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"text": "\n170959\nGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.\n\nFranceschini, N\n\nGiambartolomei, C\n\nde Vries, PS\n\nFinan, C\n\nBis, JC\n\nHuntley, RP\n\nLovering, RC\n\nTajuddin, SM\n\nWinkler, TW\n\nGraff, M\n\nKavousi, M\n\nDale, C\n\nSmith, AV\n\nHofer, E\n\nvan Leeuwen, EM\n\nNolte, IM\n\nLu, L\n\nScholz, M\n\nSargurupremraj, M\n\nPitkänen, N\n\nFranzén, O\n\nJoshi, PK\n\nNoordam, R\n\nMarioni, RE\n\nHwang, SJ\n\nMusani, SK\n\nSchminke, U\n\nPalmas, W\n\nIsaacs, A\n\nCorrea, A\n\nZonderman, AB\n\nHofman, A\n\nTeumer, A\n\nCox, AJ\n\nUitterlinden, AG\n\nWong, A\n\nSmit, AJ\n\nNewman, AB\n\nBritton, A\n\nRuusalepp, A\n\nSennblad, B\n\nHedblad, B\n\nPasaniuc, B\n\nPenninx, BW\n\nLangefeld, CD\n\nWassel, CL\n\nTzourio, C\n\nFava, C\n\nBaldassarre, D\n\nO'Leary, DH\n\nTeupser, D\n\nKuh, D\n\nTremoli, E\n\nMannarino, E\n\nGrossi, E\n\nBoerwinkle, E\n\nSchadt, EE\n\nIngelsson, E\n\nVeglia, F\n\nRivadeneira, F\n\nBeutner, F\n\nChauhan, G\n\nHeiss, G\n\nSnieder, H\n\nCampbell, H\n\nVölzke, H\n\nMarkus, HS\n\nDeary, IJ\n\nJukema, JW\n\nde Graaf, J\n\nPrice, J\n\nPott, J\n\nHopewell, JC\n\nLiang, J\n\nThiery, J\n\nEngmann, J\n\nGertow, K\n\nRice, K\n\nTaylor, KD\n\nDhana, K\n\nKiemeney, LALM\n\nLind, L\n\nRaffield, LM\n\nLauner, LJ\n\nHoldt, LM\n\nDörr, M\n\nDichgans, M\n\nTraylor, M\n\nSitzer, M\n\nKumari, M\n\nKivimaki, M\n\nNalls, MA\n\nMelander, O\n\nRaitakari, O\n\nFranco, OH\n\nRueda-Ochoa, OL\n\nRoussos, P\n\nWhincup, PH\n\nAmouyel, P\n\nGiral, P\n\nAnugu, P\n\nWong, Q\n\nMalik, R\n\nRauramaa, R\n\nBurkhardt, R\n\nHardy, R\n\nSchmidt, R\n\nde Mutsert, R\n\nMorris, RW\n\nStrawbridge, RJ\n\nWannamethee, SG\n\nHägg, S\n\nShah, S\n\nMcLachlan, S\n\nTrompet, S\n\nSeshadri, S\n\nKurl, S\n\nHeckbert, SR\n\nRing, S\n\nHarris, TB\n\nLehtimäki, T\n\nGalesloot, TE\n\nShah, T\n\nde Faire, U\n\nPlagnol, V\n\nRosamond, WD\n\nPost, W\n\nZhu, X\n\nZhang, X\n\nGuo, X\n\nSaba, Y\n\nMEGASTROKE Consortium\n\nDehghan, A\n\nSeldenrijk, A\n\nMorrison, AC\n\nHamsten, A\n\nPsaty, BM\n\nvan Duijn, CM\n\nLawlor, DA\n\nMook-Kanamori, DO\n\nBowden, DW\n\nSchmidt, H\n\nWilson, JF\n\nWilson, JG\n\nRotter, JI\n\nWardlaw, JM\n\nDeanfield, J\n\nHalcox, J\n\nLyytikäinen, LP\n\nLoeffler, M\n\nEvans, MK\n\nDebette, S\n\nHumphries, SE\n\nVölker, U\n\nGudnason, V\n\nHingorani, AD\n\nBjörkegren, JLM\n\nCasas, JP\n\nO'Donnell, CJ\n\nBeiträge in Fachzeitschriften\nISI:000451873600017\n30510157.0\n10.1038/s41467-018-07340-5\nPMC6277418\nCarotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71, 28 individuals for cIMT, and 48, 34 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.\n\nHofer, Edith\n\nSABA, Yasaman\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n155867\nEvaluation of microperfusion disturbances in the transplanted liver after Kupffer cell destruction using GdCl3: an experimental porcine study.\n\nJahnke, C\n\nMehrabi, A\n\nGolling, M\n\nFrankenberg, MV\n\nKashfi, A\n\nNentwich, H\n\nFonouni, H\n\nNickkholgh, A\n\nSchemmer, P\n\nGutt, CN\n\nWeitz, J\n\nSchmidt, J\n\nGebhard, MM\n\nBüchler, MW\n\nKraus, T\n\nBeiträge in Fachzeitschriften\nISI:000238700500098\n16797363.0\n10.1016/j.transproceed.2006.02.067\nNone\nOrgan function after liver transplantation is determined by ischemia-reperfusion injury. Destruction of Kupffer cells with gadolinium chloride (GdCl3) has been shown to have a possible preventive effect on the extent of this injury, which can be extrapolated by analyzing the distribution of hepatic microperfusion. The aim of this study was to evaluate the protective effect of GdCl3 on disturbances of microperfusion in the transplanted liver.\n Landrace pigs were randomly divided into three groups. In the control group (CG; n=6) a mapping of the native liver was conducted. For mapping, the four hepatic liver lobes were named from right to left with A to D and every lobe was divided into three vertical segments (cranial, medial, and caudal). In each of these 12 areas, microperfusion was quantified using a thermodiffusion probe (TD [mL/100 g/min]). The other two groups were considered as transplanted treated group (TTG; n=10) and transplanted nontreated group (TnTG; n=10). The TTG received an infusion of 20 mg/kg GdCl3 intravenously 24 hours before organ harvesting. Then standardized orthotopic liver transplantation was performed. In TnTG, standardized orthotopic liver transplantation was carried out without prior GdCl3 injection. In the recipients, the microperfusion of transplanted livers were mapped in both TnTG and TTG, in two different time points (1 hour [n=5] and 24 hours (n=5]) after reperfusion.\n A significant reduction of macrophages in the TTG livers in comparison to the CG and TnTG livers was observed (P<.05). However, the number of macrophages in CG and TnTG livers showed no significant difference (P>.05). Regarding liver microperfusion, in TnTG, a marked heterogeneity was detected in the livers after reperfusion. Significant differences between liver lobes (horizontal planes; P=.032) and vertical layers of intralobar liver parenchyma (P=.029) were observed. The same pattern was seen in TTG livers after reperfusion and a significant difference between horizontal (P=.024) and vertical layers (P=.018) of liver tissue were observed. Comparing intralobar regional flow data between vertical planes 24 hours after reperfusion still showed a prominent variation of hepatic tissue perfusion in TnTG livers (P=.028). Within the same horizontal layers, no significant differences between lobes were measured anymore (P=.16). Contrary to TnTG, in TTG, a homogenous pattern of regional liver tissue perfusion was recorded 24 hours after reperfusion. Comparison of TD data on the liver regions showed no significant microperfusion differences in either horizontal (P=.888) or vertical (P=.841) layers.\n Application of GdCl3 resulted in a significant reduction of Kupffer cells. Twenty four hours after transplantation microperfusion showed a homogeneous pattern, which constituted an earlier and better recovery of the transplanted liver. Therefore, destruction of Kupffer cells reduced ischemia-reperfusion injury and seemed to be responsible for the early recovery of microperfusion disturbances and thus for an improvement of graft function.\n\nSchemmer, Peter\n\n\n"
},
{
"text": "\n186226\nPatients with coronary heart disease, dilated cardiomyopathy and idiopathic ventricular tachycardia share overlapping patterns of pathogenic variation in cardiac risk genes.\n\nGuelly, C\n\nAbilova, Z\n\nNuralinov, O\n\nPanzitt, K\n\nAkhmetova, A\n\nRakhimova, S\n\nKozhamkulov, U\n\nKairov, U\n\nMolkenov, A\n\nSeisenova, A\n\nTrajanoski, S\n\nAbildinova Rashbayeva, G\n\nKaussova, G\n\nWindpassinger, C\n\nLee, JH\n\nZhumadilov, Z\n\nBekbossynova, M\n\nAkilzhanova, A\n\nBeiträge in Fachzeitschriften\nISI:000608617100011\n33552729.0\n10.7717/peerj.10711\nPMC7821765\nVentricular tachycardia (VT) is a major cause of sudden cardiac death (SCD). Clinical investigations can sometimes fail to identify the underlying cause of VT and the event is classified as idiopathic (iVT). VT contributes significantly to the morbidity and mortality in patients with coronary artery disease (CAD) and dilated cardiomyopathy (DCM). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility screening for disease-predisposing variants could improve VT diagnostics and prevent SCD in patients.