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"text": "\n142052\nGenome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.\n\nDebette, S\n\nIbrahim Verbaas, CA\n\nBressler, J\n\nSchuur, M\n\nSmith, A\n\nBis, JC\n\nDavies, G\n\nWolf, C\n\nGudnason, V\n\nChibnik, LB\n\nYang, Q\n\ndeStefano, AL\n\nde Quervain, DJ\n\nSrikanth, V\n\nLahti, J\n\nGrabe, HJ\n\nSmith, JA\n\nPriebe, L\n\nYu, L\n\nKarbalai, N\n\nHayward, C\n\nWilson, JF\n\nCampbell, H\n\nPetrovic, K\n\nFornage, M\n\nChauhan, G\n\nYeo, R\n\nBoxall, R\n\nBecker, J\n\nStegle, O\n\nMather, KA\n\nChouraki, V\n\nSun, Q\n\nRose, LM\n\nResnick, S\n\nOldmeadow, C\n\nKirin, M\n\nWright, AF\n\nJonsdottir, MK\n\nAu, R\n\nBecker, A\n\nAmin, N\n\nNalls, MA\n\nTurner, ST\n\nKardia, SL\n\nOostra, B\n\nWindham, G\n\nCoker, LH\n\nZhao, W\n\nKnopman, DS\n\nHeiss, G\n\nGriswold, ME\n\nGottesman, RF\n\nVitart, V\n\nHastie, ND\n\nZgaga, L\n\nRudan, I\n\nPolasek, O\n\nHolliday, EG\n\nSchofield, P\n\nChoi, SH\n\nTanaka, T\n\nAn, Y\n\nPerry, RT\n\nKennedy, RE\n\nSale, MM\n\nWang, J\n\nWadley, VG\n\nLiewald, DC\n\nRidker, PM\n\nGow, AJ\n\nPattie, A\n\nStarr, JM\n\nPorteous, D\n\nLiu, X\n\nThomson, R\n\nArmstrong, NJ\n\nEiriksdottir, G\n\nAssareh, AA\n\nKochan, NA\n\nWiden, E\n\nPalotie, A\n\nHsieh, YC\n\nEriksson, JG\n\nVogler, C\n\nvan Swieten, JC\n\nShulman, JM\n\nBeiser, A\n\nRotter, J\n\nSchmidt, CO\n\nHoffmann, W\n\nNöthen, MM\n\nFerrucci, L\n\nAttia, J\n\nUitterlinden, AG\n\nAmouyel, P\n\nDartigues, JF\n\nAmieva, H\n\nRäikkönen, K\n\nGarcia, M\n\nWolf, PA\n\nHofman, A\n\nLongstreth, WT\n\nPsaty, BM\n\nBoerwinkle, E\n\nDeJager, PL\n\nSachdev, PS\n\nSchmidt, R\n\nBreteler, MM\n\nTeumer, A\n\nLopez, OL\n\nCichon, S\n\nChasman, DI\n\nGrodstein, F\n\nMüller-Myhsok, B\n\nTzourio, C\n\nPapassotiropoulos, A\n\nBennett, DA\n\nIkram, MA\n\nDeary, IJ\n\nvan Duijn, CM\n\nLauner, L\n\nFitzpatrick, AL\n\nSeshadri, S\n\nMosley, TH\n\nCohorts for Heart and Aging Research in Genomic Epidemiology Consortium\n\nBeiträge in Fachzeitschriften\nISI:000352092700013\n25648963.0\n10.1016/j.biopsych.2014.08.027\nPMC4513651\nMemory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.\n We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29, 76 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10, 17 participants of European descent, 3811 African-Americans, and 1561 young adults.\n rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.\n This largest study to date exploring the genetics of memory function in ~40, 00 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.\n Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n181315\nAn Investigation of Psychosis Subgroups With Prognostic Validation and Exploration of Genetic Underpinnings: The PsyCourse Study.\n\nDwyer, DB\n\nKalman, JL\n\nBudde, M\n\nKambeitz, J\n\nRuef, A\n\nAntonucci, LA\n\nKambeitz-Ilankovic, L\n\nHasan, A\n\nKondofersky, I\n\nAnderson-Schmidt, H\n\nGade, K\n\nReich-Erkelenz, D\n\nAdorjan, K\n\nSenner, F\n\nSchaupp, S\n\nAndlauer, TFM\n\nComes, AL\n\nSchulte, EC\n\nKlöhn-Saghatolislam, F\n\nGryaznova, A\n\nHake, M\n\nBartholdi, K\n\nFlatau-Nagel, L\n\nReitt, M\n\nQuast, S\n\nStegmaier, S\n\nMeyers, M\n\nEmons, B\n\nHaußleiter, IS\n\nJuckel, G\n\nNieratschker, V\n\nDannlowski, U\n\nYoshida, T\n\nSchmauß, M\n\nZimmermann, J\n\nReimer, J\n\nWiltfang, J\n\nReininghaus, E\n\nAnghelescu, IG\n\nArolt, V\n\nBaune, BT\n\nKonrad, C\n\nThiel, A\n\nFallgatter, AJ\n\nFigge, C\n\nvon Hagen, M\n\nKoller, M\n\nLang, FU\n\nWigand, ME\n\nBecker, T\n\nJäger, M\n\nDietrich, DE\n\nScherk, H\n\nSpitzer, C\n\nFolkerts, H\n\nWitt, SH\n\nDegenhardt, F\n\nForstner, AJ\n\nRietschel, M\n\nNöthen, MM\n\nMueller, N\n\nPapiol, S\n\nHeilbronner, U\n\nFalkai, P\n\nSchulze, TG\n\nKoutsouleris, N\n\nBeiträge in Fachzeitschriften\nISI:000534040500014\n32049274.0\n10.1001/jamapsychiatry.2019.4910\nPMC7042925\nIdentifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations.