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"text": "\n162878\nGenome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.\n\nJoshi, PK\n\nPirastu, N\n\nKentistou, KA\n\nFischer, K\n\nHofer, E\n\nSchraut, KE\n\nClark, DW\n\nNutile, T\n\nBarnes, CLK\n\nTimmers, PRHJ\n\nShen, X\n\nGandin, I\n\nMcDaid, AF\n\nHansen, TF\n\nGordon, SD\n\nGiulianini, F\n\nBoutin, TS\n\nAbdellaoui, A\n\nZhao, W\n\nMedina-Gomez, C\n\nBartz, TM\n\nTrompet, S\n\nLange, LA\n\nRaffield, L\n\nvan der Spek, A\n\nGalesloot, TE\n\nProitsi, P\n\nYanek, LR\n\nBielak, LF\n\nPayton, A\n\nMurgia, F\n\nConcas, MP\n\nBiino, G\n\nTajuddin, SM\n\nSeppälä, I\n\nAmin, N\n\nBoerwinkle, E\n\nBørglum, AD\n\nCampbell, A\n\nDemerath, EW\n\nDemuth, I\n\nFaul, JD\n\nFord, I\n\nGialluisi, A\n\nGögele, M\n\nGraff, M\n\nHingorani, A\n\nHottenga, JJ\n\nHougaard, DM\n\nHurme, MA\n\nIkram, MA\n\nJylhä, M\n\nKuh, D\n\nLigthart, L\n\nLill, CM\n\nLindenberger, U\n\nLumley, T\n\nMägi, R\n\nMarques-Vidal, P\n\nMedland, SE\n\nMilani, L\n\nNagy, R\n\nOllier, WER\n\nPeyser, PA\n\nPramstaller, PP\n\nRidker, PM\n\nRivadeneira, F\n\nRuggiero, D\n\nSaba, Y\n\nSchmidt, R\n\nSchmidt, H\n\nSlagboom, PE\n\nSmith, BH\n\nSmith, JA\n\nSotoodehnia, N\n\nSteinhagen-Thiessen, E\n\nvan Rooij, FJA\n\nVerbeek, AL\n\nVermeulen, SH\n\nVollenweider, P\n\nWang, Y\n\nWerge, T\n\nWhitfield, JB\n\nZonderman, AB\n\nLehtimäki, T\n\nEvans, MK\n\nPirastu, M\n\nFuchsberger, C\n\nBertram, L\n\nPendleton, N\n\nKardia, SLR\n\nCiullo, M\n\nBecker, DM\n\nWong, A\n\nPsaty, BM\n\nvan Duijn, CM\n\nWilson, JG\n\nJukema, JW\n\nKiemeney, L\n\nUitterlinden, AG\n\nFranceschini, N\n\nNorth, KE\n\nWeir, DR\n\nMetspalu, A\n\nBoomsma, DI\n\nHayward, C\n\nChasman, D\n\nMartin, NG\n\nSattar, N\n\nCampbell, H\n\nEsko, T\n\nKutalik, Z\n\nWilson, JF\n\nBeiträge in Fachzeitschriften\nISI:000412871300006\n29030599.0\n10.1038/s41467-017-00934-5\nPMC5715013\nGenomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606, 59 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.\n\nHofer, Edith\n\nSABA, Yasaman\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n168641\nRationale and Plan for Vitamin D Food Fortification: A Review and Guidance Paper.\n\nPilz, S\n\nMärz, W\n\nCashman, KD\n\nKiely, ME\n\nWhiting, SJ\n\nHolick, MF\n\nGrant, WB\n\nPludowski, P\n\nHiligsmann, M\n\nTrummer, C\n\nSchwetz, V\n\nLerchbaum, E\n\nPandis, M\n\nTomaschitz, A\n\nGrübler, MR\n\nGaksch, M\n\nVerheyen, N\n\nHollis, BW\n\nRejnmark, L\n\nKarras, SN\n\nHahn, A\n\nBischoff-Ferrari, HA\n\nReichrath, J\n\nJorde, R\n\nElmadfa, I\n\nVieth, R\n\nScragg, R\n\nCalvo, MS\n\nvan Schoor, NM\n\nBouillon, R\n\nLips, P\n\nItkonen, ST\n\nMartineau, AR\n\nLamberg-Allardt, C\n\nZittermann, A\n\nBeiträge in Fachzeitschriften\nISI:000438912900001\n30065699.0\n10.3389/fendo.2018.00373\nPMC6056629\nVitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extraskeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. Vitamin D has a unique metabolism as it is mainly obtained through synthesis in the skin under the influence of sunlight (i.e., ultraviolet-B radiation) whereas intake by nutrition traditionally plays a relatively minor role. Dietary guidelines for vitamin D are based on a consensus that serum 25-hydroxyvitamin D (25[OH]D) concentrations are used to assess vitamin D status, with the recommended target concentrations ranging from ≥25 to ≥50 nmol/L (≥10-≥20 ng/mL), corresponding to a daily vitamin D intake of 10 to 20 μg (400-800 international units). Most populations fail to meet these recommended dietary vitamin D requirements. In Europe, 25(OH)D concentrations <30 nmol/L (12 ng/mL) and <50 nmol/L (20 ng/mL) are present in 13.0 and 40.4% of the general population, respectively. This substantial gap between officially recommended dietary reference intakes for vitamin D and the high prevalence of vitamin D deficiency in the general population requires action from health authorities. Promotion of a healthier lifestyle with more outdoor activities and optimal nutrition are definitely warranted but will not erase vitamin D deficiency and must, in the case of sunlight exposure, be well balanced with regard to potential adverse effects such as skin cancer. Intake of vitamin D supplements is limited by relatively poor adherence (in particular in individuals with low-socioeconomic status) and potential for overdosing. Systematic vitamin D food fortification is, however, an effective approach to improve vitamin D status in the general population, and this has already been introduced by countries such as the US, Canada, India, and Finland. Recent advances in our knowledge on the safety of vitamin D treatment, the dose-response relationship of vitamin D intake and 25(OH)D levels, as well as data on the effectiveness of vitamin D fortification in countries such as Finland provide a solid basis to introduce and modify vitamin D food fortification in order to improve public health with this likewise cost-effective approach.\n\nLerchbaum, Elisabeth\n\nMärz, Winfried\n\nPandis, Marlene\n\nPilz, Stefan\n\nTheiler-Schwetz, Verena\n\nTrummer, Christian\n\nVerheyen, Nicolas Dominik\n\n\n"
},
{
"text": "\n60650\nA prospective analysis of cell-free fetal DNA concentration in maternal plasma as an indicator for adverse pregnancy outcome.\n\nBauer, M\n\nHutterer, G\n\nEder, M\n\nMajer, S\n\nLeshane, E\n\nJohnson, KL\n\nPeter, I\n\nBianchi, DW\n\nPertl, B\n\nBeiträge in Fachzeitschriften\nISI:000241009600011\n16832830.0\n10.1002/pd.1513\nNone\nObjectives To evaluate whether cell-free fetal (cff) DNA in maternal plasma during the second trimester is a marker for developing pregnancy-associated complications. Two PCR techniques for the detection and quantitation of fetal DNA were compared. Methods Plasma samples were prospectively collected from 84 pregnant women carrying male fetuses before amniocentesis (14-29 weeks). We later recorded 26 pregnancies with complicated outcomes, including five cases of fetal chromosomal abnormalities. For statistical analysis, two overlapping subgroups A and B were made. Each group was separately compared for total and fetal DNA with a corresponding group considered normal using Wilcoxon rank sum test. Male fetal DNA concentration in maternal plasma was quantified using real-time quantitative polymerase chain reaction (PCR) of SRY sequences. The samples were also analyzed by quantitative fluorescent PCR (QF-PCR) using highly polymorphic short tandem repeat DNA sequences (STRs), and the percentage of relative fetal allele concentration in maternal alleles was calculated and compared to the fetal/total DNA ratio obtained by real-time PCR. Results