\n Ninety-two patients diagnosed with coronary heart disease (CHD), DCM, or iVT were included in our study. We evaluated genetic profiles and variants in known cardiac risk genes by targeted next generation sequencing (NGS) using a newly designed custom panel of 96 genes. We hypothesized that shared morphological and phenotypical features among these subgroups may have an overlapping molecular base. To our knowledge, this was the first study of the deep sequencing of 96 targeted cardiac genes in Kazakhstan. The clinical significance of the sequence variants was interpreted according to the guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015. The ClinVar and Varsome databases were used to determine the variant classifications.\n Targeted sequencing and stepwise filtering of the annotated variants identified a total of 307 unique variants in 74 genes, totally 456 variants in the overall study group. We found 168 mutations listed in the Human Genome Mutation Database (HGMD) and another 256 rare/unique variants with elevated pathogenic potential. There was a predominance of high- to intermediate pathogenicity variants in LAMA2, MYBPC3, MYH6, KCNQ1, GAA, and DSG2 in CHD VT patients. Similar frequencies were observed in DCM VT, and iVT patients, pointing to a common molecular disease association. TTN, GAA, LAMA2, and MYBPC3 contained the most variants in the three subgroups which confirm the impact of these genes in the complex pathogenesis of cardiomyopathies and VT. The classification of 307 variants according to ACMG guidelines showed that nine (2.9%) variants could be classified as pathogenic, nine (2.9%) were likely pathogenic, 98 (31.9%) were of uncertain significance, 73 (23.8%) were likely benign, and 118 (38.4%) were benign. CHD VT patients carry rare genetic variants with increased pathogenic potential at a comparable frequency to DCM VT and iVT patients in genes related to sarcomere function, nuclear function, ion flux, and metabolism.\n In this study we showed that in patients with VT secondary to coronary artery disease, DCM, or idiopathic etiology multiple rare mutations and clinically significant sequence variants in classic cardiac risk genes associated with cardiac channelopathies and cardiomyopathies were found in a similar pattern and at a comparable frequency.\n ©2021 Guelly et al.\n\nGülly, Christian\n\nPanzitt, Katrin\n\nTrajanoski, Slave\n\nWindpassinger, Christian\n\n\n"
},
{
"text": "\n136099\nGene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.\n\nTragante, V\n\nBarnes, MR\n\nGanesh, SK\n\nLanktree, MB\n\nGuo, W\n\nFranceschini, N\n\nSmith, EN\n\nJohnson, T\n\nHolmes, MV\n\nPadmanabhan, S\n\nKarczewski, KJ\n\nAlmoguera, B\n\nBarnard, J\n\nBaumert, J\n\nChang, YP\n\nElbers, CC\n\nFarrall, M\n\nFischer, ME\n\nGaunt, TR\n\nGho, JM\n\nGieger, C\n\nGoel, A\n\nGong, Y\n\nIsaacs, A\n\nKleber, ME\n\nMateo Leach, I\n\nMcDonough, CW\n\nMeijs, MF\n\nMelander, O\n\nNelson, CP\n\nNolte, IM\n\nPankratz, N\n\nPrice, TS\n\nShaffer, J\n\nShah, S\n\nTomaszewski, M\n\nvan der Most, PJ\n\nVan Iperen, EP\n\nVonk, JM\n\nWitkowska, K\n\nWong, CO\n\nZhang, L\n\nBeitelshees, AL\n\nBerenson, GS\n\nBhatt, DL\n\nBrown, M\n\nBurt, A\n\nCooper-DeHoff, RM\n\nConnell, JM\n\nCruickshanks, KJ\n\nCurtis, SP\n\nDavey-Smith, G\n\nDelles, C\n\nGansevoort, RT\n\nGuo, X\n\nHaiqing, S\n\nHastie, CE\n\nHofker, MH\n\nHovingh, GK\n\nKim, DS\n\nKirkland, SA\n\nKlein, BE\n\nKlein, R\n\nLi, YR\n\nMaiwald, S\n\nNewton-Cheh, C\n\nO'Brien, ET\n\nOnland-Moret, NC\n\nPalmas, W\n\nParsa, A\n\nPenninx, BW\n\nPettinger, M\n\nVasan, RS\n\nRanchalis, JE\n\nM Ridker, P\n\nRose, LM\n\nSever, P\n\nShimbo, D\n\nSteele, L\n\nStolk, RP\n\nThorand, B\n\nTrip, MD\n\nvan Duijn, CM\n\nVerschuren, WM\n\nWijmenga, C\n\nWyatt, S\n\nYoung, JH\n\nZwinderman, AH\n\nBezzina, CR\n\nBoerwinkle, E\n\nCasas, JP\n\nCaulfield, MJ\n\nChakravarti, A\n\nChasman, DI\n\nDavidson, KW\n\nDoevendans, PA\n\nDominiczak, AF\n\nFitzGerald, GA\n\nGums, JG\n\nFornage, M\n\nHakonarson, H\n\nHalder, I\n\nHillege, HL\n\nIllig, T\n\nJarvik, GP\n\nJohnson, JA\n\nKastelein, JJ\n\nKoenig, W\n\nKumari, M\n\nMärz, W\n\nMurray, SS\n\nO'Connell, JR\n\nOldehinkel, AJ\n\nPankow, JS\n\nRader, DJ\n\nRedline, S\n\nReilly, MP\n\nSchadt, EE\n\nKottke-Marchant, K\n\nSnieder, H\n\nSnyder, M\n\nStanton, AV\n\nTobin, MD\n\nUitterlinden, AG\n\nvan der Harst, P\n\nvan der Schouw, YT\n\nSamani, NJ\n\nWatkins, H\n\nJohnson, AD\n\nReiner, AP\n\nZhu, X\n\nde Bakker, PI\n\nLevy, D\n\nAsselbergs, FW\n\nMunroe, PB\n\nKeating, BJ\n\nBeiträge in Fachzeitschriften\nISI:000332611400009\n24560520.0\n10.1016/j.ajhg.2013.12.016\nPMC3951943\nBlood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50, 00 SNPs in up to 87, 36 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68, 68 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.\n Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n182520\nFetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study.\n\nStampalija, T\n\nThornton, J\n\nMarlow, N\n\nNapolitano, R\n\nBhide, A\n\nPickles, T\n\nBilardo, CM\n\nGordijn, SJ\n\nGyselaers, W\n\nValensise, H\n\nHecher, K\n\nSande, RK\n\nLindgren, P\n\nBergman, E\n\nArabin, B\n\nBreeze, AC\n\nWee, L\n\nGanzevoort, W\n\nRichter, J\n\nBerger, A\n\nBrodszki, J\n\nDerks, J\n\nMecacci, F\n\nMaruotti, GM\n\nMyklestad, K\n\nLobmaier, SM\n\nPrefumo, F\n\nKlaritsch, P\n\nCalda, P\n\nEbbing, C\n\nFrusca, T\n\nRaio, L\n\nVisser, GHA\n\nKrofta, L\n\nCetin, I\n\nFerrazzi, E\n\nCesari, E\n\nWolf, H\n\nLees, CC\n\nTRUFFLE-2 Group\n\nBeiträge in Fachzeitschriften\nISI:000554747100004\n32557921.0\n10.1002/uog.22125\nNone\nTo explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction.\n This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored.\n The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association.\n In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.\n © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.\n\nGreimel, Patrick\n\nKlaritsch, Philipp\n\n\n"
},
{
"text": "\n182352\nCommon Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.\n\nArmstrong, NJ\n\nMather, KA\n\nSargurupremraj, M\n\nKnol, MJ\n\nMalik, R\n\nSatizabal, CL\n\nYanek, LR\n\nWen, W\n\nGudnason, VG\n\nDueker, ND\n\nElliott, LT\n\nHofer, E\n\nBis, J\n\nJahanshad, N\n\nLi, S\n\nLogue, MA\n\nLuciano, M\n\nScholz, M\n\nSmith, AV\n\nTrompet, S\n\nVojinovic, D\n\nXia, R\n\nAlfaro-Almagro, F\n\nAmes, D\n\nAmin, N\n\nAmouyel, P\n\nBeiser, AS\n\nBrodaty, H\n\nDeary, IJ\n\nFennema-Notestine, C\n\nGampawar, PG\n\nGottesman, R\n\nGriffanti, L\n\nJack, CR\n\nJenkinson, M\n\nJiang, J\n\nKral, BG\n\nKwok, JB\n\nLampe, L\n\nC M Liewald, D\n\nMaillard, P\n\nMarchini, J\n\nBastin, ME\n\nMazoyer, B\n\nPirpamer, L\n\nRafael Romero, J\n\nRoshchupkin, GV\n\nSchofield, PR\n\nSchroeter, ML\n\nStott, DJ\n\nThalamuthu, A\n\nTrollor, J\n\nTzourio, C\n\nvan der Grond, J\n\nVernooij, MW\n\nWitte, VA\n\nWright, MJ\n\nYang, Q\n\nMorris, Z\n\nSiggurdsson, S\n\nPsaty, B\n\nVillringer, A\n\nSchmidt, H\n\nHaberg, AK\n\nvan Duijn, CM\n\nJukema, JW\n\nDichgans, M\n\nSacco, RL\n\nWright, CB\n\nKremen, WS\n\nBecker, LC\n\nThompson, PM\n\nMosley, TH\n\nWardlaw, JM\n\nIkram, MA\n\nAdams, HHH\n\nSeshadri, S\n\nSachdev, PS\n\nSmith, SM\n\nLauner, L\n\nLongstreth, W\n\nDeCarli, C\n\nSchmidt, R\n\nFornage, M\n\nDebette, S\n\nNyquist, PA\n\nBeiträge in Fachzeitschriften\nISI:000544979200041\n32517579.0\n10.1161/STROKEAHA.119.027544\nPMC7365038\nPeriventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.\n Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26, 54 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.