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"text": "\n181920\nRivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.\n\nMale, C\n\nLensing, AWA\n\nPalumbo, JS\n\nKumar, R\n\nNurmeev, I\n\nHege, K\n\nBonnet, D\n\nConnor, P\n\nHooimeijer, HL\n\nTorres, M\n\nChan, AKC\n\nKenet, G\n\nHolzhauer, S\n\nSantamaría, A\n\nAmedro, P\n\nChalmers, E\n\nSimioni, P\n\nBhat, RV\n\nYee, DL\n\nLvova, O\n\nBeyer-Westendorf, J\n\nBiss, TT\n\nMartinelli, I\n\nSaracco, P\n\nPeters, M\n\nKállay, K\n\nGauger, CA\n\nMassicotte, MP\n\nYoung, G\n\nPap, AF\n\nMajumder, M\n\nSmith, WT\n\nHeubach, JF\n\nBerkowitz, SD\n\nThelen, K\n\nKubitza, D\n\nCrowther, M\n\nPrins, MH\n\nMonagle, P\n\nEINSTEIN-Jr Phase 3 Investigators\n\nBeiträge in Fachzeitschriften\nISI:000504007100013\n31699660.0\n10.1016/S2352-3026(19)30219-4\nNone\nTreatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism.\n In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed.\n From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths.\n In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants.\n Bayer AG and Janssen Research & Development.\n Copyright © 2020 Elsevier Ltd. All rights reserved.\n\nGrangl, Gernot\n\n\n"
},
{
"text": "\n2482\nTachykinin NK1 and NK2 receptor antagonists and atropine-resistant ascending excitatory reflex to the circular muscle of the guinea-pig ileum.\n\nMaggi, CA\n\nPatacchini, R\n\nBartho, L\n\nHolzer, P\n\nSanticioli, P\n\nBeiträge in Fachzeitschriften\nISI:A1994NH08400028\n8032637.0\n10.1111/j.1476-5381.1994.tb13046.x\nPMC1910303\n1. The aim of this study was to investigate the effect of various antagonists, selective for the tachykinin NK1 or NK2 receptor, on the atropine-resistant ascending excitatory reflex (AER) to the circular muscle of the guinea-pig ileum elicited by radial stretch (balloon distension) or electrical field stimulation. 2. Submaximal and maximal atropine- (1 microM) resistant AER elicited by balloon distension averaged about 40-50% and 70-90% of maximal circular spasm to 80 mM KCl, respectively. The NK1 receptor antagonist, (+/)-CP 96, 45 (1 microM) inhibited both maximal and submaximal AER. FK 888 (1-3 microM) inhibited submaximal AER only. RP 67, 80 (1 microM) was ineffective. The NK2 receptor antagonist, GR 94, 00, inhibited both maximal and submaximal AER at all concentrations tested (0.1-3.0 microM), while SR 48, 68 was effective only at 1.0 microM. The NK2 receptor antagonists, MEN 10, 76 and MEN 10, 73 inhibited both submaximal and maximal AER at 10 and 1.0 microM, respectively. 3. In other experiments, an NK1 receptor antagonist, (+/-)-CP 96, 45 or FK 888 (1.0 microM in each case) was administered first and the effect of GR 94, 00 (1.0 microM) on the residual AER response was determined; or GR 94, 00 was administered first and the effect of (+/-)-CP 96, 45 or FK 888 was determined. The results of these experiments indicated an additive effect produced by the combined treatment with NK1 and NK2 receptor antagonists. 4. Electrical field stimulation (10 Hz for 0.5 s, 10-20 V, 0.15-0.3 ms pulse width) with electrodes placed at 1.4-1.8 cm anal to the recording site, produced ascending contractions which were almost abolished by 10 MicroM hexamethonium (electrically-evoked AER). In the presence of apamin (0.1 MicroM) and N0-nitro-L-arginine (30 MicroM) these contractions were reproducible over 10 consecutive stimulation cycles.GR 94, 00 (1 MicroM) and FK 888 (1 MicroM) both produced a partial inhibition of the electrically-evoked AER and their combined administration produced an inhibitory effect which was larger than that induced by each antagonist alone.5. FK 888 (1-3 MicroM), GR 94, 00 (1-3 MicroM), MEN 10, 73 (1 MicroM) and MEN 10, 76 (10 MicroM) did not significantly affect the atropine-sensitive twitch contractions produced by electrical field stimulation of the guinea-pig ileum longitudinal muscle-myenteric plexus preparation, which were abolished by 10-30 MicroM procaine, 1 MicroM tetrodotoxin or 1 MicroM atropine. (+/-)-CP 96, 45 (1 MicroM) and SR 48, 68 (1 ILM)produced 12% and 27% inhibition of cholinergic twitches in the longitudinal muscle of the ileum, espectively.6. We conclude that both NK1 and NK2 receptors mediate the atropine-resistant AER to the circular muscle of the ileum. NK2 receptor activation plays a more important role than NK1 receptor activation in the AER evoked by radial stretch. Since a consistent fraction of the distension- and electrically evoked atropine-resistant AER persists in the presence of combined NK1 and NK2 receptor blockade, he existence of a third excitatory transmitter to the circular muscle of the ileum, in addition to acetylcholine and tachykinins, is suggested.\n\nHolzer, Peter\n\n\n"
},
{
"text": "\n5294\nFrom when on can fungi be identified in nasal mucus of humans?\n\nLackner, A\n\nFreudenschuss, K\n\nBuzina, W\n\nStammberger, H\n\nPanzitt, T\n\nSchosteritsch, S\n\nBraun, H\n\nBeiträge in Fachzeitschriften\nISI:000189222000007\n14999588.0\n10.1055/s-2004-814208\nNone\nBACKGROUND: Fungal spores are frequent in air and their occurrence in the nasal mucus appears to be a common finding within the adult population, as we were able to show in recent studies. 