, M\n\nBeck, J\n\nBelg, A\n\nBoscher, A\n\nChapuis, D\n\nDietz, HG\n\nDöffinger, J\n\nEisenmenger, W\n\nGerstner, W\n\nGöbel, WE\n\nGrosse, P\n\nGrumme, T\n\nGutermuth, L\n\nHölzel, D\n\nHöpner, F\n\nHuf, R\n\nJaksche, H\n\nJensen, U\n\nKettemann, M\n\nKetterl, R\n\nKirmayer, U\n\nKolodziejcyk, D\n\nKöstler, W\n\nKuznik, J\n\nLackner, C\n\nLenz, G\n\nLochbihler, H\n\nLumenta, C\n\nMartin, S\n\nPreisz, A\n\nProkscha, G\n\nRegel, G\n\nReischl, H\n\nReulen, HJ\n\nRothmeier, F\n\nSackerer, D\n\nSchneck, S\n\nSchweiberer, L\n\nSommer, F\n\nSteiger, HJ\n\nStolpe, E\n\nStummer, W\n\nTanner, P\n\nTrappe, A\n\nTwickel, J\n\nUeblacker, P\n\nWambach, W\n\nWengert, P\n\nZimmerer, S\n\nStudy Group of BMBF-Research Consortium Neurotraumatology and Neuropsychological Rehabilitation\n\nBeiträge in Fachzeitschriften\nNone\n15335111.0\nNone\nNone\nTreatment of patients suffering from severe head injury is so far restricted to general procedures, whereas specific pharmacological agents of neuroprotection including hypothermia have not been found to improve the outcome in clinical trials. Albeit effective, symptomatic measures of the preclinical rescue of patients (i.e. stabilization or reestablishment of the circulatory and respiratory system) or of the early clinical care (e.g. prompt diagnosis and treatment of an intracranial space occupying mass, maintenance of a competent circulatory and respiratory system, and others) by and large constitute the current treatment based on considerable organizational and logistical efforts. These and other components of the head injury treatment are certainly worthwhile of a systematic analysis as to their efficacy or remaining deficiencies, respectively. Deficits could be associated with delays of providing preclinical rescue procedures (e.g. until intubation of the patient or administration of fluid). Delays could also be associated in the hospital with the diagnostic establishment of intracranial lesions requiring prompt neurosurgical intervention. By support of the Federal Ministry of Education and Research and under the auspices of the Forschungsverbund Neurotraumatology, University of Munich, a prospective system analysis was carried out on major aspects of the pre- and early clinical management at a population based level in patients with traumatic brain injury. Documentation of pertinent data was made from August 1998 to July 1999 covering a catchment area of Southern Bavaria (5.6 mio inhabitants). Altogether 528 cases identified to suffer from severe head injury (GCS < or = 8 or deteriorating to that level within 48 hrs) were enrolled following admission to the hospital and establishment of the diagnosis. Further, patients dying on the scene or during transport to the hospital were also documented, particularly as to the frequency of severe head injury as underlying cause of mortality. The analysis included also cases with additional peripheral trauma (polytrauma). The efficacy of the logistics and organization of the management was studied by documentation of prognosis-relevant time intervals, as for example until arrival of the rescue squad at the scene of an accident, until intubation and administration of fluid, or upon hospital admission until establishment of the CT-diagnosis and commencement of surgery or transfer to the intensive care unit, respectively. The severity of cases studied in the present analysis is evident from a mortality of far above 40% of cases admitted