\n In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.\n Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.\n\nGampawar, Piyush Gajananrao\n\nHofer, Edith\n\nPirpamer, Lukas\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n172710\nAssociation of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis.\n\nMarini, S\n\nCrawford, K\n\nMorotti, A\n\nLee, MJ\n\nPezzini, A\n\nMoomaw, CJ\n\nFlaherty, ML\n\nMontaner, J\n\nRoquer, J\n\nJimenez-Conde, J\n\nGiralt-Steinhauer, E\n\nElosua, R\n\nCuadrado-Godia, E\n\nSoriano-Tarraga, C\n\nSlowik, A\n\nJagiella, JM\n\nPera, J\n\nUrbanik, A\n\nPichler, A\n\nHansen, BM\n\nMcCauley, JL\n\nTirschwell, DL\n\nSelim, M\n\nBrown, DL\n\nSilliman, SL\n\nWorrall, BB\n\nMeschia, JF\n\nKidwell, CS\n\nTestai, FD\n\nKittner, SJ\n\nSchmidt, H\n\nEnzinger, C\n\nDeary, IJ\n\nRannikmae, K\n\nSamarasekera, N\n\nAl-Shahi Salman, R\n\nSudlow, CL\n\nKlijn, CJM\n\nvan Nieuwenhuizen, KM\n\nFernandez-Cadenas, I\n\nDelgado, P\n\nNorrving, B\n\nLindgren, A\n\nGoldstein, JN\n\nViswanathan, A\n\nGreenberg, SM\n\nFalcone, GJ\n\nBiffi, A\n\nLangefeld, CD\n\nWoo, D\n\nRosand, J\n\nAnderson, CD\n\nInternational Stroke Genetics Consortium\n\nBeiträge in Fachzeitschriften\nISI:000463873600017\n30726504.0\n10.1001/jamaneurol.2018.4519\nPMC6459133\nGenetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations.\n To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH.\n This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study.\n Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies.\n In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity.\n APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.\n\nEnzinger, Christian\n\nSchmidt, Helena\n\n\n"
},
{
"text": "\n880\nEffects of the non-peptide B2 antagonist FR173657 on kinin-induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release.\n\nGriesbacher, T\n\nSametz, W\n\nLegat, FJ\n\nDiethart, S\n\nHammer, S\n\nJuan, H\n\nBeiträge in Fachzeitschriften\nISI:A1997XA40600016\n9179388.0\n10.1038/sj.bjp.0701159\nPMC1564713\n1. The non-peptide bradykinin (BK) antagonist (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2, -dichloro-3-[(2-methyl-8-quinolin yl) oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular in vitro preparations. The investigation aimed at determining the antagonistic potency, duration of action, specificity for BK receptors and apparent mode of antagonistic action of FR173657. 2. Contractions of the isolated ileum of the guinea-pig in response to BK were inhibited by FR173657 (10-300 nM) in a concentration-dependent manner. The inhibition lasted for up to 90 min after wash-out of FR173657. Cumulative concentration-response curves to BK were shifted to the right with a concomitant decrease in the maximum effect. A pKB value of 8.7 was determined. FR173657 had no effect on contractions induced by acetylcholine, histamine, 5-hydroxytryptamine, substance P, angiotensin II or caerulein. 3. The concentration-response curves for B2 receptor-mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK effect in the presence of FR173657 (10-300 nM). A pKB of 9.0 +/- 0.2 was calculated. FR173657 had no effect on B1 receptor-mediated relaxations in response to des-Arg9-BK. 4. The concentration-response curves for BK-induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3-300 nM) in a concentration-dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of -0.98 indicating a competitive mode of antagonism. A pA2 value of 9.1 was determined. 5. Contractions of the circular smooth muscles of the guinea-pig isolated trachea in response to BK were concentration-dependently inhibited by FR173657 (10-100 nM). An affinity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaffected by FR173657. 6. In the rabbit isolated perfused ear, BK (0.01-10 nmol) produced a dose-dependent vasoconstriction. In the presence of 30 nM FR173657, the effects of BK were reduced by at least 60%, while FR173657 completely abolished the effects of all BK doses at 300 nM. FR173657 did not affect vasoconstriction induced by noradrenaline or angiotensin II. 7. The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of the prostaglandins E2 and I2 into the venous effluent. The BK-stimulated prostaglandin release was completely abolished in the presence of FR173657 (300 nM) while the basal prostaglandin release was unchanged. 8. In summary, FR173657 was shown to be a highly potent and selective BK antagonist which was active on B2, but not B1, receptors. FR173657 was a competitive antagonist in the rat uterus but showed a deviation from competitive inhibition in the other preparations studied similar to other second generation peptide antagonists. The inhibitory action in vitro was long-lasting, but was fully reversible.\n\nGriesbacher, Thomas\n\nLegat, Franz\n\n\n"
},
{
"text": "\n1069\nFibrosarcomatous (high-grade) dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance.\n\nMentzel, T\n\nBeham, A\n\nKatenkamp, D\n\nDei Tos, AP\n\nFletcher, CD\n\nBeiträge in Fachzeitschriften\nISI:000073513800009\n9591728.0\n10.1097%2F00000478-199805000-00009\nNone\nThe fibrosarcomatous variant of dermatofibrosarcoma protuberans (FS-DFSP) represents an uncommon form of DFSP, in which the prognostic influence of the fibrosarcomatous component is still debated. We analyzed the clinicopathologic and immunohistochemical features in a series of 41 patients. Patient age ranged from 8 to 87 years (median, 48 years), and 19 patients were female. Twenty five lesions were seen on the trunk, 6 on the upper limbs, and 4 on the lower limbs, and five neoplasms were located in the head/neck region; in one case, exact anatomic site was unknown. Twenty seven tumors involved purely dermal and subcutaneous tissues, in 10 cases, deeper structures were also involved, 1 case arose in the breast, and, in 3 cases, it was impossible to define exact depth of the lesion. Preoperative duration ranged from 1 month to 60 years (median, 3 years). Twenty six tumors were excised locally with clear margins, 7 were treated by wide excision, 3 by incomplete excision, and, in 4 patients, the lesion was shelled out. In one case, exact treatment was unknown. In addition, radiotherapy was administered in three cases and chemotherapy in one case. Histologically, the lesions showed areas of typical, low-grade DFSP adjacent to fibrosarcomatous areas. In four cases, a previously ordinary DFSP recurred as pure fibrosarcoma, in two cases, local recurrence of FS-DFSP showed features of ordinary DFSP. Fibrosarcomatous change was more common in the primary (de novo) lesions than in recurrent lesions (3.6:1). Proportion of fibrosarcoma varied between < 30% in 6 cases to > 70% of tumor tissue in 21 cases. An abrupt transition between both components was seen in 19 cases. The fibrosarcomatous component showed focal necrosis in seven cases and showed a higher mitotic rate in comparison with ordinary DFSP areas (mean, 13.4 versus 2.3 mitoses in 10 high-power fields). Additional histologic features included progression to pleomorphic sarcoma in 2 recurrent cases, melanin-pigmented cells (Bednar FS-DFSP) in 1 case, focal myxoid change in 13 cases, plaque or keloidlike hyalinization in 3 cases, and myoid bundles and nodules in 9 cases. Immunohistochemically, tumor cells in DFSP areas stained positively for CD34, whereas, in FS-DFSP areas, only 15 out 33 cases were positive for CD34. Follow-up in 34 of 41 patients (mean, 90 months; median, 36 months) revealed local recurrence in 20 patients (58%) (recurrence occurred in 5 patients on two or more occasions). Metastases (5 lung, 1 bone, and 1 soft tissue) were seen in 5 patients (14.7%), and 2 patients have died of tumor to date (5.8%). Necrosis, high mitotic rate (> 10 mitoses per 10 high-power fields), and presence of pleomorphic areas in FS-DFSP tended to be related with poor clinical outcome, but no statistically significant association was detected. Fibrosarcomatous change in DFSP represents a form of tumor progression in DFSP and is associated with a significantly more aggressive clinical course than in ordinary DFSP, indicating a possible need for treatment intensification in such cases.\n\n\n"