91, % of CRS patients but also healthy controls grew positive fungal cultures out of their nasal mucus. The potential role of fungal elements in nasal mucus for the pathogenesis of CRS, with or without polyposis, is currently investigated intensely and discussed very controversially. However, it was still unknown, as of when fungi could be cultured from nasal mucus in humans. We attempted to identify this point of time, in the nasal mucus of neonates. METHODS: In our study we examined nasal mucus from 30 neonates immediately after birth, on the first and fourth day post partum, and after two and four months of life. The samples obtained with sterile cotton swabs were cultured on agar plates. Fungal cultures were identified either conventionally by microscopy or with molecular techniques. To show whether fungi in nasal mucus of newborns were acquired by contamination during birth, mucus of the maternal vagina was examined as well. RESULTS: Just after birth we found in 6 of 30 (20 %) of our neonates positive fungal cultures out of their nasal mucus, in 3 of them Candida albicans, probably due to contamination passing the maternal vagina as cultures of vaginal mucus of their mothers were positive for Candida albicans too. Positive fungal cultures were obtained in 2 of 29 (7 %) neonates on the second and in 4 of 26 (15 %) neonates on the fifth day of life. In all our cases initial presence in nasal mucus contamination just after birth or on the second day of life was limited to one day only. None of the 12 of 30 (40 %) neonates with positive fungal cultures from nasal mucus in the first 5 days of life showed clinical symptoms of nasal fungal colonisation. Besides Candida albicans, Penicillium sp., Cladosporium cladosporioides, Acremonium polychromum, Beauveria bassiana and Epicoccum nigrum could be detected in the first 5 days of life. After the second month of life, examination of nasal mucus yielded positive fungal cultures in 8 of 11 (72 %), after four months even 17 of 18 (94 %) of babies, with a wide array of different species. CONCLUSIONS: Fungi can be cultured from nasal mucus as soon as contact with the environmental air exists. Furthermore, a transfer of fungi from the mother's birth canal into the nose during birth is possible. Presence of fungal spores is common but not persistent in the nose of babies in the first days of life. However, after four months the situation is similar to the one in adults: fungal cultures can be obtained from almost everyone's nose. Therefore fungal spores must be considered a normal content of nasal mucus. Fungal spores are inhaled with every breath, some stick to the mucus, are transported to the nasopharynx and swallowed. This does not cause any clinical symptoms and is therefore not a pathological finding at all.\n\nBraun, Hannes\n\nBuzina, Walter\n\n\n"
},
{
"text": "\n159791\nLarge-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.\n\nWild, PS\n\nFelix, JF\n\nSchillert, A\n\nTeumer, A\n\nChen, MH\n\nLeening, MJG\n\nVölker, U\n\nGroßmann, V\n\nBrody, JA\n\nIrvin, MR\n\nShah, SJ\n\nPramana, S\n\nLieb, W\n\nSchmidt, R\n\nStanton, AV\n\nMalzahn, D\n\nSmith, AV\n\nSundström, J\n\nMinelli, C\n\nRuggiero, D\n\nLyytikäinen, LP\n\nTiller, D\n\nSmith, JG\n\nMonnereau, C\n\nDi Tullio, MR\n\nMusani, SK\n\nMorrison, AC\n\nPers, TH\n\nMorley, M\n\nKleber, ME\n\nAragam, J\n\nBenjamin, EJ\n\nBis, JC\n\nBisping, E\n\nBroeckel, U\n\nCheng, S\n\nDeckers, JW\n\nDel Greco M, F\n\nEdelmann, F\n\nFornage, M\n\nFranke, L\n\nFriedrich, N\n\nHarris, TB\n\nHofer, E\n\nHofman, A\n\nHuang, J\n\nHughes, AD\n\nKähönen, M\n\nInvestigators, K\n\nKruppa, J\n\nLackner, KJ\n\nLannfelt, L\n\nLaskowski, R\n\nLauner, LJ\n\nLeosdottir, M\n\nLin, H\n\nLindgren, CM\n\nLoley, C\n\nMacRae, CA\n\nMascalzoni, D\n\nMayet, J\n\nMedenwald, D\n\nMorris, AP\n\nMüller, C\n\nMüller-Nurasyid, M\n\nNappo, S\n\nNilsson, PM\n\nNuding, S\n\nNutile, T\n\nPeters, A\n\nPfeufer, A\n\nPietzner, D\n\nPramstaller, PP\n\nRaitakari, OT\n\nRice, KM\n\nRivadeneira, F\n\nRotter, JI\n\nRuohonen, ST\n\nSacco, RL\n\nSamdarshi, TE\n\nSchmidt, H\n\nSharp, ASP\n\nShields, DC\n\nSorice, R\n\nSotoodehnia, N\n\nStricker, BH\n\nSurendran, P\n\nThom, S\n\nTöglhofer, AM\n\nUitterlinden, AG\n\nWachter, R\n\nVölzke, H\n\nZiegler, A\n\nMünzel, T\n\nMärz, W\n\nCappola, TP\n\nHirschhorn, JN\n\nMitchell, GF\n\nSmith, NL\n\nFox, ER\n\nDueker, ND\n\nJaddoe, VWV\n\nMelander, O\n\nRuss, M\n\nLehtimäki, T\n\nCiullo, M\n\nHicks, AA\n\nLind, L\n\nGudnason, V\n\nPieske, B\n\nBarron, AJ\n\nZweiker, R\n\nSchunkert, H\n\nIngelsson, E\n\nLiu, K\n\nArnett, DK\n\nPsaty, BM\n\nBlankenberg, S\n\nLarson, MG\n\nFelix, SB\n\nFranco, OH\n\nZeller, T\n\nVasan, RS\n\nDörr, M\n\nBeiträge in Fachzeitschriften\nISI:000400381000022\n28394258.0\n10.1172/JCI84840\nPMC5409098\nUnderstanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.\n A GWAS meta-analysis of echocardiographic traits was performed, including 46, 33 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.\n The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32, 12) and 17 cohorts for diastolic function traits (n = 21, 52). Replication was performed in 5 cohorts (n = 14, 21) and 6 cohorts (n = 16, 08), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.\n The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.\n For detailed information per study, see Acknowledgments.\n\nBirkl-Töglhofer, Anna Maria\n\nBisping, Egbert Hubertus\n\nHofer, Edith\n\nMärz, Winfried\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\nZweiker, Robert\n\n\n"
},
{
"text": "\n158465\nDefining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.\n\nD'Angelo, D\n\nLebon, S\n\nChen, Q\n\nMartin-Brevet, S\n\nSnyder, LG\n\nHippolyte, L\n\nHanson, E\n\nMaillard, AM\n\nFaucett, WA\n\nMacé, A\n\nPain, A\n\nBernier, R\n\nChawner, SJ\n\nDavid, A\n\nAndrieux, J\n\nAylward, E\n\nBaujat, G\n\nCaldeira, I\n\nConus, P\n\nFerrari, C\n\nForzano, F\n\nGérard, M\n\nGoin-Kochel, RP\n\nGrant, E\n\nHunter, JV\n\nIsidor, B\n\nJacquette, A\n\nJønch, AE\n\nKeren, B\n\nLacombe, D\n\nLe Caignec, C\n\nMartin, CL\n\nMännik, K\n\nMetspalu, A\n\nMignot, C\n\nMukherjee, P\n\nOwen, MJ\n\nPasseggeri, M\n\nRooryck-Thambo, C\n\nRosenfeld, JA\n\nSpence, SJ\n\nSteinman, KJ\n\nTjernagel, J\n\nVan Haelst, M\n\nShen, Y\n\nDraganski, B\n\nSherr, EH\n\nLedbetter, DH\n\nvan den Bree, MB\n\nBeckmann, JS\n\nSpiro, JE\n\nReymond, A\n\nJacquemont, S\n\nChung, WK\n\nCardiff University Experiences of Children With Copy Number Variants (ECHO) Study\n\n16p11.2 European Consortium\n\nSimons Variation in Individuals Project (VIP) Consortium\n\nBeiträge in Fachzeitschriften\nISI:000367820000006\n26629640.0\n10.1001/jamapsychiatry.2015.2123\nPMC5894477\nThe 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI).\n To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD.\n This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives.\n Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data.\n Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies.\n The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.\n\nKroisel, Peter\n\n\n"