to the hospital, which was increased by about 20% when including prehospital mortality. The outcome data notwithstanding, the emerging results demonstrate a high efficacy of the pre- and early clinical management, as indicated by a prompt arrival of the rescue squad at the scene, a competent prehospital and early clinical management and care, indicative of a low rate of avoidable complications. It is tentatively concluded on the basis of these findings that the patient prognosis is increasingly determined by the manifestations of primary brain damage vs. the development of secondary complications.\n\n\n"
},
{
"text": "\n65914\nPharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A.\n\nPark, JW\n\nSiekmeier, R\n\nMerz, M\n\nKrell, B\n\nHarder, S\n\nMärz, W\n\nSeidel, D\n\nSchüler, S\n\nGross, W\n\nBeiträge in Fachzeitschriften\nISI:000178419700001\n12395976.0\nNone\nNone\nBACKGROUND: Heart transplantation is an established tool for the treatment of terminal heart failure. Hyperlipidemia is a common problem following heart transplantation and has been implicated as an additional risk factor in the development of transplant coronary artery disease (TxCAD). Therefore, heart recipients are commonly treated with inhibitors of cholesterol synthesis (HMG-CoA reductase inhibitors). However, these patients have an increased risk of developing rhabdomyolysis due to elevated concentrations of HMG-CoA reductase inhibitors under co-administration with the immunosuppressive cyclosporin A (CsA). AIM OF THE STUDY: Aim of our study was to obtain pharmacokinetic data on pravastatin whilst monitoring the safety and efficiency of the lipid lowering therapy in heart-transplant recipients under immunosuppression with CsA and to compare these data to those of a healthy control group. SUBJECTS, MATERIALS AND METHODS: Eleven patients (30.2 +/- 12.3 months after transplantation) receiving immunosuppressive therapy consisting of cyclosporin A, prednisone and azathioprine with LDL cholesterol (LDL-C) concentrations exceeding 3.9 mmol/l and 8 control subjects were included into the study. In addition to the immunosuppressive therapy, the patients received a daily dose of 40 mg/day pravastatin for the first 8 days which was then reduced to 10 mg/day administered until Day 29. Blood was sampled for pharmacokinetic profiling (maximum concentration of the drug (Cmax), time to reach Cmax (tmax), area under the concentration vs. time curve (AUC(0-24h)), elimination half-life time (tcl)) and measurement of the parameters of clinical chemistry on Days 1, 8 and 29. The control group received a single dose of 60 mg pravastatin and the values of Cmax and AUC(0-24h) were normalized for a dose of 10 mg. RESULTS: Pravastatin 40 mg/day for 1 week in the patient group caused a significant reduction in total cholesterol (C) and LDL-C from 8.11 +/- 1.20 mmol/l and 5.88 +/- 1.15 mmol/l to 6.91 +/- 1.01 mmol/l and 4.72 +/- 1.05 mmol/l, respectively (p = 0.005 and p = 0.003). Triglycerides and HDL cholesterol (HDL-C) concentrations did not change significantly. Mean values for Cmax of pravastatin were 384.2 ng/ml, 392.0 ng/ml and 115.1 ng/ml in patients on Days 1, 8 and 29, respectively. After normalization for a dose of 10 mg, the corresponding values of C(max-DN10mg) and Cmax were 96.0 ng/ml, 98.0 ng/ml and 115.1 ng/ml on study Days 1, 8 and 29. These values were 7-8 times higher than the normalized value of C(max-DN10mg) for the control group (13.7 