},
{
"text": "\n157360\nDay-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study.\n\nBally, L\n\nThabit, H\n\nKojzar, H\n\nMader, JK\n\nQerimi-Hyseni, J\n\nHartnell, S\n\nTauschmann, M\n\nAllen, JM\n\nWilinska, ME\n\nPieber, TR\n\nEvans, ML\n\nHovorka, R\n\nBeiträge in Fachzeitschriften\nISI:000396829400017\n28094136.0\n10.1016/S2213-8587(17)30001-3\nPMC5379244\nTight control of blood glucose concentration in people with type 1 diabetes predisposes to hypoglycaemia. We aimed to investigate whether day-and-night hybrid closed-loop insulin delivery can improve glucose control while alleviating the risk of hypoglycaemia in adults with HbA1c below 7·5% (58 mmol/mol).\n In this open-label, randomised, crossover study, we recruited adults (aged ≥18 years) with type 1 diabetes and HbA1c below 7·5% from Addenbrooke's Hospital (Cambridge, UK) and Medical University of Graz (Graz, Austria). After a 2-4 week run-in period, participants were randomly assigned (1:1), using web-based randomly permuted blocks of four, to receive insulin via the day-and-night hybrid closed-loop system or usual pump therapy for 4 weeks, followed by a 2-4 week washout period and then the other intervention for 4 weeks. Treatment interventions were unsupervised and done under free-living conditions. During the closed-loop period, a model-predictive control algorithm directed insulin delivery, and prandial insulin delivery was calculated with a standard bolus wizard. The primary outcome was the proportion of time when sensor glucose concentration was in target range (3·9-10·0 mmol/L) over the 4 week study period. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02727231, and is completed.\n Between March 21 and June 24, 2016, we recruited 31 participants, of whom 29 were randomised. One participant withdrew during the first closed-loop period because of dissatisfaction with study devices and glucose control. The proportion of time when sensor glucose concentration was in target range was 10·5 percentage points higher (95% CI 7·6-13·4; p<0·0001) during closed-loop delivery compared with usual pump therapy (65·6% [SD 8·1] when participants used usual pump therapy vs 76·2% [6·4] when they used closed-loop). Compared with usual pump therapy, closed-loop delivery also reduced the proportion of time spent in hypoglycaemia: the proportion of time with glucose concentration below 3·5 mmol/L was reduced by 65% (53-74, p<0·0001) and below 2·8 mmol/L by 76% (59-86, p<0·0001). No episodes of serious hypoglycaemia or other serious adverse events occurred.\n Use of day-and-night hybrid closed-loop insulin delivery under unsupervised, free-living conditions for 4 weeks in adults with type 1 diabetes and HbA1c below 7·5% is safe and well tolerated, improves glucose control, and reduces hypoglycaemia burden. Larger and longer studies are warranted.\n Swiss National Science Foundation (P1BEP3_165297), JDRF, UK National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award (100574/Z/12/Z).\n Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.\n\nKojzar, Harald\n\nMader, Julia\n\nPieber, Thomas\n\nQerimi-Hyseni, Jehona\n\n\n"
},
{
"text": "\n159826\nThe 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After.\n\nBassi, C\n\nMarchegiani, G\n\nDervenis, C\n\nSarr, M\n\nAbu Hilal, M\n\nAdham, M\n\nAllen, P\n\nAndersson, R\n\nAsbun, HJ\n\nBesselink, MG\n\nConlon, K\n\nDel Chiaro, M\n\nFalconi, M\n\nFernandez-Cruz, L\n\nFernandez-Del Castillo, C\n\nFingerhut, A\n\nFriess, H\n\nGouma, DJ\n\nHackert, T\n\nIzbicki, J\n\nLillemoe, KD\n\nNeoptolemos, JP\n\nOlah, A\n\nSchulick, R\n\nShrikhande, SV\n\nTakada, T\n\nTakaori, K\n\nTraverso, W\n\nVollmer, CR\n\nWolfgang, CL\n\nYeo, CJ\n\nSalvia, R\n\nBuchler, M\n\nInternational Study Group on Pancreatic Surgery (ISGPS)\n\nBeiträge in Fachzeitschriften\nISI:000394729100004\n28040257.0\n10.1016/j.surg.2016.11.014\nNone\nIn 2005, the International Study Group of Pancreatic Fistula developed a definition and grading of postoperative pancreatic fistula that has been accepted universally. Eleven years later, because postoperative pancreatic fistula remains one of the most relevant and harmful complications of pancreatic operation, the International Study Group of Pancreatic Fistula classification has become the gold standard in defining postoperative pancreatic fistula in clinical practice. The aim of the present report is to verify the value of the International Study Group of Pancreatic Fistula definition and grading of postoperative pancreatic fistula and to update the International Study Group of Pancreatic Fistula classification in light of recent evidence that has emerged, as well as to address the lingering controversies about the original definition and grading of postoperative pancreatic fistula.\n The International Study Group of Pancreatic Fistula reconvened as the International Study Group in Pancreatic Surgery in order to perform a review of the recent literature and consequently to update and revise the grading system of postoperative pancreatic fistula.\n Based on the literature since 2005 investigating the validity and clinical use of the original International Study Group of Pancreatic Fistula classification, a clinically relevant postoperative pancreatic fistula is now redefined as a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula. Consequently, the former "grade A postoperative pancreatic fistula" is now redefined and called a "biochemical leak, because it has no clinical importance and is no longer referred to a true pancreatic fistula. Postoperative pancreatic fistula grades B and C are confirmed but defined more strictly. In particular, grade B requires a change in the postoperative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures. Grade C postoperative pancreatic fistula refers to those postoperative pancreatic fistula that require reoperation or lead to single or multiple organ failure and/or mortality attributable to the pancreatic fistula.\n This new definition and grading system of postoperative pancreatic fistula should lead to a more universally consistent evaluation of operative outcomes after pancreatic operation and will allow for a better comparison of techniques used to mitigate the rate and clinical impact of a pancreatic fistula. Use of this updated classification will also allow for more precise comparisons of surgical quality between surgeons and units who perform pancreatic surgery.\n Copyright © 2016 Elsevier Inc. All rights reserved.\n\n\n"
},
{