\n To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement.\n This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019.\n A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables.\n Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R2 = 0.41; 95% CI, 0.38-0.44), depression symptoms (R2 = 0.28; 95% CI, 0.25-0.32), global functioning (R2 = 0.16; 95% CI, 0.14-0.20), and quality of life (R2 = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean [SD] partial η2 = 0.014 [0.003]) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort.\n Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.\n\nReininghaus, Eva\n\n\n"
},
{
"text": "\n185699\nGlobal Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study.\n\nRoth, GA\n\nMensah, GA\n\nJohnson, CO\n\nAddolorato, G\n\nAmmirati, E\n\nBaddour, LM\n\nBarengo, NC\n\nBeaton, AZ\n\nBenjamin, EJ\n\nBenziger, CP\n\nBonny, A\n\nBrauer, M\n\nBrodmann, M\n\nCahill, TJ\n\nCarapetis, J\n\nCatapano, AL\n\nChugh, SS\n\nCooper, LT\n\nCoresh, J\n\nCriqui, M\n\nDeCleene, N\n\nEagle, KA\n\nEmmons-Bell, S\n\nFeigin, VL\n\nFernández-Solà, J\n\nFowkes, G\n\nGakidou, E\n\nGrundy, SM\n\nHe, FJ\n\nHoward, G\n\nHu, F\n\nInker, L\n\nKarthikeyan, G\n\nKassebaum, N\n\nKoroshetz, W\n\nLavie, C\n\nLloyd-Jones, D\n\nLu, HS\n\nMirijello, A\n\nTemesgen, AM\n\nMokdad, A\n\nMoran, AE\n\nMuntner, P\n\nNarula, J\n\nNeal, B\n\nNtsekhe, M\n\nMoraes de Oliveira, G\n\nOtto, C\n\nOwolabi, M\n\nPratt, M\n\nRajagopalan, S\n\nReitsma, M\n\nRibeiro, ALP\n\nRigotti, N\n\nRodgers, A\n\nSable, C\n\nShakil, S\n\nSliwa-Hahnle, K\n\nStark, B\n\nSundström, J\n\nTimpel, P\n\nTleyjeh, IM\n\nValgimigli, M\n\nVos, T\n\nWhelton, PK\n\nYacoub, M\n\nZuhlke, L\n\nMurray, C\n\nFuster, V\n\nGBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group\n\nBeiträge in Fachzeitschriften\nISI:000602956000013\n33309175.0\n10.1016/j.jacc.2020.11.010\nPMC7755038\nCardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.\n Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.\n\nBrodmann, Marianne\n\n\n"
},
{
"text": "\n142053\nGenetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).\n\nDavies, G\n\nArmstrong, N\n\nBis, JC\n\nBressler, J\n\nChouraki, V\n\nGiddaluru, S\n\nHofer, E\n\nIbrahim-Verbaas, CA\n\nKirin, M\n\nLahti, J\n\nvan der Lee, SJ\n\nLe Hellard, S\n\nLiu, T\n\nMarioni, RE\n\nOldmeadow, C\n\nPostmus, I\n\nSmith, AV\n\nSmith, JA\n\nThalamuthu, A\n\nThomson, R\n\nVitart, V\n\nWang, J\n\nYu, L\n\nZgaga, L\n\nZhao, W\n\nBoxall, R\n\nHarris, SE\n\nHill, WD\n\nLiewald, DC\n\nLuciano, M\n\nAdams, H\n\nAmes, D\n\nAmin, N\n\nAmouyel, P\n\nAssareh, AA\n\nAu, R\n\nBecker, JT\n\nBeiser, A\n\nBerr, C\n\nBertram, L\n\nBoerwinkle, E\n\nBuckley, BM\n\nCampbell, H\n\nCorley, J\n\nDe Jager, PL\n\nDufouil, C\n\nEriksson, JG\n\nEspeseth, T\n\nFaul, JD\n\nFord, I\n\nGeneration Scotland\n\nGottesman, RF\n\nGriswold, ME\n\nGudnason, V\n\nHarris, TB\n\nHeiss, G\n\nHofman, A\n\nHolliday, EG\n\nHuffman, J\n\nKardia, SL\n\nKochan, N\n\nKnopman, DS\n\nKwok, JB\n\nLambert, JC\n\nLee, T\n\nLi, G\n\nLi, SC\n\nLoitfelder, M\n\nLopez, OL\n\nLundervold, AJ\n\nLundqvist, A\n\nMather, KA\n\nMirza, SS\n\nNyberg, L\n\nOostra, BA\n\nPalotie, A\n\nPapenberg, G\n\nPattie, A\n\nPetrovic, K\n\nPolasek, O\n\nPsaty, BM\n\nRedmond, P\n\nReppermund, S\n\nRotter, JI\n\nSchmidt, H\n\nSchuur, M\n\nSchofield, PW\n\nScott, RJ\n\nSteen, VM\n\nStott, DJ\n\nvan