ng/ml). The corresponding values of AUC(0-24h) were 1228.2 ng/ml x h, 1214.1 ng/ml x h and 345.9 ng/ml x h in the patient group on study Days 1, 8 and 29 as well as 157.5 ng/ml x h in the control group prior to normalization. After normalization for a dose of 10 mg, the values of AUC(0-24h-DN10mg) in the patient group were approximately 12 times higher than those of the control group. However, no significant differences between the 2 groups were observed in tmax and tcl. Within the patient group, no significant increase in Cmax or AUC was found on Day 1 to Day 8. The results of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) showed also no significant increase during the observation period. CONCLUSION: Heart-transplant recipients treated with the HMG-CoA reductase inhibitor pravastatin generally show higher plasma concentrations of this drug than control subjects. However, our data suggest that the HMG-CoA reductase inhibitor pravastatin can be used effectively in these patients receiving the immunosuppressive cyclosporin A. The pharmacokinetic data obtained indicate that there is no significant cumulation of the drug following multiple dosages in spite of increased drug concentrations after a single oral dosage.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n152120\nValue of several examination systems in patients with carpal tunnel syndrome. Comparison of Dellon computer-assisted sensation test with Mellesi hand status and Levine examination scheme].\n\nRab, M\n\nSchrögendorfer, KF\n\nGirsch, W\n\nKamolz, LP\n\nBeck, H\n\nWagner, G\n\nSchlemmer, F\n\nHögler, R\n\nAszmann, O\n\nFrey, M\n\nBeiträge in Fachzeitschriften\nNone\n11329890.0\n10.1055/s-2001-12291\nNone\nThe goal of the presented carpal tunnel syndrome (CTS) follow-up study was to compare the clinical value of the Millesi hand function score with the "Pressure Specifying Sensory Device" (PSSD) introduced by A. L. Dellon using self-administered patient questionnaires. 25 patients (10 male, 15 female) with an electrodiagnostically confirmed CTS were enrolled in this study, performing one preoperative and five postoperative examinations over 24 weeks. 12 of the 25 patients underwent an "open" two-portal carpal tunnel release with two minimal incisions (group OT); the other 13 patients were treated with a two-portal endoscopic carpal tunnel release (group ET). Additionally, in eleven out of the twelve patients of group OT, an epineuriotomy of the median nerve was performed during the same session. Concerning preoperative data of the Millesi score and the PSSD, no statistically significant differences were found between group OT and ET. However, preoperative comparison with the contralateral hand demonstrated a reduction in hand function of 15% and an increase in the pressure perception threshold of 41% compared to normative data could be measured with the PSSD. The subjective functional value of the hand was objectively evacuated using the Levine score. In the second postoperative week, a significant decrease in hand function could be obtained with the Millesi score in group OT. In group ET, the decrease in hand function representing the operative trauma was significantly lower than in group OT. Data of the static one- and two-point pressure perception threshold revealed a statistically significant improvement of the sensibility in both groups. The results of the Millesi score recorded at the last examination in the 24th postoperative week