Quantities of total and fetal circulating DNA were significantly correlated (r(2) = 0.44, P < 0.0001) with a median total DNA concentration of 522 GE/mL (range 51-3047) and a median fetal DNA concentration of 8 GE/mL (range 0-879). Neither level was correlated with gestational age in pregnancies with normal (r(2) = -0.05; P = 0.66, and r(2) = 0.02; P = 0.88, respectively) and abnormal (r(2) = 0.45; P = 0.17, and r(2) = 0.11; p = 0.76, respectively) outcomes. Although both total and fetal DNA levels were always higher in women carrying pregnancies with chromosomal aberrations or having other pregnancy complications (P-values range from 0.028 to 0.267), these differences reached statistical significance only for total DNA levels between the group A and corresponding normal pregnancies (P = 0.028). The correlation between the fetal/total DNA ratio obtained by real-time PCR and the percentage of relative fetal allele concentration in maternal alleles obtained by QF-PCR was not found to be statistically significant (r(2) = 0.04; P = 0.76). Conclusion Our results confirm the clinical value of fetal DNA measurement in maternal plasma during the second trimester as a supplement for the diagnosis of aneuploidies. Its use as a screening instrument for complications that develop later in pregnancy seems to be limited but needs further investigation. Although the QF-PCR assay has the advantage of being applicable to both female and male fetuses, this approach cannot be used for quantitation of cff DNA in maternal plasma samples. Copyright (c) 2006 John Wiley & Sons, Ltd.\n\nHutterer, Georg\n\nPertl, Barbara\n\n\n"
},
{
"text": "\n5557\nCombined E-cadherin and high molecular weight cytokeratin immunoprofile differentiates lobular, ductal, and hybrid mammary intraepithelial neoplasias.\n\nBratthauer, GL\n\nMoinfar, F\n\nStamatakos, MD\n\nMezzetti, TP\n\nShekitka, KM\n\nMan, YG\n\nTavassoli, FA\n\nBeiträge in Fachzeitschriften\nISI:000177176800005\n12152161.0\n10.1053%2Fhupa.2002.124789\nNone\nThe terminal duct-lobular unit is the origin of 2 distinct variants of intraepithelial neoplasia traditionally separated into ductal and lobular types based on a combination of cytologic and architectural features. In general, distinction of the fully developed or classic lobular intraepithelial neoplasia (LIN) from various grades of ductal intraepithelial neoplasia (DIN) is not a problem. An increasing number of lesions that appear to have intermediate, overlapping ductal and lobular features are being sent to us for consultation because of the distinctly different clinical implication of the 2 diagnoses. We have separated and designated these as MIN (mammary intraepithelial neoplasia, not otherwise specified), whereas others have categorized them into either a definitive ductal or lobular subtype. The recent findings that LIN lacks immunoreaction for E-cadherin coupled with significantly diminished to absent expression of the high molecular weight (HMW) cytokeratins in more than 90% of grade 1b or higher DIN prompted us to evaluate intraepithelial neoplasias for a possibly more precise immunohistochemical categorization. One hundred and ten examples of intraepithelial neoplasias, consisting of 40 classic LIN, 20 unequivocal DIN 1c to DIN 3 (ductal carcinoma in situ), and 50 MIN, were acquired from the files of the Armed Forces Institute of Pathology. These specimens were tested with an antibody to E-cadherin and with antibody 34ssE12 reactive against HMW cytokeratins 1, 5, 10 and 14. All samples of LIN showed complete absence of reactivity with anti-E-cadherin, whereas all cases of DIN displayed a positive immunoreaction. In contrast, the DIN lesions displayed little or no reactivity with 34ssE12, whereas the lobular lesions showed cytoplasmic reactivity, often in a distinct perinuclear pattern. Twenty-three of the morphologically indeterminate cases could be classified as either ductal or lobular based on the immunoprofile, and 27 demonstrated an immunoprofile that differed from either typical DIN or classic LIN. Among the 27 MIN, 11 were negative for both markers (negative hybrids), whereas 16 were positive for both markers (positive hybrids). These 2 antibodies in combination are extremely useful in distinguishing lobular and ductal lesions and clarifying the nature of some of the morphologically intermediate cases. Also, they have confirmed the presence of a group of intraepithelial lesions (MIN) with not only overlapping morphologic features, but also immunoprofiles distinctly different from either DIN or LIN. These MIN lesions may reflect either a transient stage in the development of DIN and LIN (the immediate post-stem cell stage) or a plastic group in transition from one type to the other. This group needs further evaluation for better understanding of its significance, pattern of progression, and behavior.\n\nMoinfar, Farid\n\n\n"
},
{
"text": "\n153908\nCarotid endarterectomy significantly improves postoperative laryngeal sensitivity.\n\nHammer, GP\n\nTomazic, PV\n\nVasicek, S\n\nGraupp, M\n\nGugatschka, M\n\nBaumann, A\n\nKonstantiniuk, P\n\nKoter, SH\n\nBeiträge in Fachzeitschriften\nISI:000390042100015\n27475467.0\n10.1016/j.jvs.2016.04.032\nNone\nIatrogenic injury of the vagus nerve or its branches during carotid endarterectomy (CEA) can result in globus sensation, dysphagia, and even vocal fold immobility. Knowledge of morphologic and functional laryngopharyngeal outcomes after CEA is poor. The present study was performed to determine potential iatrogenic damage to the laryngeal innervation after CEA. An area of particular interest was the supraglottic sensory threshold, which was examined by Fiberoptic Endoscopic Evaluation of Swallowing With Sensory Testing (FEESST; Pentax Medical Company, Montvale, NJ), a validated and safe method for the determination of the motor and sensory components of swallowing.\n FEESST was used preoperatively in 32 patients scheduled to undergo CEA and twice postoperatively to examine the motor and sensory components of swallowing. In this endolaryngeal examination, laryngopharyngeal sensory thresholds (in mm Hg) were defined as normal at <4.0 mm Hg air pulse pressure (APP), moderate deficit at 4.0 to 6.0 mm Hg APP, or severe deficit at >6.0 mm Hg APP, with a value >10.0 mm Hg APP indicating abolished laryngeal adductor reflex. Acoustic voice parameters were also analyzed for further functional changes of the larynx.