"text": "\n159849\nAzacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group.\n\nPleyer, L\n\nDöhner, H\n\nDombret, H\n\nSeymour, JF\n\nSchuh, AC\n\nBeach, CL\n\nSwern, AS\n\nBurgstaller, S\n\nStauder, R\n\nGirschikofsky, M\n\nSill, H\n\nSchlick, K\n\nThaler, J\n\nHalter, B\n\nMachherndl Spandl, S\n\nZebisch, A\n\nPichler, A\n\nPfeilstöcker, M\n\nAutzinger, EM\n\nLang, A\n\nGeissler, K\n\nVoskova, D\n\nSperr, WR\n\nHojas, S\n\nRogulj, IM\n\nAndel, J\n\nGreil, R\n\nBeiträge in Fachzeitschriften\nISI:000395457700183\n28212292.0\n10.3390/ijms18020415\nPMC5343949\nWe recently published a clinically-meaningful improvement in median overall survival (OS) for patients with acute myeloid leukaemia (AML), >30% bone marrow (BM) blasts and white blood cell (WBC) count ≤15 G/L, treated with front-line azacitidine versus conventional care regimens within a phase 3 clinical trial (AZA-AML-001; NCT01074047; registered: February 2010). As results obtained in clinical trials are facing increased pressure to be confirmed by real-world data, we aimed to test whether data obtained in the AZA-AML-001 trial accurately represent observations made in routine clinical practice by analysing additional AML patients treated with azacitidine front-line within the Austrian Azacitidine Registry (AAR; NCT01595295; registered: May 2012) and directly comparing patient-level data of both cohorts. We assessed the efficacy of front-line azacitidine in a total of 407 patients with newly-diagnosed AML. Firstly, we compared data from AML patients with WBC ≤ 15 G/L and >30% BM blasts included within the AZA-AML-001 trial treated with azacitidine ("AML-001" cohort; n = 214) with AAR patients meeting the same inclusion criteria ("AAR (001-like)" cohort; n = 95). The current analysis thus represents a new sub-analysis of the AML-001 trial, which is directly compared with a new sub-analysis of the AAR. Baseline characteristics, azacitidine application, response rates and OS were comparable between all patient cohorts within the trial or registry setting. Median OS was 9.9 versus 10.8 months (p = 0.616) for "AML-001" versus "AAR (001-like)" cohorts, respectively. Secondly, we pooled data from both cohorts (n = 309) and assessed the outcome. Median OS of the pooled cohorts was 10.3 (95% confidence interval: 8.7, 12.6) months, and the one-year survival rate was 45.8%. Thirdly, we compared data from AAR patients meeting AZA-AML-001 trial inclusion criteria (n = 95) versus all AAR patients with World Health Organization (WHO)-defined AML ("AAR (WHO-AML)" cohort; n = 193). Within the registry population, median OS for AAR patients meeting trial inclusion criteria versus all WHO-AML patients was 10.8 versus 11.8 months (p = 0.599), respectively. We thus tested and confirmed the efficacy of azacitidine as a front-line agent in patients with AML, >30% BM blasts and WBC ≤ 15 G/L in a routine clinical practice setting. We further show that the efficacy of azacitidine does not appear to be limited to AML patients who meet stringent clinical trial inclusion criteria, but instead appears efficacious as front-line treatment in all patients with WHO-AML.\n\nSill, Heinz\n\nZebisch, Armin\n\n\n"
},
{
"text": "\n164374\nAssessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors\n\nHendry, S\n\nSalgado, R\n\nGevaert, T\n\nRussell, PA\n\nJohn, T\n\nThapa, B\n\nChristie, M\n\nvan de Vijver, K\n\nEstrada, MV\n\nGonzalez-Ericsson, PI\n\nSanders, M\n\nSolomon, B\n\nSolinas, C\n\nVan den Eynden, GGGM\n\nAllory, Y\n\nPreusser, M\n\nHainfellner, J\n\nPruneri, G\n\nVingiani, A\n\nDemaria, S\n\nSymmans, F\n\nNuciforo, P\n\nComerma, L\n\nThompson, EA\n\nLakhani, S\n\nKim, SR\n\nSchnitt, S\n\nColpaert, C\n\nSotiriou, C\n\nScherer, SJ\n\nIgnatiadis, M\n\nBadve, S\n\nPierce, RH\n\nViale, G\n\nSirtaine, N\n\nPenault-Llorca, F\n\nSugie, T\n\nFineberg, S\n\nPaik, S\n\nSrinivasan, A\n\nRichardson, A\n\nWang, Y\n\nChmielik, E\n\nBrock, J\n\nJohnson, DB\n\nBalko, J\n\nWienert, S\n\nBossuyt, V\n\nMichiels, S\n\nTernes, N\n\nBurchardi, N\n\nLuen, SJ\n\nSavas, P\n\nKlauschen, F\n\nWatson, PH\n\nNelson, BH\n\nCriscitiello, C\n\nO'Toole, S\n\nLarsimont, D\n\nde Wind, R\n\nCurigliano, G\n\nAndre, F\n\nLacroix-Triki, M\n\nvan de Vijver, M\n\nRojo, F\n\nFloris, G\n\nBedri, S\n\nSparano, J\n\nRimm, D\n\nNielsen, T\n\nKos, Z\n\nHewitt, S\n\nSingh, B\n\nFarshid, G\n\nLoibl, S\n\nAllison, KH\n\nTung, N\n\nAdams, S\n\nWillard-Gallo, K\n\nHorlings, HM\n\nGandhi, L\n\nMoreira, A\n\nHirsch, F\n\nDieci, MV\n\nUrbanowicz, M\n\nBrcic, I\n\nKorski, K\n\nGaire, F\n\nKoeppen, H\n\nLo, A\n\nGiltnane, J\n\nRebelatto, MC\n\nSteele, KE\n\nZha, JP\n\nEmancipator, K\n\nJuco, JW\n\nDenkert, C\n\nReis, J\n\nLoi, S\n\nFox, SB\n\nBeiträge in Fachzeitschriften\nISI:000417940400001\n28777143.0\nNone\nPMC5638696\nAssessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.\n\nBrcic, Iva\n\n\n"
},
{
"text": "\n186974\nProbability of major depression diagnostic classification based on the SCID, CIDI and MINI diagnostic interviews controlling for Hospital Anxiety and Depression Scale - Depression subscale scores: An individual participant data meta-analysis of 73 primary studies.\n\nWu, Y\n\nLevis, B\n\nSun, Y\n\nKrishnan, A\n\nHe, C\n\nRiehm, KE\n\nRice, DB\n\nAzar, M\n\nYan, XW\n\nNeupane, D\n\nBhandari, PM\n\nImran, M\n\nChiovitti, MJ\n\nSaadat, N\n\nBoruff, JT\n\nCuijpers, P\n\nGilbody, S\n\nMcMillan, D\n\nIoannidis, JPA\n\nKloda, LA\n\nPatten, SB\n\nShrier, I\n\nZiegelstein, RC\n\nHenry, M\n\nIsmail, Z\n\nLoiselle, CG\n\nMitchell, ND\n\nTonelli, M\n\nAl-Adawi, S\n\nBeraldi, A\n\nBraeken, APBM\n\nBüel-Drabe, N\n\nBunevicius, A\n\nCarter, G\n\nChen, CK\n\nCheung, G\n\nClover, K\n\nConroy, RM\n\nCukor, D\n\nda Rocha E Silva, CE\n\nDabscheck, E\n\nDaray, FM\n\nDouven, E\n\nDowning, MG\n\nFeinstein, A\n\nFerentinos, PP\n\nFischer, FH\n\nFlint, AJ\n\nFujimori, M\n\nGallagher, P\n\nGandy, M\n\nGoebel, S\n\nGrassi, L\n\nHärter, M\n\nJenewein, J\n\nJetté, N\n\nJulião, M\n\nKim, JM\n\nKim, SW\n\nKjærgaard, M\n\nKöhler, S\n\nLoosman, WL\n\nLöwe, B\n\nMartin-Santos, R\n\nMassardo, L\n\nMatsuoka, Y\n\nMehnert, A\n\nMichopoulos, I\n\nMisery, L\n\nNavines, R\n\nO'Donnell, ML\n\nÖztürk, A\n\nPeceliuniene, J\n\nPintor, L\n\nPonsford, JL\n\nQuinn, TJ\n\nReme, SE\n\nReuter, K\n\nRooney, AG\n\nSánchez-González, R\n\nSchwarzbold, ML\n\nSenturk Cankorur, V\n\nShaaban, J\n\nSharpe, L\n\nSharpe, M\n\nSimard, S\n\nSinger, S\n\nStafford, L\n\nStone, J\n\nSultan, S\n\nTeixeira, AL\n\nTiringer, I\n\nTurner, A\n\nWalker, J\n\nWalterfang, M\n\nWang, LJ\n\nWhite, J\n\nWong, DK\n\nBenedetti, A\n\nThombs, BD\n\nBeiträge in Fachzeitschriften\nISI:000509003700006\n31911325.0\n10.1016/j.jpsychores.2019.109892\nNone\nTwo previous individual participant data meta-analyses (IPDMAs) found that different diagnostic interviews classify different proportions of people as having major depression overall or by symptom levels. We compared the odds of major depression classification across diagnostic interviews among studies that administered the Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D).\n Data accrued for an IPDMA on HADS-D diagnostic accuracy were analysed. We fit binomial generalized linear mixed models to compare odds of major depression classification for the Structured Clinical Interview for DSM (SCID), Composite International Diagnostic Interview (CIDI), and Mini International Neuropsychiatric Interview (MINI), controlling for HADS-D scores and participant characteristics with and without an interaction term between interview and HADS-D scores.\n There were 15, 56 participants (1942 [12%] with major depression) from 73 studies, including 15, 35 (97%) non-psychiatric medical patients, 164 (1%) partners of medical patients, and 357 (2%) healthy adults. The MINI (27 studies, 7345 participants, 1066 major depression cases) classified participants as having major depression more often than the CIDI (10 studies, 3023 participants, 269 cases) (adjusted odds ratio [aOR] = 1.70 (0.84, 3.43)) and the semi-structured SCID (36 studies, 5488 participants, 607 cases) (aOR = 1.52 (1.01, 2.30)). The odds ratio for major depression classification with the CIDI was less likely to increase as HADS-D scores increased than for the SCID (interaction aOR = 0.92 (0.88, 0.96)).\n Compared to the SCID, the MINI may diagnose more participants as having major depression, and the CIDI may be less responsive to symptom severity.\n Copyright © 2019 Elsevier Inc. All rights reserved.\n\nJenewein, Josef\n\n\n"