Swieten, JC\n\nTaylor, KD\n\nTrollor, J\n\nTrompet, S\n\nUitterlinden, AG\n\nWeinstein, G\n\nWiden, E\n\nWindham, BG\n\nJukema, JW\n\nWright, AF\n\nWright, MJ\n\nYang, Q\n\nAmieva, H\n\nAttia, JR\n\nBennett, DA\n\nBrodaty, H\n\nde Craen, AJ\n\nHayward, C\n\nIkram, MA\n\nLindenberger, U\n\nNilsson, LG\n\nPorteous, DJ\n\nRäikkönen, K\n\nReinvang, I\n\nRudan, I\n\nSachdev, PS\n\nSchmidt, R\n\nSchofield, PR\n\nSrikanth, V\n\nStarr, JM\n\nTurner, ST\n\nWeir, DR\n\nWilson, JF\n\nvan Duijn, C\n\nLauner, L\n\nFitzpatrick, AL\n\nSeshadri, S\n\nMosley, TH\n\nDeary, IJ\n\nBeiträge in Fachzeitschriften\nISI:000349986700007\n25644384.0\n10.1038/mp.2014.188\nPMC4356746\nGeneral cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53, 49) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.\n\nHofer, Edith\n\nKoini, Marisa\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n179234\nInternational Society of Sports Nutrition Position Stand: Probiotics.\n\nJäger, R\n\nMohr, AE\n\nCarpenter, KC\n\nKerksick, CM\n\nPurpura, M\n\nMoussa, A\n\nTownsend, JR\n\nLamprecht, M\n\nWest, NP\n\nBlack, K\n\nGleeson, M\n\nPyne, DB\n\nWells, SD\n\nArent, SM\n\nSmith-Ryan, AE\n\nKreider, RB\n\nCampbell, BI\n\nBannock, L\n\nScheiman, J\n\nWissent, CJ\n\nPane, M\n\nKalman, DS\n\nPugh, JN\n\nTer Haar, JA\n\nAntonio, J\n\nBeiträge in Fachzeitschriften\nISI:000504082300001\n31864419.0\n10.1186/s12970-019-0329-0\nPMC6925426\nPosition statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: 1)Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO).2)Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications.3)Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent.4)Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown.5)The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components.6)Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes' exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections.7)Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes.8)Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise.9)The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product's shelf life, as measured by colony forming units (CFU) or live cells.10)Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population.\n\n\n"
},
{
"text": "\n144697\nGWAS for executive function and processing speed suggests involvement of the CADM2 gene.\n\nIbrahim-Verbaas, CA\n\nBressler, J\n\nDebette, S\n\nSchuur, M\n\nSmith, AV\n\nBis, JC\n\nDavies, G\n\nTrompet, S\n\nSmith, JA\n\nWolf, C\n\nChibnik, LB\n\nLiu, Y\n\nVitart, V\n\nKirin, M\n\nPetrovic, K\n\nPolasek, O\n\nZgaga, L\n\nFawns-Ritchie, C\n\nHoffmann, P\n\nKarjalainen, J\n\nLahti, J\n\nLlewellyn, DJ\n\nSchmidt, CO\n\nMather, KA\n\nChouraki, V\n\nSun, Q\n\nResnick, SM\n\nRose, LM\n\nOldmeadow, C\n\nStewart, M\n\nSmith, BH\n\nGudnason, V\n\nYang, Q\n\nMirza, SS\n\nJukema, JW\n\ndeJager, PL\n\nHarris, TB\n\nLiewald, DC\n\nAmin, N\n\nCoker, LH\n\nStegle, O\n\nLopez, OL\n\nSchmidt, R\n\nTeumer, A\n\nFord, I\n\nKarbalai, N\n\nBecker, JT\n\nJonsdottir, MK\n\nAu, R\n\nFehrmann, R\n\nHerms, S\n\nNalls, M\n\nZhao, W\n\nTurner, ST\n\nYaffe, K\n\nLohman, K\n\nvan Swieten, JC\n\nKardia, S\n\nKnopman, DS\n\nMeeks, WM\n\nHeiss, G\n\nHolliday, EG\n\nSchofield, PW\n\nTanaka, T\n\nStott, DJ\n\nWang, J\n\nRidker, P\n\nGow, AJ\n\nPattie, A\n\nStarr, JM\n\nHocking, LJ\n\nArmstrong, NJ\n\nMcLachlan, S\n\nShulman, JM\n\nPilling, LC\n\nEiriksdottir, G\n\nScott, RJ\n\nKochan, NA\n\nPalotie, A\n\nHsieh, YC\n\nEriksson, JG\n\nPenman, A\n\nGottesman, RF\n\nOostra, BA\n\nYu, L\n\nDeStefano, AL\n\nBeiser, A\n\nGarcia, M\n\nRotter, JI\n\nNöthen, MM\n\nHofman, A\n\nSlagboom, PE\n\nWestendorp, R\n\nBuckley, BM\n\nWolf, PA\n\nUitterlinden, AG\n\nPsaty, BM\n\nGrabe, HJ\n\nBandinelli, S\n\nChasman, DI\n\nGrodstein, F\n\nRäikkönen, K\n\nLambert, JC\n\nPorteous, DJ\n\nGeneration