\n The mean ± standard deviation preoperative FEESST measures showed no significant differences (P = .065) between the operated-on side (6.73 ± 1.73 mm Hg) and the opposite side (5.83 ± 1.68 mm Hg). At 2 days postoperatively, the threshold increased (P = .001) to 7.62 ± 1.98 mm Hg on the operated-on side. A laryngopharyngeal mucosal hematoma on the operated side was endoscopically detectable in eight patients (30.8%); in these patients, we found a markedly elevated (P = .021) measure of 9.50 ± 0.93 mm Hg. On the opposite (nonoperated-on) side of the laryngopharynx, the thresholds remained at the same level as preoperatively over all assessments (P >.05), whereas the differences between the operated and nonoperated-on sides and the hematoma and nonhematoma groups were highly significant (P = .004 and P = .001, respectively). Surprisingly, the sensory threshold on the operated-on side (6.08 ± 2.02 mm Hg) decreased significantly at the 6-week follow-up, even in relation to the preoperative measure (P = .022). With the exception of one patient with permanent unilateral vocal fold immobility, no signs of nerve injury were detected.\n In accordance with previous reports, injuries to the recurrent laryngeal nerve during CEA seem to be rare. In most patients, postoperative symptoms (globus, dysphagia, dysphonia) and signs fade within a few weeks without any specific therapeutic intervention. This study shows an improved long-term postoperative superior laryngeal nerve function with regard to laryngopharyngeal sensitivity.\n Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.\n\nBaumann, Anneliese\n\nGraupp, Matthias\n\nGugatschka, Markus\n\nHammer, Georg\n\nKonstantiniuk, Peter\n\nKoter, Stephan Herwig\n\nTomazic, Peter Valentin\n\nVasicek, Sarah Marvis\n\n\n"
},
{
"text": "\n160206\nAdult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis.\n\nNüesch, E\n\nDale, C\n\nPalmer, TM\n\nWhite, J\n\nKeating, BJ\n\nvan Iperen, EP\n\nGoel, A\n\nPadmanabhan, S\n\nAsselbergs, FW\n\nEPIC-Netherland Investigators\n\nVerschuren, WM\n\nWijmenga, C\n\nVan der Schouw, YT\n\nOnland-Moret, NC\n\nLange, LA\n\nHovingh, GK\n\nSivapalaratnam, S\n\nMorris, RW\n\nWhincup, PH\n\nWannamethe, GS\n\nGaunt, TR\n\nEbrahim, S\n\nSteel, L\n\nNair, N\n\nReiner, AP\n\nKooperberg, C\n\nWilson, JF\n\nBolton, JL\n\nMcLachlan, S\n\nPrice, JF\n\nStrachan, MW\n\nRobertson, CM\n\nKleber, ME\n\nDelgado, G\n\nMärz, W\n\nMelander, O\n\nDominiczak, AF\n\nFarrall, M\n\nWatkins, H\n\nLeusink, M\n\nMaitland-van der Zee, AH\n\nde Groot, MC\n\nDudbridge, F\n\nHingorani, A\n\nBen-Shlomo, Y\n\nLawlor, DA\n\nUCLEB Investigators\n\nAmuzu, A\n\nCaufield, M\n\nCavadino, A\n\nCooper, J\n\nDavies, TL\n\nIN Day\n\nDrenos, F\n\nEngmann, J\n\nFinan, C\n\nGiambartolomei, C\n\nHardy, R\n\nHumphries, SE\n\nHypponen, E\n\nKivimaki, M\n\nKuh, D\n\nKumari, M\n\nOng, K\n\nPlagnol, V\n\nPower, C\n\nRichards, M\n\nShah, S\n\nShah, T\n\nSofat, R\n\nTalmud, PJ\n\nWareham, N\n\nWarren, H\n\nWhittaker, JC\n\nWong, A\n\nZabaneh, D\n\nDavey Smith, G\n\nWells, JC\n\nLeon, DA\n\nHolmes, MV\n\nCasas, JP\n\nBeiträge in Fachzeitschriften\nISI:000398261100031\n25979724.0\n10.1093/ije/dyv074\nPMC5841831\nWe investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis.\n We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D.\n IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively], hich agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index ( P < 0.001), triglycerides ( P < 0.001), non high-density (non-HDL) cholesterol ( P < 0.001), C-reactive protein ( P = 0.042), and systolic blood pressure ( P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity ( P < 0.001 for both).\n Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.\n © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n99633\nCoexpression of integrin alpha(v)beta3 and matrix metalloproteinase-2 (MMP-2) coincides with MMP-2 activation: correlation with melanoma progression.\n\nHofmann, UB\n\nWestphal, JR\n\nWaas, ET\n\nBecker, JC\n\nRuiter, DJ\n\nvan Muijen, GNP\n\nBeiträge in Fachzeitschriften\nISI:000089816700005\n10998134.0\n10.1046/j.1523-1747.2000.00114.x\nNone\nTumor cell invasion and metastasis formation depend on both adhesive and proteolytic mechanisms. Previous studies have shown that expression of matrix metalloproteinase-2 and integrin alphavbeta3 correlate with melanoma progression. Recently, direct binding of matrix metalloproteinase-2 to alpha(v)beta3 was implicated in presenting activated matrix metalloproteinase-2 on the cell surface of invasive cells. In this study we investigated this, using the highly metastatic, alpha(v)beta3-negative melanoma cell lines MV3 and BLM, their beta3-transfected alpha(v)beta3 expressing counterparts, xenografts derived from these cell lines, and fresh human cutaneous melanoma lesions comprising all stages of melanoma progression. Expression and activation status of matrix metalloproteinase-2 were studied by reverse transcription-polymerase chain reaction, immunohistochemistry, western blotting, and zymographic analysis, respectively. Matrix metalloproteinase-2 protein expression in vitro was similar in both alpha(v)beta3-negative and alpha(v)beta3-positive cell lines Remarkable differences, however, exist in the localization of inactive and active matrix metalloproteinase-2. Soluble active matrix metalloproteinase-2 was detectable only in the conditioned medium of alpha(v)beta3-negative cell lines and undetectable in the alpha(v)beta3-positive cell lines. Conversely, active matrix metalloproteinase-2 was present exclusively on the cell surface of the alpha(v)beta3 expressing transfectants. Western blot analysis of other components that are involved in matrix metalloproteinase-2 activation showed that processing of proMT1-matrix metalloproteinase to the activated form was enhanced in beta3 transfectants, whereas secretion of tissue inhibitor of metalloproteinase-2 was decreased. In vivo, the presence of functionally active matrix metalloproteinase-2 was significantly higher in xenografts derived from the alpha(v)beta3 expressing MV3 and BLM cell lines. In human cutaneous melanoma lesions, neither matrix metalloproteinase-2 nor integrin alpha(v)beta3 is detectable in melanoma in situ as determined by immunohistochemistry. In contrast, the number of matrix metalloproteinase-2-positive and alphavbeta3-positive tumor cells was clearly increased in primary melanomas, and melanoma metastases. Double staining experiments and confocal laser microscopy demonstrated that the percentage of cells coexpressing matrix metalloproteinase-2 and alpha(v)beta3 increased in advanced primary melanomas and melanoma metastases. In addition, zymography showed that functionally active matrix metalloproteinase-2 was frequently present in melanoma metastases. In these lesions a high proportion of matrix metalloproteinase-2- and alphavbeta3-double-positive melanoma cells were detectable. Our study demonstrates that the presence of activated matrix metalloproteinase-2 correlates with expression of alpha(v)beta3 in human melanoma cells both in vitro and in vivo, and also in fresh human melanoma lesions. These findings strongly suggest that co-ordinated expression of both factors may be required for melanoma cell invasion and metastasis formation.\n\n\n"