showed an improvement in hand function in both groups compared to preoperative data. Concerning static one- and two-point measurements with the PSSD, distinct improvements compared to the preoperative data could also be detected in both groups although significant differences between group OT and ET were evident: Data of group OT regarding the whole postoperative course demonstrate a continuous improvement in sensibility of the index finger. In contrast, the analysis of the PSSD measurements in group ET revealed an increase in all the parameters starting in the sixth postoperative week and ending with significantly worse static one- and two-point threshold measurements than in group OT. On the other hand, data of self-administered patient questionnaires using the Levine Score revealed significant improvements in hand function and reduction in pain intensity in both groups compared to preoperative results. Differences between both groups at the end of the examination course were not evident. In conclusion, the Millesi hand score with its emphasis on the motor function proved to be a reliable method to record the severity of CTS preoperatively, the severity of the surgical trauma and changes in the course of rehabilitation of the affected hand. A good correlation was found between data obtained with the Millesi Score and the self-administered patient questionnaires according to Levine. But when compared with the PSSD, both methods could not directly document the preoperative status and postoperative changes of the median nerve. Preoperative static two-point pressure threshold measurements with the PSSD confirmed their status as a screening parameter as published by A. L. Dellon. In the postoperative course of group ET, a distinct worsening in the sensibility of the index and little finger could only be detected with the PSSD before the patients noticed the onset of related symptoms.\n\nKamolz, Lars-Peter\n\n\n"
},
{
"text": "\n186220\nSex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.\n\nLagou, V\n\nMägi, R\n\nHottenga, JJ\n\nGrallert, H\n\nPerry, JRB\n\nBouatia-Naji, N\n\nMarullo, L\n\nRybin, D\n\nJansen, R\n\nMin, JL\n\nDimas, AS\n\nUlrich, A\n\nZudina, L\n\nGådin, JR\n\nJiang, L\n\nFaggian, A\n\nBonnefond, A\n\nFadista, J\n\nStathopoulou, MG\n\nIsaacs, A\n\nWillems, SM\n\nNavarro, P\n\nTanaka, T\n\nJackson, AU\n\nMontasser, ME\n\nO'Connell, JR\n\nBielak, LF\n\nWebster, RJ\n\nSaxena, R\n\nStafford, JM\n\nPourcain, BS\n\nTimpson, NJ\n\nSalo, P\n\nShin, SY\n\nAmin, N\n\nSmith, AV\n\nLi, G\n\nVerweij, N\n\nGoel, A\n\nFord, I\n\nJohnson, PCD\n\nJohnson, T\n\nKapur, K\n\nThorleifsson, G\n\nStrawbridge, RJ\n\nRasmussen-Torvik, LJ\n\nEsko, T\n\nMihailov, E\n\nFall, T\n\nFraser, RM\n\nMahajan, A\n\nKanoni, S\n\nGiedraitis, V\n\nKleber, ME\n\nSilbernagel, G\n\nMeyer, J\n\nMüller-Nurasyid, M\n\nGanna, A\n\nSarin, AP\n\nYengo, L\n\nShungin, D\n\nLuan, J\n\nHorikoshi, M\n\nAn, P\n\nSanna, S\n\nBoettcher, Y\n\nRayner, NW\n\nNolte, IM\n\nZemunik, T\n\nIperen, EV\n\nKovacs, P\n\nHastie, ND\n\nWild, SH\n\nMcLachlan, S\n\nCampbell, S\n\nPolasek, O\n\nCarlson, O\n\nEgan, J\n\nKiess, W\n\nWillemsen, G\n\nKuusisto, J\n\nLaakso, M\n\nDimitriou, M\n\nHicks, AA\n\nRauramaa, R\n\nBandinelli, S\n\nThorand, B\n\nLiu, Y\n\nMiljkovic, I\n\nLind, L\n\nDoney, A\n\nPerola, M\n\nHingorani, A\n\nKivimaki, M\n\nKumari, M\n\nBennett, AJ\n\nGroves, CJ\n\nHerder, C\n\nKoistinen, HA\n\nKinnunen, L\n\nFaire, U\n\nBakker, SJL\n\nUusitupa, M\n\nPalmer, CNA\n\nJukema, JW\n\nSattar, N\n\nPouta, A\n\nSnieder, H\n\nBoerwinkle, E\n\nPankow, JS\n\nMagnusson, PK\n\nKrus, U\n\nScapoli, C\n\nde