},
{
"text": "\n178782\nInternational prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study.\n\nSperr, WR\n\nKundi, M\n\nAlvarez-Twose, I\n\nvan Anrooij, B\n\nOude Elberink, JNG\n\nGorska, A\n\nNiedoszytko, M\n\nGleixner, KV\n\nHadzijusufovic, E\n\nZanotti, R\n\nBonadonna, P\n\nBonifacio, M\n\nPerkins, C\n\nIllerhaus, A\n\nElena, C\n\nMerante, S\n\nShoumariyeh, K\n\nvon Bubnoff, N\n\nParente, R\n\nJawhar, M\n\nBelloni Fortina, A\n\nCaroppo, F\n\nBrockow, K\n\nZink, A\n\nFuchs, D\n\nKilbertus, AJ\n\nYavuz, AS\n\nDoubek, M\n\nHägglund, H\n\nPanse, J\n\nSabato, V\n\nBretterklieber, A\n\nNiederwieser, D\n\nBreynaert, C\n\nHartmann, K\n\nTriggiani, M\n\nNedoszytko, B\n\nReiter, A\n\nOrfao, A\n\nHermine, O\n\nGotlib, J\n\nArock, M\n\nKluin-Nelemans, HC\n\nValent, P\n\nBeiträge in Fachzeitschriften\nISI:000499118000009\n31676322.0\n10.1016/S2352-3026(19)30166-8\nPMC7115823\nThe WHO classification separates mastocytosis into distinct variants, but prognostication remains a clinical challenge. The aim of this study was to improve prognostication for patients with mastocytosis.\n We analysed data of the registry of the European Competence Network on Mastocytosis including 1639 patients (age 17-90 years) diagnosed with mastocytosis according to WHO criteria between Jan 12, 1978, and March 16, 2017. Univariate and multivariate analyses with Cox regression were applied to identify prognostic variables predicting survival outcomes and to establish a prognostic score. We validated this International Prognostic Scoring System in Mastocytosis (IPSM) with data of 462 patients (age 17-79 years) from the Spanish network Red Española de Mastocitosis diagnosed between Jan 22, 1998, and Nov 2, 2017.\n The prognostic value of the WHO classification was confirmed in our study (p<0·0001). For patients with non-advanced mastocytosis (n=1380), we identified age 60 years or older (HR 10·75, 95% CI 5·68-20·32) and a concentration of alkaline phosphatase 100 U/L or higher (2·91, 1·60-5·30) as additional independent prognostic variables for overall survival. The resulting scoring system divided patients with non-advanced mastocytosis into three groups: low (no risk factors), intermediate 1 (one risk factor), and intermediate 2 (two risk factors). Overall survival and progression-free survival differed significantly among these groups (p<0·0001). In patients with advanced mastocytosis (n=259), age 60 years or older (HR 2·14, 95% CI 1·42-3·22), a concentration of tryptase 125 ng/mL or higher (1·81, 1·20-2·75), a leukocyte count of 16 × 109 per L or higher (1·88, 1·27-2·79), haemoglobin of 11 g/dL or lower (1·71, 1·13-2·57), a platelet count of 100 × 109 per L or lower (1·63, 1·13-2·34), and skin involvement (0·46, 0·30-0·69) were prognostic variables. Based on these variables, a separate score for advanced mastocytosis with four risk categories was established, with significantly different outcomes for overall survival and progression-free survival (p<0·0001). The prognostic value of both scores was confirmed in 413 patients with non-advanced disease and 49 with advanced mastocytosis from the validation cohort.\n The IPSM scores for patients with non-advanced and advanced mastocytosis can be used to predict survival outcomes and guide treatment decisions. However, the predictive value of the IPSM needs to be confirmed in forthcoming trials.\n Austrian Science Fund, Deutsche Forschungsgemeinschaft, Koeln Fortune Program, Charles and Ann Johnson Foundation, Instituto de Salud Carlos III, Fondos FEDER, Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek, Clinical Research-Fund of the University Hospitals Leuven, and Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek.\n Copyright © 2019 Elsevier Ltd. All rights reserved.\n\n\n"
},
{
"text": "\n187852\nSubchondral Bone Changes Following Sacroiliac Joint Arthrodesis - A Morpho-mechanical Assessment of Surgical Treatment of the Painful Joint\n\nPoilliot, A\n\nKurosawa, D\n\nToranelli, M\n\nZhang, M\n\nZwirner, J\n\nMuller-Gerbl, M\n\nHammer, N\n\nBeiträge in Fachzeitschriften\nISI:000652433400006\n33988953.0\nNone\nNone\nBackground: Sacroiliac joint arthrodesis is an ultima ratio treatment option for sacroiliac joint dysfunction. Fusion drastically reduces sacroiliac joint movement providing long-lasting pain-relief associated with tension-relief to the innervated sacroiliac joint structures involved in force closure. Objectives: To display the bone mineralization distribution patterns of the subchondral bone plate in 3 distinct regions (superior, anterior, and inferior) of the sacral and iliac counterparts of the sacroiliac joint pre- and post-sacroiliac joint arthrodesis and compare patterns of sacroiliac joint dysfunction post-sacroiliac joint fusion with sacroiliac joint dysfunction pre- arthrodesis patterns and those from healthy controls. Study Design: An observational study. Setting: The research took place at the University of Basel, Switzerland, where the specific image analysis program (Analyze, v7.4, Biomedical Imaging Resources, Mayo Foundation, Rochester, NY, USA) was made available. Methods: Mineralization densitograms of 18 sacroiliac joint dysfunction patients pre- and post-sacroiliac joint arthrodesis (>= 6, >= 12, and >= 24 months post-surgery) were obtained using computed tomography osteoabsorptiometry. For each patient, pre- vs. post-surgery statistical comparisons were undertaken, using the Hounsfield unit values derived from the subchondral mineralization of superior, anterior, and inferior regions on the iliac and sacral auricular surfaces. Post-operative values were also compared to those from a healthy control cohort (n = 39). Results: In the pre-operative cohort at all 3 follow-up times, the superior iliac region showed significantly higher Hounsfield unit values than the corresponding sacral region (P < 0.01). Mineralization comparisons were similar for the sacrum and ilium in the anterior and inferior regions at all follow-up points (P > 0.5) with no surgery-related changes. Sacral density increased significantly in the post-operative state; not observed on the ilium. Post-operative sacroiliac joints showed a significantly increased mineralization in the superior sacrum after >= 6 months (P < 0.05), not replicated after = 12 nor = 24 months. Further comparison of post-operative scans versus healthy controls revealed significantly increased mineralization in the superior sacral region at (>=) 6, 12, and 24 months (P < 0.01), likely related to bone grafting, and in the anterior and inferior regions in post-operative scans at >= 12 and >= 24 months follow-up (P < 0.05). Limitations: The given study is limited in sample size. Post-operative computed tomography scans had screws which may have left artifacts or partial volume effects on the surfaces. Healthy controls were different patients to the sacroiliac joint dysfunction and post-operative cohorts. Both cohorts were agematched but this comparison did not take into account potential population differences. Size differences in the regions may have also been an influencing factor of the results as the regions were based on the size and shape of the articular surface. Conclusions: Sacroiliac joint arthrodesis results in an increased morpho-mechanical conformity in the anterior and inferior sacrum and reflects variable morpho-mechanical density patterns compared to the healthy state due to permanent alterations in the kinematics of the posterior pelvis.\n\nHammer, Niels\n\n\n"