},
{
"text": "\n170122\nPanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents.\n\nByrne, J\n\nGrabow, D\n\nCampbell, H\n\nO'Brien, K\n\nBielack, S\n\nAm Zehnhoff-Dinnesen, A\n\nCalaminus, G\n\nKremer, L\n\nLanger, T\n\nvan den Heuvel-Eibrink, MM\n\nvan Dulmen-den Broeder, E\n\nBaust, K\n\nBautz, A\n\nBeck, JD\n\nBerger, C\n\nBinder, H\n\nBorgmann-Staudt, A\n\nBroer, L\n\nCario, H\n\nCasagranda, L\n\nClemens, E\n\nDeuster, D\n\nde Vries, A\n\nDirksen, U\n\nFalck Winther, J\n\nFosså, S\n\nFont-Gonzalez, A\n\nGrandage, V\n\nHaupt, R\n\nHecker-Nolting, S\n\nHjorth, L\n\nKaiser, M\n\nKenborg, L\n\nKepak, T\n\nKepáková, K\n\nKnudsen, LE\n\nKrawczuk-Rybak, M\n\nKruseova, J\n\nKuehni, CE\n\nKunstreich, M\n\nKuonen, R\n\nLackner, H\n\nLeiper, A\n\nLoeffen, EAH\n\nLuks, A\n\nModan-Moses, D\n\nMulder, R\n\nParfitt, R\n\nPaul, NW\n\nRanft, A\n\nRuud, E\n\nSchilling, R\n\nSpix, C\n\nStefanowicz, J\n\nStrauβ, G\n\nUitterlinden, AG\n\nvan den Berg, M\n\nvan der Kooi, AL\n\nvan Dijk, M\n\nvan Leeuwen, F\n\nZolk, O\n\nZöller, D\n\nKaatsch, P\n\nPanCareLIFE consortium\n\nBeiträge in Fachzeitschriften\nISI:000447292100027\n30273888.0\n10.1016/j.ejca.2018.08.007\nNone\nSurvival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies.\n PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning.\n PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10, 00 survivors.\n The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being.\n Copyright © 2018 Elsevier Ltd. All rights reserved.\n\nKaiser, Melanie\n\nLackner, Herwig\n\n\n"
},
{
"text": "\n176355\nAssociation Between Surgical Skin Markings in Dermoscopic Images and Diagnostic Performance of a Deep Learning Convolutional Neural Network for Melanoma Recognition.\n\nWinkler, JK\n\nFink, C\n\nToberer, F\n\nEnk, A\n\nDeinlein, T\n\nHofmann-Wellenhof, R\n\nThomas, L\n\nLallas, A\n\nBlum, A\n\nStolz, W\n\nHaenssle, HA\n\nBeiträge in Fachzeitschriften\nISI:000491999300007\n31411641.0\n10.1001/jamadermatol.2019.1735\nPMC6694463\nDeep learning convolutional neural networks (CNNs) have shown a performance at the level of dermatologists in the diagnosis of melanoma. Accordingly, further exploring the potential limitations of CNN technology before broadly applying it is of special interest.\n To investigate the association between gentian violet surgical skin markings in dermoscopic images and the diagnostic performance of a CNN approved for use as a medical device in the European market.\n A cross-sectional analysis was conducted from August 1, 2018, to November 30, 2018, using a CNN architecture trained with more than 120 000 dermoscopic images of skin neoplasms and corresponding diagnoses. The association of gentian violet skin markings in dermoscopic images with the performance of the CNN was investigated in 3 image sets of 130 melanocytic lesions each (107 benign nevi, 23 melanomas).\n The same lesions were sequentially imaged with and without the application of a gentian violet surgical skin marker and then evaluated by the CNN for their probability of being a melanoma. In addition, the markings were removed by manually cropping the dermoscopic images to focus on the melanocytic lesion.\n Sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic (ROC) curve for the CNN's diagnostic classification in unmarked, marked, and cropped images.\n In all, 130 melanocytic lesions (107 benign nevi and 23 melanomas) were imaged. In unmarked lesions, the CNN achieved a sensitivity of 95.7% (95% CI, 79%-99.2%) and a specificity of 84.1% (95% CI, 76.0%-89.8%). The ROC AUC was 0.969. In marked lesions, an increase in melanoma probability scores was observed that resulted in a sensitivity of 100% (95% CI, 85.7%-100%) and a significantly reduced specificity of 45.8% (95% CI, 36.7%-55.2%, P < .001). The ROC AUC was 0.922. Cropping images led to the highest sensitivity of 100% (95% CI, 85.7%-100%), specificity of 97.2% (95% CI, 92.1%-99.0%), and ROC AUC of 0.993. Heat maps created by vanilla gradient descent backpropagation indicated that the blue markings were associated with the increased false-positive rate.\n This study's findings suggest that skin markings significantly interfered with the CNN's correct diagnosis of nevi by increasing the melanoma probability scores and consequently the false-positive rate. A predominance of skin markings in melanoma training images may have induced the CNN's association of markings with a melanoma diagnosis. Accordingly, these findings suggest that skin markings should be avoided in dermoscopic images intended for analysis by a CNN.\n German Clinical Trial Register (DRKS) Identifier: DRKS00013570.\n\nDeinlein, Teresa Maria\n\nHofmann-Wellenhof, Rainer\n\n\n"
},
{
"text": "\n183755\n<i>In silico</i> Comparison of Left Atrial Ablation Techniques That Target the Anatomical, Structural, and Electrical Substrates of Atrial Fibrillation.\n\nRoney, CH\n\nBeach, ML\n\nMehta, AM\n\nSim, I\n\nCorrado, C\n\nBendikas, R\n\nSolis-Lemus, JA\n\nRazeghi, O\n\nWhitaker, J\n\nO'Neill, L\n\nPlank, G\n\nVigmond, E\n\nWilliams, SE\n\nO'Neill, MD\n\nNiederer, SA\n\nBeiträge in Fachzeitschriften\nISI:000576321500001\n33041850.0\n10.3389/fphys.2020.572874\nPMC7526475\nCatheter ablation therapy for persistent atrial fibrillation (AF) typically includes pulmonary vein isolation (PVI) and may include additional ablation lesions that target patient-specific anatomical, electrical, or structural features. Clinical centers employ different ablation strategies, which use imaging data together with electroanatomic mapping data, depending on data availability. The aim of this study was to compare ablation techniques across a virtual cohort of AF patients. We constructed 20 paroxysmal and 30 persistent AF patient-specific left atrial (LA) bilayer models incorporating fibrotic remodeling from late-gadolinium enhancement (LGE) MRI scans. AF was simulated and post-processed using phase mapping to determine electrical driver locations over 15 s. Six different ablation approaches were tested: (i) PVI alone, modeled as wide-area encirclement of the pulmonary veins; PVI together with: (ii) roof and inferior lines to