},
{
"text": "\n182936\nCOVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.\n\nGötzinger, F\n\nSantiago-García, B\n\nNoguera-Julián, A\n\nLanaspa, M\n\nLancella, L\n\nCalò Carducci, FI\n\nGabrovska, N\n\nVelizarova, S\n\nPrunk, P\n\nOsterman, V\n\nKrivec, U\n\nLo Vecchio, A\n\nShingadia, D\n\nSoriano-Arandes, A\n\nMelendo, S\n\nLanari, M\n\nPierantoni, L\n\nWagner, N\n\nL'Huillier, AG\n\nHeininger, U\n\nRitz, N\n\nBandi, S\n\nKrajcar, N\n\nRoglić, S\n\nSantos, M\n\nChristiaens, C\n\nCreuven, M\n\nBuonsenso, D\n\nWelch, SB\n\nBogyi, M\n\nBrinkmann, F\n\nTebruegge, M\n\nptbnet COVID-19 Study Group\n\nBeiträge in Fachzeitschriften\nISI:000570772300010\n32593339.0\n10.1016/S2352-4642(20)30177-2\nPMC7316447\nTo date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic.\n This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network-the Paediatric Tuberculosis Network European Trials Group (ptbnet)-that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission.\n 582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5-12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2-11, range 1-34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. Significant risk factors for requiring ICU admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% CI 1·72-14·87; p=0·0035), male sex (2·12, 1·06-4·21; p=0·033), pre-existing medical conditions (3·27, 1·67-6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16-21·23; p<0·0001). The most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir-ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). Immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). Four children died (case-fatality rate 0·69%, 95% CI 0·20-1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support.\n COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed.\n ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit.\n Copyright © 2020 Elsevier Ltd. All rights reserved.\n\nKohlfürst, Daniela\n\nStrenger, Volker\n\n\n"
},
{
"text": "\n183284\nAssociation of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.\n\nMahmoodi, BK\n\nTragante, V\n\nKleber, ME\n\nHolmes, MV\n\nSchmidt, AF\n\nMcCubrey, RO\n\nHowe, LJ\n\nDirek, K\n\nAllayee, H\n\nBaranova, EV\n\nBraund, PS\n\nDelgado, GE\n\nEriksson, N\n\nGijsberts, CM\n\nGong, Y\n\nHartiala, J\n\nHeydarpour, M\n\nPasterkamp, G\n\nKotti, S\n\nKuukasjärvi, P\n\nLenzini, PA\n\nLevin, D\n\nLyytikäinen, LP\n\nMuehlschlegel, JD\n\nNelson, CP\n\nNikus, K\n\nPilbrow, AP\n\nWilson Tang, WH\n\nvan der Laan, SW\n\nvan Setten, J\n\nVilmundarson, RO\n\nDeanfield, J\n\nDeloukas, P\n\nDudbridge, F\n\nJames, S\n\nMordi, IR\n\nTeren, A\n\nBergmeijer, TO\n\nBody, SC\n\nBots, M\n\nBurkhardt, R\n\nCooper-DeHoff, RM\n\nCresci, S\n\nDanchin, N\n\nDoughty, RN\n\nGrobbee, DE\n\nHagström, E\n\nHazen, SL\n\nHeld, C\n\nHoefer, IE\n\nHovingh, GK\n\nJohnson, JA\n\nKaczor, MP\n\nKähönen, M\n\nKlungel, OH\n\nLaurikka, JO\n\nLehtimäki, T\n\nMaitland-van der Zee, AH\n\nMcPherson, R\n\nPalmer, CN\n\nKraaijeveld, AO\n\nPepine, CJ\n\nSanak, M\n\nSattar, N\n\nScholz, M\n\nSimon, T\n\nSpertus, JA\n\nStewart, AFR\n\nSzczeklik, W\n\nThiery, J\n\nVisseren, FLJ\n\nWaltenberger, J\n\nRichards, AM\n\nLang, CC\n\nCameron, VA\n\nÅkerblom, A\n\nPare, G\n\nMärz, W\n\nSamani, NJ\n\nHingorani, AD\n\nTen Berg, JM\n\nWallentin, L\n\nAsselbergs, FW\n\nPatel, RS\n\nBeiträge in Fachzeitschriften\nISI:000562734100013\n32654539.0\n10.1161/CIRCULATIONAHA.119.045526\nPMC7493828\nStudies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.\n We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.\n The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I\n2\n=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.\n Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n4999\nNephron-sparing procedures in 11 patients with Wilms' tumor.\n\nLinni, K\n\nUrban, C\n\nLackner, H\n\nHöllwarth, ME\n\nBeiträge in Fachzeitschriften\nISI:000184984500011\n12756594.0\n10.1007/s00383-003-0957-x\nNone\nPURPOSE: In unilateral Wilms' tumor (WT), tumor nephrectomy is the standard surgical approach, whereas partial nephrectomy (PN) is controversially discussed. The aim of our retrospective study was to show that in selected cases of unilateral WT kidney-sparing operations could be a reasonable alternative to nephrectomy and to discuss the results of patients with bilateral WT treated by tumor enucleation. MATERIALS AND METHODS: From 1981 to 1998, seven patients with unilateral nephroblastoma (four stage I, one stage III and two stage IV) had tumor resection by PN (five right side, two left side), which was planned when the tumor volume was reduced after 4 to 6 weeks of chemotherapy by at least 50%, when the tumor occupied one pole or was easily resectable, when 50% or more of the kidney tissue remained and when paraaortic lymph nodes were free by intraoperative histological examination. In four patients with bilateral WT (stage V) bilateral tumor enucleation was carried out-except in one patient in whom the contralateral kidney had to been removed because of extension of the tumor via the inferior vena cava to the right atrium. All patients ( n = 11) received pre- and postoperative chemotherapy followed by radiotherapy in four patients. RESULTS: All patients with unilateral WT ( n = 7) are still alive and disease free (follow-up time: mean 6.6 years, range: 28 months to 11 years) with normal renal function, although two patients with secondary nephrectomy revealed creatinine clearance levels at the lower range. In six patients primary PN was performed successfully. In a stage III tumor patient (intraperitoneal metastasis, free lymph nodes), secondary nephrectomy was necessary due to renal arterial thrombosis 2 days after PN. In one stage IV tumor patient (lung metastasis, free lymph nodes), the primary resection was not far enough away from the tumor margin so that an additional slice of tissue with then tumor-free margins had to be resected. This patient evolved a local relapse 19 months after PN and had to be nephrectomised thereafter. In