Scotland\n\nPrice, JF\n\nSachdev, PS\n\nFerrucci, L\n\nAttia, JR\n\nRudan, I\n\nHayward, C\n\nWright, AF\n\nWilson, JF\n\nCichon, S\n\nFranke, L\n\nSchmidt, H\n\nDing, J\n\nde Craen, A\n\nFornage, M\n\nBennett, DA\n\nDeary, IJ\n\nIkram, MA\n\nLauner, LJ\n\nFitzpatrick, AL\n\nSeshadri, S\n\nvan Duijn, CM\n\nMosley, TH\n\nBeiträge in Fachzeitschriften\nISI:000370817800005\n25869804.0\n10.1038/mp.2015.37\nPMC4722802\nTo identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32, 70 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n119109\nAntiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial.\n\nHankey, GJ\n\nEikelboom, JW\n\nYi, Q\n\nLees, KR\n\nChen, C\n\nXavier, D\n\nNavarro, JC\n\nRanawaka, UK\n\nUddin, W\n\nRicci, S\n\nGommans, J\n\nSchmidt, R\n\nfor the VITATOPS trial study group\n\nBeiträge in Fachzeitschriften\nISI:000304789800012\n22554931.0\n10.1016/S1474-4422(12)70091-1\nPMC3361667\nBackground Previous studies have suggested that any benefits of folic acid-based therapy to lower serum homocysteine in prevention of cardiovascular events might be offset by concomitant use of antiplatelet therapy. We aimed to establish whether there is an interaction between antiplatelet therapy and the effects of folic acid-based homocysteine-lowering therapy on major vascular events in patients with stroke or transient ischaemic attack enrolled in the vitamins to prevent stroke (VITATOPS) trial. Methods In the VITATOPS trial, 8164 patients with recent stroke or transient ischaemic attack were randomly allocated to double-blind treatment with one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B-6, and 500 mu g vitamin B-12) and followed up for a median 3.4 years (IQR 2-0-5.5) for the primary composite outcome of stroke, myocardial infarction, or death from vascular causes. In our post-hoc analysis of the interaction between antiplatelet therapy and the effects of treatment with B vitamins on the primary outcome, we used Cox proportional hazards regression before and after adjusting for imbalances in baseline prognostic factors in participants who were and were not taking antiplatelet drugs at baseline and in participants assigned to receive B vitamins or placebo. We also assessed the interaction in different subgroups of patients and different secondary outcomes. The VITATOPS trial is registered with ClinicalTrials.gov, number NCT00097669, and Current Controlled Trials, number ISRCTN74743444. Findings At baseline, 6609 patients were taking antiplatelet therapy and 1463 were not. Patients not receiving antiplatelet therapy were more likely to be younger, east Asian, and disabled, to have a haemorrhagic stroke or cardioembolic ischaemic stroke, and to have a history of hypertension or atrial fibrillation. They were less likely to be smokers and to have a history of peripheral artery disease, hypercholesterolaemia, diabetes, ischaemic heart disease, and a revascularisation procedure. Of the participants taking antiplatelet drugs at baseline, B vitamins had no significant effect on the primary outcome (488 patients in the B-vitamins group [15%] vs 519 in the placebo group [16%]; hazard ratio [HA] 0.94, 95% CI 0.83-1.07). By contrast, of the participants not taking antiplatelet drugs at baseline, B vitamins had a significant effect on the primary outcome (123 in the B-vitamins group [17%] vs 153 in the placebo group [21%]; HR 0.76, 0.60-0.96). The interaction between antiplatelet therapy and the effect of B vitamins on the primary outcome was significant after adjusting for imbalance in the baseline variables (adjusted p for interaction=0.0204). Interpretation Our findings support the hypothesis that antiplatelet therapy modifies the potential benefits of lowering homocysteine with B-vitamin supplementation in the secondary prevention of major vascular events. If validated, B vitamins might have a role in the prevention of ischaemic events in high-risk individuals with an allergy, intolerance, or lack of indication for antiplatelet therapy. Funding Australia National Health and Medical Research Council, UK Medical Research Council, Singapore Biomedical Research Council, and Singapore National Medical Research Council.