},
{
"text": "\n2484\nTachykinin receptors are involved in the "local efferent" motor response to capsaicin in the guinea-pig small intestine and oesophagus.\n\nBarthó, L\n\nLénárd, L\n\nPatacchini, R\n\nHalmai, V\n\nWilhelm, M\n\nHolzer, P\n\nMaggi, CA\n\nBeiträge in Fachzeitschriften\nISI:000078937400020\n10188948.0\n10.1016/S0306-4522(98)00459-X\nNone\nThe sensory neuron stimulant drug capsaicin stimulates primary afferent nerve endings in the guinea-pig small intestine, which in turn activate myenteric cholinergic neurons by an unknown mechanism. The tachykinins substance P and neurokinin A are present in primary afferent neurons. This study was performed to assess the possible involvement of endogenous tachykinins acting via neurokinin-1, neurokinin-2 and neurokinin-3 receptors in the contractile effect of capsaicin in the isolated guinea-pig ileum and oesophagus by using the receptor-specific antagonists GR 82334 (3 microM) for neurokinin-1 receptors, MEN 10627 (3 microM; ileum) or MEN 11420 (1 microM; oesophagus) for neurokinin-2 receptors and SR 142801 (0.1 microM) for neurokinin-3 receptors. In the ileum, the peak contraction evoked by capsaicin (2 microM) was not reduced when tachykinin neurokinin-1, neurokinin-2 or neurokinin-3 receptors were blocked separately, whereas an inhibition of neurokinin-3 receptors diminished the area under the curve of the capsaicin response. A combined blockade of neurokinin-1 and neurokinin-3 receptors significantly depressed the effect of capsaicin; the amplitude of the contractile response was 53.3+/-3.7% of the maximal longitudinal spasm in control preparations, whereas in the presence of GR 82334 plus SR 142801 it reached only 27.6+/-5% (P<0.001, Kruskal-Wallis test; n=9 and 10, respectively). Also, the area under the curve of the contractile response to capsaicin was more than 85% lower in the group of preparations treated with GR 82334 plus SR 142801 than in the control group (P<0.001). Including a neurokinin-2 blocker in the combination did not produce any further inhibition. A concomitant tachyphylaxis to substance P (natural neurokinin-1 receptor stimulant) and the neurokinin-3 receptor agonist senktide (5 and 1 microM, respectively) also reduced the contractile effect of capsaicin. In the oesophagus, capsaicin (1 microM) induced biphasic contractions which were strongly inhibited by atropine (1 microM) or capsaicin pretreatment (1 microM for 10 min). Here again, a blockade of tachykinin neurokinin-1, neurokinin-2 or neurokinin-3 receptors separately failed to inhibit the response to capsaicin, whereas a combined blockade of any two tachykinin receptors caused a partial inhibition. The reduction of the contractile effect of capsaicin was strongest when all three tachykinin receptors were blocked. In seven control preparations, peaks for the first and second phases of contraction reached 35.3+/-3.7% and 20+/-3.2% of maximal longitudinal spasm; the corresponding values in the presence of a combination of GR 82334, MEN 11420 and SR 142801 were 7.5+/-0.8% and 9.1+/-2.2%, respectively (n=6, P<0.001 and 0.05, respectively). Tetrodotoxin (0.5 microM) practically abolished the contractile effect of capsaicin in both tissues studied. It is concluded that an interplay of neuronal tachykinin neurokinin-1 and neurokinin-3 receptors (ileum) and neurokinin-1, neurokinin-2 and neurokinin-3 receptors (oesophagus) is involved in the contractile action of capsaicin, probably in mediating excitation of myenteric neurons by tachykinins released from primary afferents. In both tissues, there also seems to be a non-tachykininergic component of the capsaicin-induced contraction.\n\nHolzer, Peter\n\n\n"
},
{
"text": "\n5254\nDifferential diagnosis of cutaneous infiltrates of B lymphocytes with follicular growth pattern.\n\nLeinweber, B\n\nColli, C\n\nChott, A\n\nKerl, H\n\nCerroni, L\n\nBeiträge in Fachzeitschriften\nISI:000188471300002\n14726817.0\n10.1097%2F00000372-200402000-00002\nNone\nThe differential diagnosis of cutaneous B-cell infiltrates with follicular pattern of growth is one of the most vexing problems in dermatopathology. In this study we focused on histopathologic, immunophenotypic, and molecular differential diagnostic criteria between Borrelia burgdorferi (Bb)-associated lymphocytoma cutis (LC), primary cutaneous follicle center cell lymphoma (FCCL), and primary cutaneous marginal zone lymphoma (MZL) with reactive germinal centers (GCs). A total of 47 patients were included in the study, including 12 cases of LC (M:F = 2:1; mean age: 38.0; median: 31; range: 9-75), 29 cases of FCCL (M:F = 1.2:1; mean age: 57.5; median: 57; range: 24-97), and 6 cases of MZL (M:F = 1:1; mean age: 63.8; median: 67.5; range: 38-86). In all cases complete phenotypic data were available. In addition, the IgH gene rearrangement and the t(14;18) were analyzed using the polymerase chain reaction technique (PCR) in 41 (FCCL = 27, LC = 10, MZL = 4) and 18 cases (FCCL = 15, LC = 2, MZL = 1), respectively. Histology revealed in all cases of FCCL one or more atypical feature of the follicles including the lack of or a reduced mantle zone, lack of polarization, tendency to confluence, and absence of tingible body macrophages. In most cases of Bb-associated LC, the GCs were devoid of mantle zone, lacked polarization, and revealed tendency to confluence as well, but all cases showed the presence of several tingible body macrophages. In MZL, follicles showed typical features of reactive GCs. Immunohistology revealed a reduced proliferative activity of neoplastic follicles as detected by MIB-1 antibody in 23 of 29 cases of FCCL (79.3%), but only in 1 case of LC (8.3%). Proliferation of the GCs was normal in all cases of MZL. Positivity for CD10 and/or Bcl-6 was found in small clusters outside the follicles in 19 cases of FCCL (65.5%), and in 3 cases of LC (25%), but in no case of MZL. The intensity of CD10 staining on follicular cells on average was stronger in cases of FCCL, but overlapping features could be observed. Finally, staining for Bcl-2 protein was consistently negative on GC cells in cases of LC and MZL, and was positive on a variable proportion of the cells in 8 cases of FCCL (28.6%). Molecular analyses showed no evidence of the t(14;18) in all cases tested. Analysis of the IgH gene rearrangement revealed a monoclonal pattern in 1 of 10 cases of LC (10%), 14 of 27 cases of FCCL (51.9%), and 2 of 4 cases of MZL (50%) tested. In summary, Bb-associated LC and FCCL show sometimes overlapping histopathologic, immunohistochemical, and molecular features, whereas follicles in MZL show clear-cut aspects of reactive GCs. Absence of tingible body macrophages within follicles, reduced proliferation of the follicles as detected by immunohistology, presence of positivity for Bcl-2 protein within follicular cells, and monoclonality by PCR are the main criteria suggestive of malignancy. Diagnosis of cutaneous infiltrates of B lymphocytes with follicular growth pattern should be achieved by integration of clinical data with histopathologic, immunohistochemical, and molecular features of the lesions.\n\nCerroni, Lorenzo\n\nKerl, Helmut\n\n\n"