the group of bilateral WT patients ( n = 4), one child died 2 months after surgery during chemotherapy because of central venous line sepsis. One patient who additionally suffered from inferior vena cava tumor thrombosis extending to the right atrium making nephrectomy of the right kidney necessary developed chronic renal failure 4.7 years postoperatively. The other two stage V tumor patients have creatinine clearance levels within the normal range. CONCLUSIONS: Kidney-sparing procedures remain the operative approach of choice in patients with bilateral WT, but bear the risk of chronic renal failure when one kidney has to be removed. PN in children with unilateral WT, carried out by an experienced surgeon, is a reasonable alternative to nephrectomy if strict guidelines such as excellent tumor response to preoperative chemotherapy and easy resectability far away from the tumor margins through healthy kidney tissue are followed. Paraaortic lymph nodes must be free of tumor invasion in order to avoid local radiotherapy. PN prevents the patient from having to have dialysis in cases of contralateral nephrectomy resulting from metachronous WT or subsequent renal trauma.\n\nHöllwarth, Michael\n\nLackner, Herwig\n\nUrban, Ernst-Christian\n\n\n"
},
{
"text": "\n161378\nValidation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy.\n\nWolf, J\n\nPetroff, D\n\nRichter, T\n\nAuth, MKH\n\nUhlig, HH\n\nLaass, MW\n\nLauenstein, P\n\nKrahl, A\n\nHändel, N\n\nde Laffolie, J\n\nHauer, AC\n\nKehler, T\n\nFlemming, G\n\nSchmidt, F\n\nRodrigues, A\n\nHasenclever, D\n\nMothes, T\n\nBeiträge in Fachzeitschriften\nISI:000406040600020\n28461188.0\n10.1053/j.gastro.2017.04.023\nNone\nA diagnosis of celiac disease is made based on clinical, genetic, serologic, and duodenal morphology features. Recent pediatric guidelines, based largely on retrospective data, propose omitting biopsy analysis for patients with concentrations of IgA against tissue transglutaminase (IgA-TTG) >10-fold the upper limit of normal (ULN) and if further criteria are met. A retrospective study concluded that measurements of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients with and without celiac disease. Patients were assigned to categories of no celiac disease, celiac disease, or biopsy required, based entirely on antibody assays. We aimed to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures.\n We performed a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. We compared findings from serologic analysis with findings from biopsy analyses, follow-up data, and diagnoses made by the pediatric gastroenterologists (celiac disease, no celiac disease, or no final diagnosis). Assays to measure IgA-TTG, IgG-DGL, and endomysium antibodies were performed by blinded researchers, and tissue sections were analyzed by local and blinded reference pathologists. We validated 2 procedures for diagnosis: total-IgA and IgA-TTG (the TTG-IgA procedure), as well as IgG-DGL with IgA-TTG (TTG-DGL procedure). Patients were assigned to categories of no celiac disease if all assays found antibody concentrations <1-fold the ULN, or celiac disease if at least 1 assay measured antibody concentrations >10-fold the ULN. All other cases were considered to require biopsy analysis. ULN values were calculated using the cutoff levels suggested by the test kit manufacturers. HLA typing was performed for 449 participants. We used models that considered how specificity values change with prevalence to extrapolate the PPV and NPV to populations with lower prevalence of celiac disease.\n Of the participants, 592 were found to have celiac disease, 345 were found not to have celiac disease, and 24 had no final diagnosis. The TTG-IgA procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.934; the TTG-DGL procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.958. Based on our extrapolation model, we estimated that the PPV and NPV would remain >0.95 even at a disease prevalence as low as 4%. Tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG ≥10-fold the ULN. Notably, 4.2% of pathologists disagreed in their analyses of duodenal morphology-a rate comparable to the error rate for serologic assays.\n In a prospective study, we validated the TTG-IgA procedure and the TTG-DGL procedure in identification of pediatric patients with or without celiac disease, without biopsy. German Clinical Trials Registry no.: DRKS00003854.\n Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.\n\nHauer, Almuthe\n\n\n"
},
{
"text": "\n176392\nGenome-wide association study of cerebral small vessel disease reveals established and novel loci.\n\nChung, J\n\nMarini, S\n\nPera, J\n\nNorrving, B\n\nJimenez-Conde, J\n\nRoquer, J\n\nFernandez-Cadenas, I\n\nTirschwell, DL\n\nSelim, M\n\nBrown, DL\n\nSilliman, SL\n\nWorrall, BB\n\nMeschia, JF\n\nDemel, S\n\nGreenberg, SM\n\nSlowik, A\n\nLindgren, A\n\nSchmidt, R\n\nTraylor, M\n\nSargurupremraj, M\n\nTiedt, S\n\nMalik, R\n\nDebette, S\n\nDichgans, M\n\nLangefeld, CD\n\nWoo, D\n\nRosand, J\n\nAnderson, CD\n\nBeiträge in Fachzeitschriften\nISI:000504322300028\n31430377.0\n10.1093/brain/awz233\nPMC6763741\nIntracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.\n © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n118810\nAdult burn patients with more than 60% TBSA involved-Meek and other techniques to overcome restricted skin harvest availability--the Viennese Concept.