model posterior wall box isolation; (iii) isolating the largest fibrotic area (identified by LGE-MRI); (iv) isolating all fibrotic areas; (v) isolating the largest driver hotspot region [identified as high simulated phase singularity (PS) density]; and (vi) isolating all driver hotspot regions. Ablation efficacy was assessed to predict optimal ablation therapies for individual patients. We subsequently trained a random forest classifier to predict ablation response using (a) imaging metrics alone, (b) imaging and electrical metrics, or (c) imaging, electrical, and ablation lesion metrics. The optimal ablation approach resulting in termination, or if not possible atrial tachycardia (AT), varied among the virtual patient cohort: (i) 20% PVI alone, (ii) 6% box ablation, (iii) 2% largest fibrosis area, (iv) 4% all fibrosis areas, (v) 2% largest driver hotspot, and (vi) 46% all driver hotspots. Around 20% of cases remained in AF for all ablation strategies. The addition of patient-specific and ablation pattern specific lesion metrics to the trained random forest classifier improved predictive capability from an accuracy of 0.73 to 0.83. The trained classifier results demonstrate that the surface areas of pre-ablation driver regions and of fibrotic tissue not isolated by the proposed ablation strategy are both important for predicting ablation outcome. Overall, our study demonstrates the need to select the optimal ablation strategy for each patient. It suggests that both patient-specific fibrosis properties and driver locations are important for planning ablation approaches, and the distribution of lesions is important for predicting an acute response.\n Copyright © 2020 Roney, Beach, Mehta, Sim, Corrado, Bendikas, Solis-Lemus, Razeghi, Whitaker, O’Neill, Plank, Vigmond, Williams, O’Neill and Niederer.\n\nPlank, Gernot\n\n\n"
},
{
"text": "\n183013\nC-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study.\n\nRiedl, JM\n\nBarth, DA\n\nBrueckl, WM\n\nZeitler, G\n\nForis, V\n\nMollnar, S\n\nStotz, M\n\nRossmann, CH\n\nTerbuch, A\n\nBalic, M\n\nNiedrist, T\n\nBertsch, T\n\nStoeger, H\n\nPichler, M\n\nOlschewski, H\n\nAbsenger, G\n\nFicker, JH\n\nGerger, A\n\nPosch, F\n\nBeiträge in Fachzeitschriften\nISI:000579014000001\n32824580.0\n10.3390/cancers12082319\nPMC7464328\nBiomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents.\n We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort (n = 90), confirm these findings in an external validation cohort (n = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively.\n In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16-1.63, p < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18-1.71, p < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51-0.92, p = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15-1.30, p < 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14-154.54, p = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83-0.99, p = 0.036), respectively.\n These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.\n\nAbsenger, Gudrun\n\nBalic, Marija\n\nBarth, Dominik Andreas\n\nForis, Vasile\n\nGerger, Armin\n\nNiedrist, Tobias\n\nOlschewski, Horst\n\nPichler, Martin\n\nPosch, Florian\n\nRiedl, Jakob\n\nStoeger, Herbert\n\nTerbuch, Angelika\n\n\n"
},
{
"text": "\n355\nBone density variation and its effects on risk of vertebral deformity in men and women studied in thirteen European centers: the EVOS Study.\n\nLunt, M\n\nFelsenberg, D\n\nReeve, J\n\nBenevolenskaya, L\n\nCannata, J\n\nDequeker, J\n\nDodenhof, C\n\nFalch, JA\n\nMasaryk, P\n\nPols, HA\n\nPoor, G\n\nReid, DM\n\nScheidt-Nave, C\n\nWeber, K\n\nVarlow, J\n\nKanis, JA\n\nO'Neill, TW\n\nSilman, AJ\n\nBeiträge in Fachzeitschriften\nISI:A1997YE19400015\n9383693.0\n10.1359/jbmr.1997.12.11.1883\nNone\nIn Europe there is a 3-fold variation, according to geographical center, in risk of vertebral deformity in men and women over the age of 50. We investigated the relationship between bone density, as assessed by dual-energy X-ray absorptiometry (DEXA) of the spine and hip and prevalent vertebral deformities in 13 of the 36 centers participating in the European Vertebral Osteoporosis Study (EVOS). Each center recruited an age-stratified sample of men and women aged 50 years and over, and of those who agreed to densitometry, 288/2088 women and 233/1908 men were found to have one or more deformities of the vertebrae between T4 and L4 as assessed by the McCloskey algorithm. DEXA was in each case performed on L2-L4, the proximal femur, or both. Bone densitometry results were cross-calibrated between centers using the European Spine Phantom prototype and results expressed as bone mineral density (BMD, g/cm2). In both genders, subjects with deformities involving loss of anterior vertebral body height alone comprised over 20% of the total with deformities and these related poorly to BMD. Other classes of deformity were found by logistic regression to relate significantly to BMD in one or both genders, with odds ratios for the risk of any of these ranging from 1.67 to 2.11 for a 1 SD reduction in bone density at spine, femoral neck, or trochanter (p < 0.001). Adjusting for anthropometric variables and BMD did not remove the effect of age on risk which rose 1.67- to 1.78-fold per decade according to gender. The greater unadjusted rate of increase in deformity risk with age in women was attributable to their faster rate of bone loss with age; after adjusting for age, body mass index (BMI), and BMD at the trochanter in grams per square centimeter, men had a 2-fold higher risk of deformity than women. Analysis of the relationship between mean bone density and the prevalence of deformity in each center demonstrated no significant differences between centers in either gender, after adjusting for BMD, age, and BMI together with an a posteriori statistical adjustment for imperfect cross-calibration of densitometers. It is concluded that BMD is an important determinant of deformity risk in both genders. Together with age, BMD explains much of the differences in risk both between the sexes and between individual geographical centers in Europe.\n\nWeber, Kurt\n\n\n"
},
{