\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n159533\nEffect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase-4 trial\n\nRosenkranz, A\n\nBeiträge in Fachzeitschriften\nISI:000393502100007\nNone\n10.1016/S2213-8587(15)00377-0\nNone\nBackground: Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium-sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control. Methods: We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK. Eligible patients were aged 18-80 years; had clinic systolic blood pressure of 140 mm Hg or higher and home systolic blood pressure of 130 mmHg or higher on permitted background drugs of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or direct renin inhibitors (previously untreated patients were also eligible in specific circumstances); and had at least one component of the metabolic syndrome in addition to hypertension. Patients with known diabetes were excluded. Patients were randomly assigned (1: 1: 1) to 24 weeks of daily oral treatment with starting doses of 10 mg amiloride, 25 mg hydrochlorothiazide, or 5 mg amiloride plus 12, mg hydrochlorothiazide; all doses were doubled after 12 weeks. Random assignment was done via a central computer system. Both participants and investigators were masked to assignment. Our hierarchical primary endpoints, assessed on a modified intention-to-treat basis at 12 and 24 weeks, were the differences from baseline in blood glucose measured 2 h after a 75 g oral glucose tolerance test (OGTT), compared first between the hydrochlorothiazide and amiloride groups, and then between the hydrochlorothiazide and combination groups. A key secondary endpoint was change in home systolic blood pressure at 12 and 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862, and the MHRA, Eudract number 2009-010068-41, and is now complete. Findings: Between Nov 18, 2009, and Dec 15, 2014, 145 patients were randomly assigned to amiloride, 146 to hydrochlorothiazide, and 150 to the combination group. 132 participants in the amiloride group, 134 in the hydrochlorothiazide group, and 133 in the combination group were included in the modified intention-to-treat analysis. 2 h glucose concentrations after OGTT, averaged at 12 and 24 weeks, were significantly lower in the amiloride group than in the hydrochlorothiazide group (mean difference -0, 5 mmol/L [95 % CI -0, 6 to -0, 4]; p = 0, 093) and in the combination group than in the hydrochlorothiazide group (-0, 2 mmol/L [-0, 4 to -0, 04]; p = 0, 48). The mean reduction in home systolic blood pressure during 24 weeks did not differ significantly between the amiloride and hydrochlorothiazide groups, but the fall in blood pressure in the combination group was significantly greater than that in the hydrochlorothiazide group (p = 0, 068). Hyperkalaemia was reported in seven (4, %) patients in the amiloride group and three (2, %) patients in the combination group; the highest recorded potassium concentration was 5, mmol/L in a patient in the amiloride group. 13 serious adverse events occurred but the frequency did not differ significantly between groups. Interpretation: The combination of amiloride with hydrochlorothiazide, at doses equipotent on blood pressure, prevents glucose intolerance and improves control of blood pressure compared with montherapy with either drug. These findings, together with previous data about morbidity and mortality for the combination, support first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic.\n\nRosenkranz, Alexander\n\n\n"