\n\nLumenta, DB\n\nKamolz, LP\n\nFrey, M\n\nBeiträge in Fachzeitschriften\nISI:000263738900004\n19165111.0\n10.1097/BCR.0b013e318198a2d6\nNone\nDespite the fact that early excision and grafting has significantly improved outcome over the last decades, the management of severely burned adult patients with >/=60% total body surface area (% TBSA) burned still represents a challenging task for burn care specialists all over the world. In this article, we present our current treatment concept for this entity of severely burned patients and analyze its effect in a comparative cohort study. Surgical strategy comprised the use of split-thickness skin grafts (Meek, mesh) for permanent coverage, fluidized microsphere bead-beds for wound conditioning, temporary coverage (polyurethane sheets, Epigard; nanocrystalline silver dressings, Acticoat; synthetic copolymer sheets based on lactic acid, Suprathel; acellular bovine derived collagen matrices, Matriderm; allogeneic cultured keratinocyte sheets; and allogeneic split-thickness skin grafts), and negative-pressure wound therapy (vacuum-assisted closure). The autologous split-thickness skin graft expansion using the Meek technique for full-thickness burns and the delayed approach for treating dorsal burn wounds is discussed in detail. To demonstrate differences before and after the introduction of the Meek technique, we have compared patients of 2007 with >/=60% TBSA (n = 10) to those in a matched observation period (n = 7). In the first part of the comparative analysis, all patients of the two samples were analyzed with regard to age, abbreviated burn severity index, Baux, different entities of % TBSA, and survival. In the second step, only the survivors of both years were separated in two groups as follows: patients receiving skin grafts, using the Meek technique (n = 6), were compared with those without Meek grafting (n = 4). When comparing the severely burned patients of 2007 with a cohort of 2006, there were no differences for age (2007: 46.4 +/- 13.4 vs. 2006: 39.1 +/- 14.8 years), abbreviated burn severity index score (2007: 12.2 +/- 1.0 vs. 2006: 12.1 +/- 1.2) or % TBSA (2007: 72.1 +/- 11.7 vs. 2006: 69.3 +/- 8.7% TBSA). In these two rather small groups of severely burned patients with >/=60% TBSA, the overall survival rate of patients was 70.0% (7/10) in 2007 and 42.9% (3/7) in 2006, respectively. Almost all nonsurvivors in both years died within the first 5 days after admission. If assessing the different treatment modalities of the survivors, we found that although the Meek group patients were older (Meek 48.8 +/- 13.3 vs. non-Meek 26.8 +/- 11.5 years, P = .0381) and had consequently higher Baux scores (Meek 124.0 +/- 2.9 vs. non-Meek 93.8 +/- 8.5, P = .0095) than the non-Meek patients, this seemed to have no effect on length-of-stay (80.5 +/- 9.7 vs. non-Meek 79.8 +/- 33.0 days), hospital length-of-stay (85.7 +/- 14.8 vs. non-meek 84.3 +/- 26.1 days) or number of operations (6.5 +/- 1.0 vs. non-Meek 7.0 +/- 4.1 operations). The achieved results represent a combination of various treatment changes and, therefore, cannot be attributed to a single modality. The Meek technique is one of the technical options to choose from, to achieve permanent skin replacement; we think that it has its place if integrated in a whole treatment concept for management of severely burned patients.\n\nKamolz, Lars-Peter\n\nLumenta, David Benjamin\n\n\n"
},
{
"text": "\n186522\nGlobal, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.\n\nGBD Chronic Kidney Disease Collaboration\n\nBeiträge in Fachzeitschriften\nISI:000516755200029\n32061315.0\n10.1016/S0140-6736(20)30045-3\nPMC7049905\nHealth system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout.\n The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function.\n Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, -1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, -1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function.\n Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI.\n Bill & Melinda Gates Foundation.\n Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access Article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n186545\nPlasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.\n\nWallentin, L\n\nEriksson, N\n\nOlszowka, M\n\nGrammer, TB\n\nHagström, E\n\nHeld, C\n\nKleber, ME\n\nKoenig, W\n\nMärz, W\n\nStewart, RAH\n\nWhite, HD\n\nÅberg, M\n\nSiegbahn, A\n\nBeiträge in Fachzeitschriften\nISI:000610192000002\n33439866.0\n10.1371/journal.pmed.1003513\nPMC7817029\nCirculating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.\n The derivation cohort consisted of 605 cases with CV death and 2, 88 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1, 42 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.\n Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.\n ClinicalTrials.gov NCT00799903.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n71245\nTemperature-controlled radiofrequency catheter ablation of manifest accessory pathways.\n\nWillems, S\n\nChen, X\n\nKottkamp, H\n\nHindricks, G\n\nHaverkamp, W\n\nRotman, B\n\nShenasa, M\n\nBreithardt, G\n\nBorggrefe, M\n\nBeiträge in Fachzeitschriften\nISI:A1996UF54400021\n8737220.0\nNone\nNone\nOBJECTIVES: The primary objectives of this study were to assess the feasibility of temperature-controlled radiofrequency catheter ablation of left and right sided manifest accessory pathways in patients with Wolff-Parkinson-White syndrome and to gain more insights into biophysical aspects of temperature-controlled catheter ablation in humans. BACKGROUND: The electrode-tissue interface temperature and other biophysical parameters are among important variables determining the efficacy and safety of radiofrequency ablation of accessory pathways. Experimental studies have shown that radiofrequency-induced tissue necrosis can be accurately predicted by monitoring of catheter tip temperature. METHODS: 38 consecutive patients (14 f, 24 m; aged 42 +/- 12 years) with anterograde conducting accessory pathways (left sided: n = 22; right sided: n = 16) underwent temperature-controlled radiofrequency ablation (HAT 200S, Dr Osypka, Germany). The electrode temperature was monitored via a thermistor embedded into a 4 mm catheter tip. Power output was adjusted automatically during energy delivery in a closed loop system (preselected temp.: 70.1 +/- 5.8 degrees C). RESULTS: Accessory pathway conduction was successfully abolished in all patients after the delivery of 2.3 +/- 2.1 radiofrequency pulses (range: 1-9, median: 2). Interruption of the accessory pathway as evidenced by loss of preexcitation occurred after 5.9 +/- 5.4 s. At the time of the interruption of the accessory pathway the catheter tip temperature measured 54.2 +/- 11.2 degrees