"text": "\n174041\nGenome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.\n\nSabater-Lleal, M\n\nHuffman, JE\n\nde Vries, PS\n\nMarten, J\n\nMastrangelo, MA\n\nSong, C\n\nPankratz, N\n\nWard-Caviness, CK\n\nYanek, LR\n\nTrompet, S\n\nDelgado, GE\n\nGuo, X\n\nBartz, TM\n\nMartinez-Perez, A\n\nGermain, M\n\nde Haan, HG\n\nOzel, AB\n\nPolasek, O\n\nSmith, AV\n\nEicher, JD\n\nReiner, AP\n\nTang, W\n\nDavies, NM\n\nStott, DJ\n\nRotter, JI\n\nTofler, GH\n\nBoerwinkle, E\n\nde Maat, MPM\n\nKleber, ME\n\nWelsh, P\n\nBrody, JA\n\nChen, MH\n\nVaidya, D\n\nSoria, JM\n\nSuchon, P\n\nvan Hylckama Vlieg, A\n\nDesch, KC\n\nKolcic, I\n\nJoshi, PK\n\nLauner, LJ\n\nHarris, TB\n\nCampbell, H\n\nRudan, I\n\nBecker, DM\n\nLi, JZ\n\nRivadeneira, F\n\nUitterlinden, AG\n\nHofman, A\n\nFranco, OH\n\nCushman, M\n\nPsaty, BM\n\nMorange, PE\n\nMcKnight, B\n\nChong, MR\n\nFernandez-Cadenas, I\n\nRosand, J\n\nLindgren, A\n\nINVENT Consortium\n\nMEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC)\n\nGudnason, V\n\nWilson, JF\n\nHayward, C\n\nGinsburg, D\n\nFornage, M\n\nRosendaal, FR\n\nSouto, JC\n\nBecker, LC\n\nJenny, NS\n\nMärz, W\n\nJukema, JW\n\nDehghan, A\n\nTrégouët, DA\n\nMorrison, AC\n\nJohnson, AD\n\nO'Donnell, CJ\n\nStrachan, DP\n\nLowenstein, CJ\n\nSmith, NL\n\nBeiträge in Fachzeitschriften\nISI:000459432400011\n30586737.0\n10.1161/CIRCULATIONAHA.118.034532\nPMC6438386\nFactor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.\n We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.\n We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.\n The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n171427\nImmunogenicity, safety, and tolerability of the measles-vectored chikungunya virus vaccine MV-CHIK: a double-blind, randomised, placebo-controlled and active-controlled phase 2 trial.\n\nReisinger, EC\n\nTschismarov, R\n\nBeubler, E\n\nWiedermann, U\n\nFirbas, C\n\nLoebermann, M\n\nPfeiffer, A\n\nMuellner, M\n\nTauber, E\n\nRamsauer, K\n\nBeiträge in Fachzeitschriften\nISI:000453990500026\n30409443.0\n10.1016/S0140-6736(18)32488-7\nNone\nChikungunya fever is an emerging viral disease and substantial threat to public health. We aimed to assess the safety, tolerability, and immunogenicity of a live-attenuated, measles-vectored chikungunya vaccine (MV-CHIK).\n In this double-blind, randomised, placebo-controlled and active-controlled phase 2 trial, we enrolled healthy volunteers aged 18-55 years at four study sites in Austria and Germany. Participants were randomly assigned to receive intramuscular injections with MV-CHIK (5 × 104 or 5 × 105 50% tissue culture infectious dose), control vaccine, or measles prime and MV-CHIK, in two different administration regimens. Randomisation was done by use of three-digit randomisation codes in envelopes provided by a data management service. The participants and investigators were masked to treatment assignment, which was maintained by use of sterile saline as a placebo injection. The primary endpoint was immunogenicity, defined as the presence of neutralising antibodies against chikungunya virus, at day 56, which is 28 days after one or two immunisations. The primary endpoint was assessed in all participants who completed the study without major protocol deviations (per-protocol population) and in all randomised participants who received at least one study treatment (modified intention-to-treat population). The safety analysis included all participants who received at least one study treatment. This trial is registered with ClinicalTrials.gov (NCT02861586) and EudraCT (2015-004037-26) and is completed.\n Between Aug 17, 2016, and May 31, 2017, we randomly assigned 263 participants to receive control vaccine (n=34), MV-CHIK (n=195), or measles prime and MV-CHIK (n=34). 247 participants were included in the per-protocol population. Neutralising antibodies against chikungunya virus were detected in all MV-CHIK treatment groups after one or two immunisations, with geometric mean titres ranging from 12·87 (95% CI 8·75-18·93) to 174·80 (119·10-256·50) and seroconversion rates ranging from 50·0% to 95·9% depending on the dose and administration schedule. Adverse events were similar between groups, with solicited adverse events reported in 168 (73%) of 229 participants assigned to MV-CHIK and 24 (71%) of 34 assigned to control vaccine (p=0·84) and unsolicited adverse events in 116 (51%) participants assigned to MV-CHIK and 17 (50%) assigned to control vaccine (p=1·00). No serious adverse events related to the vaccine were reported.\n MV-CHIK showed excellent safety and tolerability and good immunogenicity, independent of pre-existing immunity against the vector. MV-CHIK is a promising candidate vaccine for the prevention of chikungunya fever, an emerging disease of global concern.\n Themis.\n Copyright © 2018 Elsevier Ltd. All rights reserved.\n\nBeubler, Eckhard\n\n\n"
},
{
"text": "\n177174\nEURACAN/IASLC Proposals for Updating the Histologic Classification of Pleural Mesothelioma: Towards a More Multidisciplinary Approach.\n\nNicholson, AG\n\nSauter, JL\n\nNowak, AK\n\nKindler, HL\n\nGill, RR\n\nRemy-Jardin, M\n\nArmato, SG\n\nFernandez-Cuesta, L\n\nBueno, R\n\nAlcala, N\n\nFoll, M\n\nPass, H\n\nAttanoos, R\n\nBaas, P\n\nBeasley, MB\n\nBrcic, L\n\nButnor, KJ\n\nChirieac, LR\n\nChurg, A\n\nCourtiol, P\n\nDacic, S\n\nDe Perrot, M\n\nFrauenfelder, T\n\nGibbs, A\n\nHirsch, FR\n\nHiroshima, K\n\nHusain, A\n\nKlebe, S\n\nLantuejoul, S\n\nMoreira, A\n\nOpitz, I\n\nPerol, M\n\nRoden, A\n\nRoggli, V\n\nScherpereel, A\n\nTirode, F\n\nTazelaar, H\n\nTravis, WD\n\nTsao, MS\n\nvan Schil, P\n\nVignaud, JM\n\nWeynand, B\n\nLang-Lazdunski, L\n\nCree, I\n\nRusch, VW\n\nGirard, N\n\nGalateau-Salle, F\n\nBeiträge in Fachzeitschriften\nISI:000509463500013\n31546041.0\n10.1016/j.jtho.2019.08.2506\nNone\nMolecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes.\n A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification.\n Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome.\n These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.\n Copyright © 2019 International Association for the Study of Lung Cancer. All rights reserved.\n\nBrcic, Luka\n\n\n"
},
{
"text": "\n147158\nHome Use of an Artificial Beta Cell in Type 1 Diabetes.\n\nThabit, H\n\nTauschmann, M\n\nAllen, JM\n\nLeelarathna, L\n\nHartnell, S\n\nWilinska, ME\n\nAcerini, CL\n\nDellweg, S\n\nBenesch, C\n\nHeinemann, L\n\nMader, JK\n\nHolzer, M\n\nKojzar, H\n\nExall, J\n\nYong, J\n\nPichierri, J\n\nBarnard, KD\n\nKollman, C\n\nCheng, P\n\nHindmarsh, PC\n\nCampbell, FM\n\nArnolds, S\n\nPieber, TR\n\nEvans, ML\n\nDunger, DB\n\nHovorka, R\n\nBeiträge in Fachzeitschriften\nISI:000365354800007\n26379095.0\n10.1056/NEJMoa1509351\nPMC4697362\nThe feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established.\n In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents.\n Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use.\n Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).\n\nKojzar, Harald\n\nMader, Julia\n\nPieber, Thomas\n\n\n"
},
{