},
{
"text": "\n147148\nChanges in pelvic organ prolapse mesh mechanical properties following implantation in rats.\n\nUlrich, D\n\nEdwards, SL\n\nAlexander, DLJ\n\nRosamilia, A\n\nWerkmeister, JA\n\nGargett, CE\n\nLetouzey, V\n\nBeiträge in Fachzeitschriften\nISI:000369518200015\n26348376.0\n10.1016/j.ajog.2015.08.071\nNone\nPelvic organ prolapse (POP) is a multifactorial disease that manifests as the herniation of the pelvic organs into the vagina. Surgical methods for prolapse repair involve the use of a synthetic polypropylene mesh. The use of this mesh has led to significantly higher anatomical success rates compared with native tissue repairs, and therefore, despite recent warnings by the Food and Drug Administration regarding the use of vaginal mesh, the number of POP mesh surgeries has increased over the last few years. However, mesh implantation is associated with higher postsurgery complications, including pain and erosion, with higher consecutive rates of reoperation when placed vaginally. Little is known on how the mechanical properties of the implanted mesh itself change in vivo. It is assumed that the mechanical properties of these meshes remain unchanged, with any differences in mechanical properties of the formed mesh-tissue complex attributed to the attached tissue alone. It is likely that any changes in mesh mechanical properties that do occur in vivo will have an impact on the biomechanical properties of the formed mesh-tissue complex.\n The objective of the study was to assess changes in the multiaxial mechanical properties of synthetic clinical prolapse meshes implanted abdominally for up to 90 days, using a rat model. Another objective of the study was to assess the biomechanical properties of the formed mesh-tissue complex following implantation.\n Three nondegradable polypropylene clinical synthetic mesh types for prolapse repair (Gynemesh PS, Polyform Lite, and Restorelle) and a partially degradable polypropylene/polyglecaprone mesh (UltraPro) were mechanically assessed before and after implantation (n = 5/ mesh type) in Sprague Dawley rats for 30 (Gynemesh PS, Polyform Lite, and Restorelle) and 90 (UltraPro and Polyform Lite) days. Stiffness and permanent extension following cyclic loading, and breaking load, of the preimplanted mesh types, explanted mesh-tissue complexes, and explanted meshes were assessed using a multi-axial (ball-burst) method.\n The 4 clinical meshes varied from each other in weight, thickness, porosity, and pore size and showed significant differences in stiffness and breaking load before implantation. Following 30 days of implantation, the mechanical properties of some mesh types altered, with significant decreases in mesh stiffness and breaking load, and increased permanent extension. After 90 days these changes were more obvious, with significant decreases in stiffness and breaking load and increased permanent extension. Similar biomechanical properties of formed mesh-tissue complexes were observed for mesh types of different preimplant stiffness and structure after 90 days implantation.\n This is the first study to report on intrinsic changes in the mechanical properties of implanted meshes and how these changes have an impact on the estimated tissue contribution of the formed mesh-tissue complex. Decreased mesh stiffness, strength, and increased permanent extension following 90 days of implantation increase the biomechanical contribution of the attached tissue of the formed mesh-tissue complex more than previously thought. This needs to be considered when using meshes for prolapse repair.\n Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.\n\nGold ehem Ulrich, Daniela\n\n\n"
},
{
"text": "\n88233\nDeterminants of ski-jump performance and implications for health, safety and fairness.\n\nMüller, W\n\nBeiträge in Fachzeitschriften\nISI:000264316100001\n19203132.0\nNone\nNone\nSki jumping puts high demands on the athlete's ability to control posture and movement. The athlete has to solve extremely difficult optimization problems. These implicit decisions and the resulting control manoeuvres can be understood by means of computer simulations. Computer simulations based on wind tunnel input data can identify the determinants for high performance and answer many questions of training methods, safety and health, role of weight, fairness, optimized hill design, sport development, and changes to the regulations. Each of the performance determinants has to be seen in the context of all others in order to understand its importance; the predominant factors are: high in-run velocity, high momentum perpendicular to the ramp at take-off due to the jump and the lift force, accurate timing of the take-off with respect to the ramp edge, appropriate angular momentum at take-off in order to obtain an aerodynamically advantageous and stable flight position as soon as possible, choice of advantageous body and equipment configurations during the entire flight in order to obtain optimum lift and drag values, and the ability to control the flight stability. Wind blowing up the hill increases the jump length dramatically and decreases the landing velocity, which eases the landing, and vice versa for wind from behind. Improvements to reduce unfairness due to changing wind are urgently needed. The current practice of the judges to reduce the score when the athlete has to perform body movements in order to counteract dangerous gusts is irrational. The athletes should rather be rewarded and not punished for their ability to handle such dangerous situations. For the quantification of underweight it is suggested to use the mass index: MI=0.28 m/s2 (where m is the jumper mass and s is the sitting height), which indirectly considers the individual leg length. The MI formula is similar to the body mass index (BMI) formula: the height is replaced by the sitting height s and a factor of 0.28 effects that the MI is equal to the BMI for persons with average leg length. The classification of underweight is not only a question of the cut-off point, as much it is a question of the measure for relative bodyweight used. Low weight is one of the performance determinants; however, it should be considered that very low weight can cause severe performance setbacks due to decreased jumping force, general weakness, reduced ability to cope with pressure, and increased susceptibility for diseases. In the past, several cases of anorexia nervosa among ski jumpers had come to light. The development toward extremely low weight was stopped in 2004 by new Fédération Internationale de Ski ski-jumping regulations, which relate relative body mass to maximum ski length. The 2006/7 and 2008/9 seasons showed that light athletes who had to use skis with just 142% of their height could still win competitions. A further increase of the borderline weight is being discussed. The current regulations are based on the well known BMI; the use of the MI instead of the BMI should be explored in future studies.\n\nMüller, Wolfram\n\n\n"
}
]
}