C in patients with left and 44.9 +/- 5.0 degrees C in patients with right sided accessory pathways, respectively (P < 0.008). Higher temperature levels during left sided applications did not shorten the time it took for the effect to appear (left sided accessory pathway: 7.5 +/- 6.3 s, right sided accessory pathway: 3.7 +/- 2.9 s; ns). The catheter tip temperature was significantly higher during left compared to right sided applications after 5 (52.1 +/- 3.1 degrees C vs 47.2 +/- 4.3 degrees C) and 10 s (61.5 +/- 6.2 degrees C vs 52.7 +/- 4.2 degrees C) following initiation of the impulse (P < 0.005). Power output and delivered energy did not differ significantly at the time of accessory pathway abolition. Peak values of delivered power (45.1 +/- 10.9 W vs 41.3 +/- 10.6 W; P < 0.05) and total delivered energy (2452 +/- 1335 J vs 1392 +/- 762 J; P < 0.02) were significantly higher in the group of right sided pathways compared to left sided applications. The peak temperature measured 77.1 +/- 13 degrees C during effective and 69.9 +/- 14 degrees C during ineffective energy applications (P < 0.05). The time it took for the effect to appear was significantly longer in transiently effective pulses (10.4 +/- 7.2 s) compared to permanently effective applications (5.9 +/- 5.4 s; P < 0.02). Despite temperature control, an abrupt rise in impedance was observed in 10 of 89 (11%) energy applications. No procedure-related complications occurred. CONCLUSIONS: Temperature-controlled radiofrequency ablation of manifest accessory pathways is highly effective and safe. The temperature response is faster and significantly higher in left-sided energy applications compared to right-sided pulses. Peak temperature levels measured at the electrode tip are significantly higher during effective than ineffective pulses. Sudden rises in impedance are not completely prevented during temperature-controlled radiofrequency ablation of accessory pathway, although no procedure-related complications were noted in this patient cohort.\n\n\n"
},
{
"text": "\n131277\nPreparing for prospective clinical trials: a national initiative of an excellence registry for consecutive pancreatic cancer resections.\n\nGangl, O\n\nSahora, K\n\nKornprat, P\n\nMargreiter, C\n\nPrimavesi, F\n\nBareck, E\n\nSchindl, M\n\nLängle, F\n\nÖfner, D\n\nMischinger, HJ\n\nPratschke, J\n\nGnant, M\n\nFügger, R\n\nBeiträge in Fachzeitschriften\nISI:000329638300027\n24121365.0\n10.1007/s00268-013-2283-3\nNone\nDespite significant improvements in perioperative mortality as well as response rates to multimodality treatment, results after surgical resection of pancreatic adenocarcinoma with respect to long-term outcomes remain disappointing. Patient recruitment for prospective international trials on adjuvant and neoadjuvant regimens is challenging for various reasons. We set out to assess the preconditions and potential to perform perioperative trials for pancreatic cancer within a well-established Austrian nationwide network of surgical and medical oncologists (Austrian Breast & Colorectal Cancer Study Group).\n From 2005 to 2010 five high-volume centers and one medium-volume center completed standardized data entry forms with 33 parameters (history and patient related data, preoperative clinical staging and work-up, surgical details and intraoperative findings, postoperative complications, reinterventions, reoperations, 30-day mortality, histology, and timing of multimodality treatment). Outside of the study group, in Austria pancreatic resections are performed in three “high-volume” centers (>10 pancreatic resections per year), three “medium-volume” centers (5–10 pancreatic resections per year), and the rest in various low-volume centers (<5 pancreatic resections per year) in Austria. Nationwide data for prevalence of and surgical resections for pancreatic adenocarcinoma were contributed by the National Cancer Registry of Statistics of Austria and the Austrian Health Institute.\n In total, 492 consecutive patients underwent pancreatic resection for ductal adenocarcinoma. All postoperative complications leading to hospital readmission were treated at the primary surgical department and documented in the database. Overall morbidity and pancreatic fistula rate were 45.5 % and 10.1 %, respectively. Within the entire cohort there were 9.8 % radiological reinterventions and 10.4 % reoperations. Length of stay was 16 days in median (0–209); 12 of 492 patients died within 30 days after operation, resulting in a 30-day mortality rate of 2.4 %. Seven of the total 19 deaths (36.8 %) occurred after 30 days, during hospitalization at the surgical department, resulting in a hospital mortality rate of 3.9 % (19/492). With a standardized histopathological protocol, there were 70 % (21/30) R0 resections, 30 % (9/30) R1 resections, and no R2 resections in Vienna and 62.7 % (32/51) R0 resections, 35.3 % (18/51) R1 resections, and 2 % (1/51) R2 resections in Salzburg. Resection margin status with nonstandardized protocols was classified as R0 in 82 % (339/411), R1 in 16 % (16/411), and R2 in 1.2 % (5/411). Perioperative chemotherapy was administered in 81.1 % of patients (8.3 % neoadjuvant; 68.5 % adjuvant; 4.3 % palliative); chemoradiotherapy (1.6 % neoadjuvant; 3 % adjuvant; 0.2 % palliative), in 4.9 % of patients. The six centers that contributed to this registry initiative provided surgical treatment to 40 % of all Austrian patients, resulting in a median annual recruitment of 85 (51–104) patients for the entire ABCSG-group and a median of 11.8 (0–38) surgeries for each individual department.\n Surgical quality data of the ABCSG core pancreatic group are in line with international standards. With continuing centralization the essential potential to perform prospective clinical trials for pancreatic adenocarcinoma is given in Austria. Several protocol proposals aiming at surgical and multimodality research questions are currently being discussed\n\nKornprat, Peter\n\nMischinger, Hans-Joerg\n\n\n"
},
{