"text": "\n177019\nAntibiotic stewardship: conception and implementation in pediatric and adolescent inpatient medicine New AWMF S2k guidelines (AWMF register number 048/015) under the direction of the German Society for Pediatric Infectiology\n\nHubner, J\n\nvon Both, U\n\nTenenbaum, T\n\nWeichert, S\n\nLiese, J\n\nHufnagel, M\n\nPecar, A\n\nStrenger, V\n\nSimon, A\n\nBeiträge in Fachzeitschriften\nISI:000481846000010\nNone\n10.1007/s00112-019-0663-y\nNone\nBackground The worldwide increase in antibiotic resistance has resulted in a focus on a rational and critical use of antibiotics in all areas of medicine. A wealth of structural measures has been developed, particularly for inpatient treatment, which are referred to as antibiotic stewardship (ABS) although only few summaries and guidelines are available for children. Objectives In the interdisciplinary guidelines summarized here, a team of authors has reviewed the published literature in the field of pediatrics and, on the basis of these publications, has drawn up recommendations and reached a consensus with specialist societies involved in antibiotic treatment of children. The guidelines are intended to ensure a rational, restrictive and guideline-compliant use of antibiotics in inpatients in pediatric hospitals, as well as the sensible use of microbiological diagnostics. In the long term these guidelines should improve the quality of antibiotic prescriptions in inpatient treatment of children and adolescents, protecting patients from the undesired effects of inadequate antibiotic therapy and reducing the risk of selection of bacterial pathogens with special resistances and multi-drug resistance. Material and methods The guidelines were developed by the working group Antibiotic Stewardship of the DGPI by an editorial committee consisting of J. Hubner, A. Simon, T. Tenenbaum, J. Liese, M. Hufnagel, S. Weichert, U. von Both, A. Pecar and V. Strenger and consented by mandated representatives of other professional associations (ADKA, DAKJ, DGHM, DGKJ, DGI, GNPI, GPOH, GPGE, GPP, oGKJ, PIGS, PEG, BVKJ, DGKH, DGKCH) in an internet-based Delphi procedure. The working group Antibiotic Stewardship of the DGPI compiled a thematically structured bibliography after a literature search via Medline/PubMed including the bibliographies of current reviews and meta-analyses. Keywords were "antibiotic stewardship", "antimicrobial stewardship", "pediatrics", "pediatric antimicrobial stewardship", "stewardship" and "antimicrobial resistance". Conflicts of interest were disclosed in accordance with the AWMF regulations. Results A total of 70 recommendations on structural conditions, antimicrobial therapy, diagnostic aspects (microbiology, resistance testing), further education and training, quality indicators and clinical infectiology audits, role of information technology, nosocomial infections, significance of Clostridium difficile in pediatric patients, management of multi-drug resistant pathogens and the pediatric specialties neonatology and pediatric oncology were developed. Conclusion The guidelines presented here represent the first such guidelines for the field of pediatrics in the German-speaking area and will be helpful in establishing and evaluating ABS programs in pediatrics and pediatric oncology.\n\nStrenger, Volker\n\n\n"
},
{
"text": "\n184844\nTreatment of allergic rhinitis during and outside the pollen season using mobile technology. A MASK study.\n\nBédard, A\n\nBasagaña, X\n\nAnto, JM\n\nGarcia-Aymerich, J\n\nDevillier, P\n\nArnavielhe, S\n\nBedbrook, A\n\nOnorato, GL\n\nCzarlewski, W\n\nMurray, R\n\nAlmeida, R\n\nFonseca, JA\n\nCorreia da Sousa, J\n\nCosta, E\n\nMorais-Almeida, M\n\nTodo-Bom, A\n\nCecchi, L\n\nDe Feo, G\n\nIllario, M\n\nMenditto, E\n\nMonti, R\n\nStellato, C\n\nVentura, MT\n\nAnnesi-Maesano, I\n\nBosse, I\n\nFontaine, JF\n\nPham-Thi, N\n\nThibaudon, M\n\nSchmid-Grendelmeier, P\n\nSpertini, F\n\nChavannes, NH\n\nFokkens, WJ\n\nReitsma, S\n\nDubakiene, R\n\nEmuzyte, R\n\nKvedariene, V\n\nValiulis, A\n\nKuna, P\n\nSamolinski, B\n\nKlimek, L\n\nMösges, R\n\nPfaar, O\n\nShamai, S\n\nRoller-Wirnsberger, RE\n\nTomazic, PV\n\nRyan, D\n\nSheikh, A\n\nHaahtela, T\n\nToppila-Salmi, S\n\nValovirta, E\n\nCardona, V\n\nMullol, J\n\nValero, A\n\nMakris, M\n\nPapadopoulos, NG\n\nProkopakis, EP\n\nPsarros, F\n\nBachert, C\n\nHellings, PW\n\nPugin, B\n\nBindslev-Jensen, C\n\nEller, E\n\nKull, I\n\nMelén, E\n\nWickman, M\n\nDe Vries, G\n\nvan Eerd, M\n\nAgache, I\n\nAnsotegui, IJ\n\nBosnic-Anticevich, S\n\nCruz, AA\n\nCasale, T\n\nIvancevich, JC\n\nLarenas-Linnemann, DE\n\nSofiev, M\n\nWallace, D\n\nWaserman, S\n\nYorgancioglu, A\n\nLaune, D\n\nBousquet, J\n\nMASK study group\n\nBeiträge in Fachzeitschriften\nISI:000600111200002\n33298191.0\n10.1186/s13601-020-00342-x\nPMC7726888\nThe analysis of mobile health (mHealth) data has generated innovative insights into improving allergic rhinitis control, but additive information is needed. A cross-sectional real-world observational study was undertaken in 17 European countries during and outside the estimated pollen season. The aim was to collect novel information including the phenotypic characteristics of the users.\n The Allergy Diary-MASK-air-mobile phone app, freely available via Google Play and App, was used to collect the data of daily visual analogue scales (VASs) for overall allergic symptoms and medication use. Fluticasone Furoate (FF), Mometasone Furoate (MF), Azelastine Fluticasone Proprionate combination (MPAzeFlu) and eight oral H1-antihistamines were studied. Phenotypic characteristics were recorded at entry. The ARIA severity score was derived from entry data. This was an a priori planned analysis.\n 9037 users filled in 70, 86 days of VAS in 2016, 2017 and 2018. The ARIA severity score was lower outside than during the pollen season. Severity was similar for all treatment groups during the pollen season, and lower in the MPAzeFlu group outside the pollen season. Days with MPAzeFlu had lower VAS levels and a higher frequency of monotherapy than the other treatments during the season. Outside the season, days with MPAzeFlu also had a higher frequency of monotherapy. The number of reported days was significantly higher with MPAzeFlu during and outside the season than with MF, FF or oral H1-antihistamines.\n This study shows that the overall efficacy of treatments is similar during and outside the pollen season and indicates that medications are similarly effective during the year.\n\nRoller-Wirnsberger, Regina\n\nTomazic, Peter Valentin\n\n\n"
},
{