},
{
"text": "\n137309\nGene-wide analysis detects two new susceptibility genes for Alzheimer's disease.\n\nEscott-Price, V\n\nBellenguez, C\n\nWang, LS\n\nChoi, SH\n\nHarold, D\n\nJones, L\n\nHolmans, P\n\nGerrish, A\n\nVedernikov, A\n\nRichards, A\n\nDeStefano, AL\n\nLambert, JC\n\nIbrahim-Verbaas, CA\n\nNaj, AC\n\nSims, R\n\nJun, G\n\nBis, JC\n\nBeecham, GW\n\nGrenier-Boley, B\n\nRusso, G\n\nThornton-Wells, TA\n\nDenning, N\n\nSmith, AV\n\nChouraki, V\n\nThomas, C\n\nIkram, MA\n\nZelenika, D\n\nVardarajan, BN\n\nKamatani, Y\n\nLin, CF\n\nSchmidt, H\n\nKunkle, B\n\nDunstan, ML\n\nVronskaya, M\n\nUnited Kingdom Brain Expression Consortium\n\nJohnson, AD\n\nRuiz, A\n\nBihoreau, MT\n\nReitz, C\n\nPasquier, F\n\nHollingworth, P\n\nHanon, O\n\nFitzpatrick, AL\n\nBuxbaum, JD\n\nCampion, D\n\nCrane, PK\n\nBaldwin, C\n\nBecker, T\n\nGudnason, V\n\nCruchaga, C\n\nCraig, D\n\nAmin, N\n\nBerr, C\n\nLopez, OL\n\nDe Jager, PL\n\nDeramecourt, V\n\nJohnston, JA\n\nEvans, D\n\nLovestone, S\n\nLetenneur, L\n\nHernández, I\n\nRubinsztein, DC\n\nEiriksdottir, G\n\nSleegers, K\n\nGoate, AM\n\nFiévet, N\n\nHuentelman, MJ\n\nGill, M\n\nBrown, K\n\nKamboh, MI\n\nKeller, L\n\nBarberger-Gateau, P\n\nMcGuinness, B\n\nLarson, EB\n\nMyers, AJ\n\nDufouil, C\n\nTodd, S\n\nWallon, D\n\nLove, S\n\nRogaeva, E\n\nGallacher, J\n\nGeorge-Hyslop, PS\n\nClarimon, J\n\nLleo, A\n\nBayer, A\n\nTsuang, DW\n\nYu, L\n\nTsolaki, M\n\nBossù, P\n\nSpalletta, G\n\nProitsi, P\n\nCollinge, J\n\nSorbi, S\n\nGarcia, FS\n\nFox, NC\n\nHardy, J\n\nNaranjo, MC\n\nBosco, P\n\nClarke, R\n\nBrayne, C\n\nGalimberti, D\n\nScarpini, E\n\nBonuccelli, U\n\nMancuso, M\n\nSiciliano, G\n\nMoebus, S\n\nMecocci, P\n\nZompo, MD\n\nMaier, W\n\nHampel, H\n\nPilotto, A\n\nFrank-García, A\n\nPanza, F\n\nSolfrizzi, V\n\nCaffarra, P\n\nNacmias, B\n\nPerry, W\n\nMayhaus, M\n\nLannfelt, L\n\nHakonarson, H\n\nPichler, S\n\nCarrasquillo, MM\n\nIngelsson, M\n\nBeekly, D\n\nAlvarez, V\n\nZou, F\n\nValladares, O\n\nYounkin, SG\n\nCoto, E\n\nHamilton-Nelson, KL\n\nGu, W\n\nRazquin, C\n\nPastor, P\n\nMateo, I\n\nOwen, MJ\n\nFaber, KM\n\nJonsson, PV\n\nCombarros, O\n\nO'Donovan, MC\n\nCantwell, LB\n\nSoininen, H\n\nBlacker, D\n\nMead, S\n\nMosley, TH\n\nBennett, DA\n\nHarris, TB\n\nFratiglioni, L\n\nHolmes, C\n\nde Bruijn, RF\n\nPassmore, P\n\nMontine, TJ\n\nBettens, K\n\nRotter, JI\n\nBrice, A\n\nMorgan, K\n\nForoud, TM\n\nKukull, WA\n\nHannequin, D\n\nPowell, JF\n\nNalls, MA\n\nRitchie, K\n\nLunetta, KL\n\nKauwe, JS\n\nBoerwinkle, E\n\nRiemenschneider, M\n\nBoada, M\n\nHiltunen, M\n\nMartin, ER\n\nSchmidt, R\n\nRujescu, D\n\nDartigues, JF\n\nMayeux, R\n\nTzourio, C\n\nHofman, A\n\nNöthen, MM\n\nGraff, C\n\nPsaty, BM\n\nHaines, JL\n\nLathrop, M\n\nPericak-Vance, MA\n\nLauner, LJ\n\nVan Broeckhoven, C\n\nFarrer, LA\n\nvan Duijn, CM\n\nRamirez, A\n\nSeshadri, S\n\nSchellenberg, GD\n\nAmouyel, P\n\nWilliams, J\n\nCardiovascular Health Study (CHS)\n\nBeiträge in Fachzeitschriften\nISI:000338701300002\n24922517.0\n10.1371/journal.pone.0094661\nPMC4055488\nAlzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25, 80 Alzheimer's cases and 48, 66 controls.\n In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.