"text": "\n4546\nEndothelial cell-derived lipase mediates uptake and binding of high-density lipoprotein (HDL) particles and the selective uptake of HDL-associated cholesterol esters independent of its enzymic activity.\n\nStrauss, JG\n\nZimmermann, R\n\nHrzenjak, A\n\nZhou, Y\n\nKratky, D\n\nLevak-Frank, S\n\nKostner, GM\n\nZechner, R\n\nFrank, S\n\nBeiträge in Fachzeitschriften\nISI:000179424700008\n12164779.0\n10.1042/BJ20020306\nPMC1222966\nEndothelial cell-derived lipase (EDL) is a new member of the lipase gene family with high sequence homology with lipoprotein lipase (LPL). EDL is a phospholipase with very little triacylglycerol lipase activity. To investigate the effects of EDL on binding and uptake of high-density lipoprotein (HDL), as well as on the selective uptake of HDL-derived cholesterol esters (CEs), HepG2 cells were infected with adenovirus coding for EDL. For comparison, cells were also infected with LPL and with lacZ as a control. Both HDL binding and particle uptake were increased 1.5-fold and selective HDL-CE uptake was increased 1.8-fold in EDL-infected HepG2 cells compared with controls. The effect of LPL was less pronounced, resulting in 1.1-fold increase in particle uptake and 1.3-fold increase in selective uptake. Inhibition of the enzymic activity with tetrahydrolipstatin (THL) significantly enhanced the effect of EDL, as reflected by a 5.2-fold increase in binding, a 2.6-fold increase in particle uptake and a 1.1-fold increase in CE selective uptake compared with incubations without THL. To elucidate the mechanism responsible for the effects of THL, we analysed the abundance of heparin-releasable EDL protein from infected HepG2 cells upon incubations with THL, HDL and free (non-esterified) fatty acids (FFAs). In the presence of THL, vastly more EDL protein remained bound to the cell surface. Additionally, HDL and FFAs reduced the amount of cell-surface-bound EDL, suggesting that fatty acids that are liberated from phospholipids in HDL release EDL from the cell surface. This was substantiated further by the finding that, in contrast with EDL, the amount of cell-surface-bound enzymically inactive mutant EDL (MUT-EDL) was not reduced in the presence of HDL and foetal calf serum. The increased amount of cell-surface-bound MUT-EDL in the presence of THL suggested that the enzymic inactivity of MUT-EDL, as well as an augmenting effect of THL that is independent of its ability to inactivate the enzyme, are responsible for the increased amount of cell-surface-bound EDL in the presence of THL. Furthermore, in cells expressing MUT-EDL, binding and holoparticle uptake were markedly higher compared with cells expressing the active EDL, and could be increased further in the presence of THL. Despite 1.7-fold higher binding and 1.8-fold higher holoparticle uptake, the selective CE uptake by MUT-EDL-expressing cells was comparable with EDL-expressing cells and was even decreased 1.3-fold with THL. Experiments in CLA-1 (CD-36 and LIMPII analogous 1, the human homologue of scavenger receptor class B type I)-deficient HEK-293 cells demonstrated that EDL alone has the ability to stimulate HDL-CE selective uptake independently of CLA-1. Thus our results demonstrate that EDL mediates both HDL binding and uptake, and the selective uptake of HDL-CE, independently of lipolysis and CLA-1.\n\nFrank, Sasa\n\nHrzenjak, Andelko\n\nKostner, Gerhard\n\nKratky, Dagmar\n\nLevak, Sanja\n\n\n"
},
{
"text": "\n149468\nGeneral Movements in preterm infants undergoing craniosacral therapy: a randomised controlled pilot-trial.\n\nRaith, W\n\nMarschik, PB\n\nSommer, C\n\nMaurer-Fellbaum, U\n\nAmhofer, C\n\nAvian, A\n\nLöwenstein, E\n\nSoral, S\n\nMüller, W\n\nEinspieler, C\n\nUrlesberger, B\n\nBeiträge in Fachzeitschriften\nISI:000367903400001\n26758035.0\n10.1186/s12906-016-0984-5\nPMC4710971\nThe objective of this study was to investigate neurological short-term effects of craniosacral therapy as an ideal form of osteopathic manipulative treatment (OMT) due to the soft kinaesthetic stimulation.\n Included were 30 preterm infants, with a gestational age between 25 and 33 weeks, who were admitted to the neonatal intensive care unit of the University Hospital of Graz, Austria. The infants were randomized either into the intervention group (IG) which received standardised craniosacral therapy, or the control group (CG) which received standard care. To guarantee that only preterm infants with subsequent normal neurodevelopment were included, follow up was done regularly at the corrected age (= actual age in weeks minus weeks premature) of 12 and 24 months. After 2 years 5 infants had to be excluded (IG; n = 12; CG: n = 13). General Movements (GMs) are part of the spontaneous movement repertoire and are present from early fetal life onwards until the end of the first half year of life. To evaluate the immediate result of such an intervention, we selected the General Movement Assessment (GMA) as an appropriate tool. Besides the global GMA (primary outcome) we used as detailed GMA, the General Movement Optimality Score (GMOS- secondary outcome), based on Prechtl's optimality concept. To analyse GMOS (secondary outcome) a linear mixed model with fixed effects for session, time point (time point refers to the comparisons of the measurements before vs. after each session) and intervention (IG vs. CG), random effect for individual children and a first order autoregressive covariance structure was used for calculation of significant differences between groups and interactions. Following interaction terms were included in the model: session*time point, session*intervention, time point*intervention and session*time point*intervention. Exploratory post hoc analyses (interaction: session*time point*intervention) were performed to determine group differences for all twelve measurement (before and after all 6 sessions) separately.\n Between groups no difference in the global GMA (primary outcome) could be observed. The GMOS (secondary outcome) did not change from session to session (main effect session: p = 0.262) in the IG or the CG. Furthermore no differences between IG and CG (main effect group: p = 0.361) and no interaction of time*session could be observed (p = 0.658). Post hoc analysis showed a trend toward higher values before (p = 0.085) and after (p = 0.075) the first session in CG compared to IG. At all other time points GMOS were not significantly different between groups.