"text": "\n177494\nThe role of zinc in the biocorrosion behavior of resorbable Mg‒Zn‒Ca alloys.\n\nCihova, M\n\nMartinelli, E\n\nSchmutz, P\n\nMyrissa, A\n\nSchäublin, R\n\nWeinberg, AM\n\nUggowitzer, PJ\n\nLöffler, JF\n\nBeiträge in Fachzeitschriften\nISI:000501646900035\n31539653.0\n10.1016/j.actbio.2019.09.021\nNone\nZinc- and calcium-containing magnesium alloys, denominated ZX alloys, excel as temporary implant materials because of their composition made of physiologically essential minerals and lack of commonly used rare-earth alloying elements. This study documents the specific role of nanometric intermetallic particles (IMPs) on the in vitro and in vivo biocorrosion behavior of two ZX-lean alloys, Mg‒Zn1.0‒Ca0.3 (ZX10) and Mg‒Zn1.5‒Ca0.25 (ZX20) (in wt.%). These alloys were designed according to thermodynamic considerations by finely adjusting the nominal Zn content towards microstructures that differ solely in the type of phase composing the IMPs: ZX10, with 1.0 wt.% Zn, hosts binary Mg2Ca-phase IMPs, while ZX20, with 1.5 wt.% Zn, hosts ternary IM1-phase IMPs. Electrochemical methods and the hydrogen-gas evolution method were deployed and complemented by transmission electron microscopy analyses. These techniques used in concert reveal that the Mg2Ca-type IMPs anodically dissolve preferentially and completely, while the IM1-type IMPs act as nano-cathodes, facilitating a faster dissolution of ZX20 compared to ZX10. Additionally, a dynamically increasing cathodic reactivity with progressing dissolution was observed for both alloys. This effect is explained by redeposits of Zn on the corroding surface, which act as additional nano-cathodes and facilitate enhanced cathodic reaction kinetics. The higher degradation rate of ZX20 was verified in vivo via micro-computed tomography upon implantation of both materials into femurs of Sprague DawleyⓇ rats. Both alloys were well integrated with direct bone‒implant contact observable 4 weeks post operationem, and an appropriately slow and homogeneous degradation could be observed with no adverse effects on the surrounding tissue. The results suggest that both alloys qualify as new temporary implant materials, and that a minor adjustment of the Zn content may function as a lever for tuning the degradation rate towards desired applications. STATEMENT OF SIGNIFICANCE: In Mg‒Zn‒Ca (ZX)-lean alloys Zn is the most electropositive element, and thus requires special attention in the investigation of biocorrosion mechanisms acting on these alloys. Even a small increase of only 0.5 wt.% Zn is shown to accelerate the biodegradation rate in both simulated body conditions and in vivo. This is possible due to Zn's role in influencing the type of intermetallic particles (IMPs) in these alloys. These IMPs in turn, even though minute in size, are shown to govern the biocorrosion behavior on the macroscopic scale. The deep understanding gained in this study on the role of Zn and of the IMP type it governs is crucial to ensuring a safe and controllable implant degradation.\n Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.\n\nWeinberg, Annelie-Martina\n\n\n"
},
{
"text": "\n22207\nElectric myocardial impedance registration in humoral rejection after heart transplantation.\n\nGrauhan, O\n\nMüller, J\n\nKnosalla, C\n\nCohnert, T\n\nSiniawski, H\n\nVolk, HD\n\nFietze, E\n\nKupetz, W\n\nHetzer, R\n\nBeiträge in Fachzeitschriften\nISI:A1996TY72400003\n8672516.0\nNone\nNone\nBACKGROUND: Because of the absent lymphocyte infiltrate, humoral-mediated rejection after heart transplantation is not diagnosed by the usual staining technique (hematoxylin-eosin method) of the endomyocardial biopsy specimen. However, humoral rejection is characterized by a distinct myocardial edema caused by capillary leakage. Because tissue edema increases the electric myocardial impedance of the corresponding tissue compartment the electric myocardial impedance method should be able to detect these episodes more reliably than biopsy. METHODS: To evaluate this hypothesis eight DLA-matched beagle dogs were subjected to heterotopic neck heart transplantation after multiple sensitization by skin grafts of the heart donor. For electric myocardial impedance registrations rectangular impulses (wide 1 msec) were applied over two intramyocardial electrodes and the impulse response was registered. Day-to-day comparisons were made and an increase of electric myocardial impedance of 10% or more was used as an indicator of rejection. To assess the influence of edema caused by electrode implantation, cortisone administration, narcosis, ischemia, or reperfusion on the electric myocardial impedance, identical electrodes were implanted in the native hearts of five additional dogs via lateral thoracotomy. These animals each received 100 mg methylprednisolone between postoperative days 20 and 22 and underwent heterotopic neck heart transplantation on postoperative day 28 without previous sensitization (protocol 2). Electric myocardial impedance electrodes were also implanted in these allografts (protocol 3). After transplantation myocardial biopsies were done every 2 days and the samples graded according to the International Society for Heart and Lung Transplantation classification in all dogs. RESULTS: Despite triple-drug immunosuppression (cyclosporine A, prednisolone, azathioprine) humoral rejection developed in all sensitized dogs as established by immunofluorescent staining of myocardial biopsy samples and functional deterioration. All episodes were diagnosed by electric myocardial impedance (sensitivity 100%), whereas only in one case the biopsy specimen was positive (International Society for Heart and Lung Transplantation grade > 1) (sensitivity 12.5%). All eight episodes could be treated successfully, that is, myocardial performance and electric myocardial impedance showed an immediate and full recovery. During the first 12 days none of the nonsensitized dogs exhibited rejection. Protocol 2 indicated that narcosis and the administration of cortisone did not per se have an influence on electric myocardial impedance and the influence of electrode implantation was negligible. Contrarily, edema caused by ischemia and reperfusion during transplantation (protocols 1 and 3) led to a significant increase in electric myocardial impedance. However, after 2 days this edema had faded away such that it no longer disturbed rejection diagnosis. CONCLUSION: We conclude that the registration of the electric myocardial impedance diagnoses humoral rejection episodes after heart transplantation not only reliably but also early, that is, before the onset of irreversible graft damage.\n\nCohnert, Tina Ulrike\n\n\n"
}
]
}