Geus, EJCN\n\nBlüher, M\n\nWolffenbuttel, BHR\n\nProvince, MA\n\nAbecasis, GR\n\nMeigs, JB\n\nHovingh, GK\n\nLindström, J\n\nWilson, JF\n\nWright, AF\n\nDedoussis, GV\n\nBornstein, SR\n\nSchwarz, PEH\n\nTönjes, A\n\nWinkelmann, BR\n\nBoehm, BO\n\nMärz, W\n\nMetspalu, A\n\nPrice, JF\n\nDeloukas, P\n\nKörner, A\n\nLakka, TA\n\nKeinanen-Kiukaanniemi, SM\n\nSaaristo, TE\n\nBergman, RN\n\nTuomilehto, J\n\nWareham, NJ\n\nLangenberg, C\n\nMännistö, S\n\nFranks, PW\n\nHayward, C\n\nVitart, V\n\nKaprio, J\n\nVisvikis-Siest, S\n\nBalkau, B\n\nAltshuler, D\n\nRudan, I\n\nStumvoll, M\n\nCampbell, H\n\nvan Duijn, CM\n\nGieger, C\n\nIllig, T\n\nFerrucci, L\n\nPedersen, NL\n\nPramstaller, PP\n\nBoehnke, M\n\nFrayling, TM\n\nShuldiner, AR\n\nPeyser, PA\n\nKardia, SLR\n\nPalmer, LJ\n\nPenninx, BW\n\nMeneton, P\n\nHarris, TB\n\nNavis, G\n\nHarst, PV\n\nSmith, GD\n\nForouhi, NG\n\nLoos, RJF\n\nSalomaa, V\n\nSoranzo, N\n\nBoomsma, DI\n\nGroop, L\n\nTuomi, T\n\nHofman, A\n\nMunroe, PB\n\nGudnason, V\n\nSiscovick, DS\n\nWatkins, H\n\nLecoeur, C\n\nVollenweider, P\n\nFranco-Cereceda, A\n\nEriksson, P\n\nJarvelin, MR\n\nStefansson, K\n\nHamsten, A\n\nNicholson, G\n\nKarpe, F\n\nDermitzakis, ET\n\nLindgren, CM\n\nMcCarthy, MI\n\nFroguel, P\n\nKaakinen, MA\n\nLyssenko, V\n\nWatanabe, RM\n\nIngelsson, E\n\nFlorez, JC\n\nDupuis, J\n\nBarroso, I\n\nMorris, AP\n\nProkopenko, I\n\nMeta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)\n\nBeiträge in Fachzeitschriften\nISI:000610431700001\n33402679.0\n10.1038/s41467-020-19366-9\nPMC7785747\nDifferences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73, 89/50, 04 women and 67, 06/47, 06 men) and sex-combined (151, 88/105, 56 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.\n\nMärz, Winfried\n\nSilbernagel, Günther\n\n\n"
},
{
"text": "\n164988\nPrediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study\n\nFilippi, M\n\nPreziosa, P\n\nMeani, A\n\nCiccarelli, O\n\nMesaros, S\n\nRovira, A\n\nFrederiksen, J\n\nEnzinger, C\n\nBarkhof, F\n\nGasperini, C\n\nBrownlee, W\n\nDrulovic, J\n\nMontalban, X\n\nCramer, SP\n\nPichler, A\n\nHagens, M\n\nRuggieri, S\n\nMartinelli, V\n\nMiszkiel, K\n\nTintore, M\n\nComi, G\n\nDekker, I\n\nUitdehaag, B\n\nDujmovic-Basuroski, I\n\nRocca, MA\n\nBeiträge in Fachzeitschriften\nISI:000422828500011\n29275979.0\n10.1016/S1474-4422(17)30469-6\nNone\nIn 2016, the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network proposed modifications to the MRI criteria to define dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis in patients with clinically isolated syndrome (CIS). Changes to the DIS definition included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested. We compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for multiple sclerosis diagnosis in a large multicentre cohort of patients with CIS to provide evidence to guide revisions of multiple sclerosis diagnostic criteria.