\n We were able to indicate that a group of "healthy" preterm infants undergoing an intervention with craniosacral therapy (IG) showed no significant changes in GMs compared to preterm infants without intervention (CG). In view of the fact that the global GMA (primary outcome) showed no difference between groups and the GMOS (detailed GMA-secondary outcome) did not deteriorate in the IG, craniosacral therapy seems to be safe in preterm infants.\n German Clinical Trials Register DRKS00004258 .\n\nAvian, Alexander\n\nEinspieler, Christa\n\nMarschik, Peter\n\nMaurer-Fellbaum, Ute\n\nMüller, Wilhelm\n\nRaith, Wolfgang\n\nSommer, Constanze\n\nUrlesberger, Berndt\n\n\n"
},
{
"text": "\n123473\nEAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy.\n\nCalderon, MA\n\nDemoly, P\n\nGerth van Wijk, R\n\nBousquet, J\n\nSheikh, A\n\nFrew, A\n\nScadding, G\n\nBachert, C\n\nMalling, HJ\n\nValenta, R\n\nBilo, B\n\nNieto, A\n\nAkdis, C\n\nJust, J\n\nVidal, C\n\nVarga, EM\n\nAlvarez-Cuesta, E\n\nBohle, B\n\nBufe, A\n\nCanonica, WG\n\nCardona, V\n\nDahl, R\n\nDidier, A\n\nDurham, SR\n\nEng, P\n\nFernandez-Rivas, M\n\nJacobsen, L\n\nJutel, M\n\nKleine-Tebbe, J\n\nKlimek, L\n\nLötvall, J\n\nMoreno, C\n\nMosges, R\n\nMuraro, A\n\nNiggemann, B\n\nPajno, G\n\nPassalacqua, G\n\nPfaar, O\n\nRak, S\n\nSenna, G\n\nSenti, G\n\nValovirta, E\n\nvan Hage, M\n\nVirchow, JC\n\nWahn, U\n\nPapadopoulos, N\n\nBeiträge in Fachzeitschriften\nNone\n23110958.0\n10.1186/2045-7022-2-20\nPMC3514324\nAllergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe's policy-makers to coordinate actions and improve individual and public health in allergy by:Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.\n\nVarga, Eva-Maria\n\n\n"
},
{
"text": "\n177401\nA Systematic Review of the Normal Sacroiliac Joint Anatomy and Adjacent Tissues for Pain Physicians.\n\nPoilliot, AJ\n\nZwirner, J\n\nDoyle, T\n\nHammer, N\n\nBeiträge in Fachzeitschriften\nISI:000487972900001\n31337164.0\nNone\nNone\nThe sacroiliac joint (SIJ) forms a complex joint and has shown to be underappreciated in its involvement with lower back pain. Research efforts have intensified on SIJ anatomy and biomechanics because of its predisposing position to pain and dysfunction in individuals suffering from lower back discomfort. Previous work has focused on SIJ anatomy including bone and joint structure, innervation, as well as biomechanics and the treatment of SIJ pain. However, to date, no review exists describing the range of 'normal' anatomic features of the SIJ.\n To describe the normal appearance of the SIJ and adjacent tissues, as opposed to 'abnormal' conditions involving SIJ morphology. It will also identify key areas that require further study because of lacking information or disagreement.\n A systematic literature review.\n The research took place at the University of Otago, New Zealand. All published research on 'normal SIJ anatomy' available from MEDLINE, OVID, Scopus, Web of Science, PubMed, and Science Direct were included, available until December 2018, in English, French, and German. Subject areas included bony landmarks, joint type, bone morphology, ligamentous attachments, muscular and fascial relationships, blood supply, fatty infiltration, and morphologic variation.\n Articles met the selection criteria if they contained specific information on SIJ anatomy, including bone morphology and architecture, ligaments, muscle attachments, innervation, vasculature, and the presence of fat. Biomechanics and kinematics related keywords were used as the literature often couples these with the anatomy. Keywords of individual articles were named as 'structures of interest.'\n A total of 88 primary and 101 secondary articles were identified in the time frame from 1851 to 2018. Primary articles provided quantitative data and detailed anatomic descriptions. Secondary articles did not focus specifically on the anatomy of the SIJ. Although research appeared to be in general agreement on bony landmarks, joint type, myofascial attachments, vasculature, and innervation of the SIJ, there was only part consensus on ligament attachments and cartilage structure. Information regarding bone density of the articulating surfaces of the SIJ is lacking. Despite its potential clinical significance, fatty infiltration within the joint lacks research to date.\n Only the given databases were used for the initial search. Keyword combinations used for this review may not have been inclusive of all articles relevant to the SIJ. Work in languages other than the ones listed or work that is not available via the internet may be missing.\n This study provides an overview of normal SIJ structures, including all neuromusculoskeletal elements related to the joint. There is a lack of knowledge on the SIJ ligaments warranting further investigation. Furthermore, there are discrepancies in relation to the nomenclature, layers, attachment sites, and on the topographical relationships between ligamentous tissues and nerves. Subsequent studies on the quantification of fat and bone density in the SIJ have been suggested. These could be useful radiologic parameters to assess the condition of the joint clinically. This review may provide insight into the clinical signs and abnormal biomechanical features of the joint for the purposes of treating SIJ pain.\n Bone density, bony landmarks, fat infiltration, innervation, ligaments morphology, muscles, sacroiliac joint, vasculature.\n\nHammer, Niels\n\n\n"
},
{
"text": "\n161899\nAssessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research\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, YH\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:000407297300001\n28777142.0\n10.1097/PAP.0000000000000162\nPMC5564448\nAssessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.\n\nBrcic, Iva\n\n\n"
}
]
}