\n Brain and spinal cord MRI and optic nerve assessments from patients with typical CIS suggestive of multiple sclerosis done less than 3 months from clinical onset in eight European multiple sclerosis centres were included in this retrospective study. Eligible patients were 16-60 years, and had a first CIS suggestive of CNS demyelination and typical of relapsing-remitting multiple sclerosis, a complete neurological examination, a baseline brain and spinal cord MRI scan obtained less than 3 months from clinical onset, and a follow-up brain scan obtained less than 12 months from CIS onset. We recorded occurrence of a second clinical attack (clinically definite multiple sclerosis) at months 36 and 60. We evaluated MRI criteria performance for DIS, DIT, and DIS plus DIT with a time-dependent receiver operating characteristic curve analysis.\n Between June 16, 1995, and Jan 27, 2017, 571 patients with CIS were screened, of whom 368 met all study inclusion criteria. At the last evaluation (median 50·0 months [IQR 27·0-78·4]), 189 (51%) of 368 patients developed clinically definite multiple sclerosis. At 36 months, the two DIS criteria showed high sensitivity (2010 McDonald 0·91 [95% CI 0·85-0·94] and 2016 MAGNIMS 0·93 [0·88-0·96]), similar specificity (0·33 [0·25-0·42] and 0·32 [0·24-0·41]), and similar area under the curve values (AUC; 0·62 [0·57-0·67] and 0·63 [0·58-0·67]). Performance was not affected by inclusion of symptomatic lesions (sensitivity 0·92 [0·87-0·96], specificity 0·31 [0·23-0·40], AUC 0·62 [0·57-0·66]) or cortical lesions (sensitivity 0·92 [0·87-0·95], specificity 0·32 [0·24-0·41], AUC 0·62 [0·57-0·67]). Requirement of three periventricular lesions resulted in slightly lower sensitivity (0·85 [0·78-0·90], slightly higher specificity (0·40 [0·32-0·50], and similar AUC (0·63 [0·57-0·68]). Inclusion of optic nerve evaluation resulted in similar sensitivity (0·92 [0·87-0·96]), and slightly lower specificity (0·26 [0·18-0·34]) and AUC (0·59 [0·55-0·64]). AUC values were also similar for DIT (2010 McDonald 0·61 [0·55-0·67] and 2016 MAGNIMS 0·61 [0·55-0·66]) and DIS plus DIT (0·62 [0·56-0·67] and 0·64 [0·58-0·69]).\n The 2016 MAGNIMS criteria showed similar accuracy to the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis. Inclusion of symptomatic lesions is expected to simplify the clinical use of MRI criteria without reducing accuracy, and our findings suggest that needing three lesions to define periventricular involvement might slightly increase specificity, suggesting that these two factors could be considered during further revisions of multiple sclerosis diagnostic criteria.\n UK MS Society, National Institute for Health Research University College London Hospitals Biomedical Research Centre, Dutch MS Research Foundation.\n Copyright © 2017 Elsevier Ltd. All rights reserved.\n\nEnzinger, Christian\n\nPichler, Alexander\n\n\n"
},
{
"text": "\n167768\nStudy of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.\n\nDavies, G\n\nLam, M\n\nHarris, SE\n\nTrampush, JW\n\nLuciano, M\n\nHill, WD\n\nHagenaars, SP\n\nRitchie, SJ\n\nMarioni, RE\n\nFawns-Ritchie, C\n\nLiewald, DCM\n\nOkely, JA\n\nAhola-Olli, AV\n\nBarnes, CLK\n\nBertram, L\n\nBis, JC\n\nBurdick, KE\n\nChristoforou, A\n\nDeRosse, P\n\nDjurovic, S\n\nEspeseth, T\n\nGiakoumaki, S\n\nGiddaluru, S\n\nGustavson, DE\n\nHayward, C\n\nHofer, E\n\nIkram, MA\n\nKarlsson, R\n\nKnowles, E\n\nLahti, J\n\nLeber, M\n\nLi, S\n\nMather, KA\n\nMelle, I\n\nMorris, D\n\nOldmeadow, C\n\nPalviainen, T\n\nPayton, A\n\nPazoki, R\n\nPetrovic, K\n\nReynolds, CA\n\nSargurupremraj, M\n\nScholz, M\n\nSmith, JA\n\nSmith, AV\n\nTerzikhan, N\n\nThalamuthu, A\n\nTrompet, S\n\nvan der Lee, SJ\n\nWare, EB\n\nWindham, BG\n\nWright, MJ\n\nYang, J\n\nYu, J\n\nAmes, D\n\nAmin, N\n\nAmouyel, P\n\nAndreassen, OA\n\nArmstrong, NJ\n\nAssareh, AA\n\nAttia, JR\n\nAttix, D\n\nAvramopoulos, D\n\nBennett, DA\n\nBöhmer, AC\n\nBoyle, PA\n\nBrodaty, H\n\nCampbell, H\n\nCannon, TD\n\nCirulli, ET\n\nCongdon, E\n\nConley, ED\n\nCorley, J\n\nCox, SR\n\nDale, AM\n\nDehghan, A\n\nDick, D\n\nDickinson, D\n\nEriksson, JG\n\nEvangelou, E\n\nFaul, JD\n\nFord, I\n\nFreimer, NA\n\nGao, H\n\nGiegling, I\n\nGillespie, NA\n\nGordon, SD\n\nGottesman, RF\n\nGriswold, ME\n\nGudnason, V\n\nHarris, TB\n\nHartmann, AM\n\nHatzimanolis, A\n\nHeiss, G\n\nHolliday, EG\n\nJoshi, PK\n\nKähönen, M\n\nKardia, SLR\n\nKarlsson, I\n\nKleineidam, L\n\nKnopman, DS\n\nKochan, NA\n\nKonte, B\n\nKwok, JB\n\nLe Hellard, S\n\nLee, T\n\nLehtimäki, T\n\nLi, SC\n\nLiu, T\n\nKoini, M\n\nLondon, E\n\nLongstreth, WT\n\nLopez, OL\n\nLoukola, A\n\nLuck, T\n\nLundervold, AJ\n\nLundquist, A\n\nLyytikäinen, LP\n\nMartin, NG\n\nMontgomery, GW\n\nMurray, AD\n\nNeed, AC\n\nNoordam, R\n\nNyberg, L\n\nOllier, W\n\nPapenberg, G\n\nPattie, A\n\nPolasek, O\n\nPoldrack, RA\n\nPsaty, BM\n\nReppermund, S\n\nRiedel-Heller, SG\n\nRose, RJ\n\nRotter, JI\n\nRoussos, P\n\nRovio, SP\n\nSaba, Y\n\nSabb, FW\n\nSachdev, PS\n\nSatizabal, CL\n\nSchmid, M\n\nScott, RJ\n\nScult, MA\n\nSimino, J\n\nSlagboom, PE\n\nSmyrnis, N\n\nSoumaré, A\n\nStefanis, NC\n\nStott, DJ\n\nStraub, RE\n\nSundet, K\n\nTaylor, AM\n\nTaylor, KD\n\nTzoulaki, I\n\nTzourio, C\n\nUitterlinden, A\n\nVitart, V\n\nVoineskos, AN\n\nKaprio, J\n\nWagner, M\n\nWagner, H\n\nWeinhold, L\n\nWen, KH\n\nWiden, E\n\nYang, Q\n\nZhao, W\n\nAdams, HHH\n\nArking, DE\n\nBilder, RM\n\nBitsios, P\n\nBoerwinkle, E\n\nChiba-Falek, O\n\nCorvin, A\n\nDe Jager, PL\n\nDebette, S\n\nDonohoe, G\n\nElliott, P\n\nFitzpatrick, AL\n\nGill, M\n\nGlahn, DC\n\nHägg, S\n\nHansell, NK\n\nHariri, AR\n\nIkram, MK\n\nJukema, JW\n\nVuoksimaa, E\n\nKeller, MC\n\nKremen, WS\n\nLauner, L\n\nLindenberger, U\n\nPalotie, A\n\nPedersen, NL\n\nPendleton, N\n\nPorteous, DJ\n\nRäikkönen, K\n\nRaitakari, OT\n\nRamirez, A\n\nReinvang, I\n\nRudan, I\n\nDan Rujescu, I\n\nSchmidt, R\n\nSchmidt, H\n\nSchofield, PW\n\nSchofield, PR\n\nStarr, JM\n\nSteen, VM\n\nTrollor, JN\n\nTurner, ST\n\nVan Duijn, CM\n\nVillringer, A\n\nWeinberger, DR\n\nWeir, DR\n\nWilson, JF\n\nMalhotra, A\n\nMcIntosh, AM\n\nGale, CR\n\nSeshadri, S\n\nMosley, TH\n\nBressler, J\n\nLencz, T\n\nDeary, IJ\n\nBeiträge in Fachzeitschriften\nISI:000433297900009\n29844566.0\n10.1038/s41467-018-04362-x\nPMC5974083\nGeneral cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300, 86; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.\n\nHofer, Edith\n\nKoini, Marisa\n\nSABA, Yasaman\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n66289\nMolecular mechanisms that underlie structural and functional changes at the postsynaptic membrane during synaptic plasticity.\n\nWheal, HV\n\nChen, Y\n\nMitchell, J\n\nSchachner, M\n\nMaerz, W\n\nWieland, H\n\nVan Rossum, D\n\nKirsch, J\n\nBeiträge in Fachzeitschriften\nISI:000074545400006\n9670221.0\n10.1016/S0301-0082(98)00026-4\nNone\nThe synaptic plasticity that is addressed in this review follows neurodegeneration in the brain and thus has both structural as well as functional components. The model of neurodegeneration that has been selected is the kainic acid lesioned hippocampus. Degeneration of the CA3 pyramidal cells results in a loss of the Schaffer collateral afferents innervating the CA1 pyramidal cells. This is followed by a period of structural plasticity where new synapses are formed. These are associated with changes in the numbers and shapes of spines as well as changes in the morphometry of the dendrites. It is suggested that this synaptogenesis is responsible for an increase in the ratio of NMDA to AMPA receptors mediating excitatory synaptic transmission at these synapses. Changes in the temporal and spatial properties of these synapses resulted in an altered balance between LTP and LTD. These properties together with a reduction in the inhibitory drive increased the excitability of the surviving CA1 pyramidal cells which in turn triggered epileptiform bursting activity. In this review we discuss the insights that may be gained from studies of the underlying molecular machinery. Developments in one of the collections of the cogs in this machinery has been summarized through recent studies characterizing the roles of neural recognition molecules in synaptic plasticity in the adult nervous systems of vertebrates and invertebrates. Such investigations of neural cell adhesion molecules, cadherins and amyloid precursor protein have shown the involvement of these molecules on the morphogenetic level of synaptic changes, on the one hand, and signal transduction effects, on the other. Further complex cogs are found in the forms of the low-density lipoprotein receptor (LDL-R) family of genes and their ligands play pivotal roles in the brain development and in regulating the growth and remodelling of neurones. Evidence is discussed for their role in the maintenance of cognitive function as well as Alzheimer's. The molecular mechanisms responsible for the clustering and maintenance of transmitter receptors at postsynaptic sites are the final cogs in the machinery that we have reviewed. Postsynaptic densities (PSD) from excitatory synapses have yielded many cytoskeletal proteins including actin, spectrin, tubulin, microtubule-associated proteins and calcium/calmodulin-dependent protein kinase II. Isolated PSDs have also been shown to be enriched in AMPA, kainate and NMDA receptors. However, recently, a new family of proteins, the MAGUKs (for membrane-associated guanylate kinase) has emerged. The role of these proteins in clustering different NMDA receptor subunits is discussed. The MAGUK proteins are also thought to play a role in synaptic plasticity mediated by nitric oxide (NO). Both NMDA and non-NMDA receptors are highly clustered at excitatory postsynaptic sites in cortical and hippocampal neurones but have revealed differences in their choice of molecular components. Both GABAA and glycine (Gly) receptors mediate synaptic inhibition in the brain and spinal cord. Whilst little is known about how GABAA receptors are localized in the postsynaptic membrane, considerable progress has been made towards the elucidation of the molecular mechanisms underlying the formation of Gly receptors. It has been shown that the peripheral membrane protein gephyrin plays a pivotal role in the formation of Gly receptor clusters most likely by anchoring the receptor to the subsynaptic cytoskeleton. Evidence for the distribution as well as function of gephyrin and Gly receptors is discussed. Postsynaptic membrane specializations are complex molecular machinery subserving a multitude of functions in the proper communication between neurones. Despite the fact that only a few key players have been identified it will be a fascinating to watch the story as to how they contribute to structural and functional plasticity unfold.\n\nMärz, Winfried\n\n\n"
}
]
}