\n The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n174083\nAdjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial\n\nGnant, M\n\nPfeiler, G\n\nSteger, GG\n\nEgle, D\n\nGreil, R\n\nFitzal, F\n\nWette, V\n\nBalic, M\n\nHaslbauer, F\n\nMelbinger-Zeinitzer, E\n\nBjelic-Radisic, V\n\nJakesz, R\n\nMarth, C\n\nSevelda, P\n\nMlineritsch, B\n\nExner, R\n\nFesl, C\n\nFrantal, S\n\nSinger, CF\n\nBeiträge in Fachzeitschriften\nISI:000459953700041\n30795951.0\n10.1016/S1470-2045(18)30862-3\nNone\nIn postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported.\n Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up.\n Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69-0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6-90·8) at 5 years and 80·6% (78·1-83·1) at 8 years of follow-up, compared with 87·3% (85·7-89·0) at 5 years and 77·5% (74·8-80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group.\n Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy.\n Amgen.\n Copyright © 2019 Elsevier Ltd. All rights reserved.\n\nBalic, Marija\n\nBjelic-Radisic, Vesna\n\n\n"
},
{
"text": "\n165946\nOncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients.\n\nde Haan, J\n\nVerheecke, M\n\nVan Calsteren, K\n\nVan Calster, B\n\nShmakov, RG\n\nMhallem Gziri, M\n\nHalaska, MJ\n\nFruscio, R\n\nLok, CAR\n\nBoere, IA\n\nZola, P\n\nOttevanger, PB\n\nde Groot, CJM\n\nPeccatori, FA\n\nDahl Steffensen, K\n\nCardonick, EH\n\nPolushkina, E\n\nRob, L\n\nCeppi, L\n\nSukhikh, GT\n\nHan, SN\n\nAmant, F\n\nInternational Network on Cancer and Infertility Pregnancy (INCIP)\n\nBeiträge in Fachzeitschriften\nISI:000426466100049\n29395867.0\n10.1016/S1470-2045(18)30059-7\nNone\nAwareness is growing that cancer can be treated during pregnancy, but the effect of this change on maternal and neonatal outcomes is unknown. The International Network on Cancer, Infertility and Pregnancy (INCIP) registers the incidence and maternal, obstetric, oncological, and neonatal outcomes of cancer occurring during pregnancy. We aimed to describe the oncological management and obstetric and neonatal outcomes of patients registered in INCIP and treated in the past 20 years, and assess associations between cancer type or treatment modality and obstetric and neonatal outcomes.\n This descriptive cohort study included pregnant patients with cancer registered from all 37 centres (from 16 countries) participating in the INCIP registry. Oncological, obstetric, and neonatal outcome data of consecutive patients diagnosed with primary invasive cancer during pregnancy between Jan 1, 1996, and Nov 1, 2016, were retrospectively and prospectively collected. We analysed changes over time in categorical patient characteristics, outcomes, and treatment methods with log-binomial regression. We used multiple logistic regression to analyse preterm, prelabour rupture of membranes (PPROM) or preterm contractions, small for gestational age, and admission to the neonatal intensive care unit (NICU). The INCIP registry study is registered with ClinicalTrials.gov, number NCT00330447, and is ongoing.\n 1170 patients were included in the analysis and 779 (67%) received treatment during pregnancy. Breast cancer was the most common malignant disease (462 [39%]). Every 5 years, the likelihood of receiving treatment during pregnancy increased (relative risk [RR] 1·10, 95% CI 1·05-1·15), mainly related to an increase of chemotherapeutic treatment (1·31, 1·20-1·43). Overall, 955 (88%) of 1089 singleton pregnancies ended in a livebirth, of which 430 (48%) of 887 pregnancies ended preterm. Each 5 years, we observed more livebirths (RR 1·04, 95% CI 1·01-1·06) and fewer iatrogenic preterm deliveries (0·91, 0·84-0·98). Our data suggest a relationship between platinum-based chemotherapy and small for gestational age (odds ratio [OR] 3·12, 95% CI 1·45-6·70), and between taxane chemotherapy and NICU admission (OR 2·37, 95% CI 1·31-4·28). NICU admission seemed to depend on cancer type, with gastrointestinal cancers having highest risk (OR 7·13, 95% CI 2·86-17·7) and thyroid cancers having lowest risk (0·14, 0·02-0·90) when compared with breast cancer. Unexpectedly, the data suggested that abdominal or cervical surgery was associated with a reduced likelihood of NICU admission (OR 0·30, 95% CI 0·17-0·55). Other associations between treatment or cancer type and outcomes were less clear.\n Over the years, the proportion of patients with cancer during pregnancy who received antenatal treatment increased, especially treatment with chemotherapy. Our data indicate that babies exposed to antenatal chemotherapy might be more likely to develop complications, specifically small for gestational age and NICU admission, than babies not exposed. We therefore recommend involving hospitals with obstetric high-care units in the management of these patients.\n Research Foundation-Flanders, European Research Council, Charles University, Ministry of Health of the Czech Republic.\n Copyright © 2018 Elsevier Ltd. All rights reserved.\n\nBjelic-Radisic, Vesna\n\nKlaritsch, Philipp\n\n\n"
},
{
"text": "\n143058\nStationery injuries in the upper aerodigestive system: results from the Susy Safe Project.\n\nFoltran, F\n\nBerchialla, P\n\nGregori, D\n\nPitkäranta, A\n\nSlapak, I\n\nJakubíková, J\n\nBellussi, L\n\nPassali, D\n\nSusy Safe Working Group\n\nBeiträge in Fachzeitschriften\nISI:000303901500014\n22341476.0\n10.1016/j.ijporl.2012.02.016\nNone\nForeign body (FB) injuries are a relatively frequent event in young children. Clinical picture can be evidently affected from different variables. Among those size, shape, type and FB location cover an important issue. Increased attempts have been made in order to encourage normative interventions for products devoted to children's care and entertainment, reaching acceptable safety level; on the contrary, fewer efforts have been devoted to investigate the risk associated to objects that--even if not expressly created for children--are easy accessed by children, like stationery. The aim of the present study is to characterize the risk of complications and prolonged hospitalization due to stationery items according to age and gender of patients, FB characteristics and FB location, circumstances of the accident, as emerging from the Susy Safe Registry.\n From 2005 to 2010 case were collected from 70 centers in 32 different countries. Details on the injuries, identified by means of the International Classification of Diseases, Ninth Revision (ICD-9) codes listed on hospital discharge records, were gathered through a standardized case report form, that provides a full set of information on injuries, with specific details on age and gender of the child, location, shape, volume, consistency and ellipticity of the foreign body, behavioral aspects linked to the injury, like the supervision of the parents or the activity concomitant to the accident, any complication occurred, length of hospitalization.\n In the years 2005-2010 a total of 17, 05 FB injuries in children aged 0-14 years were registered in Susy Safe Database. Among them 425 (2.5%) were due to a stationery item. The majority of FBs were retrieved in the nose (179, meaning 42.1%) and in the ears (176, 41.4%) only 5 cases were observed in children younger than 1 year, while most of the cases, 80.6%, were recorded in children older than 3 years. 193 patients (45.4%) were female, while 232 (54.6%) were male. Adult supervision was indicated in 212 cases. In 143 of these accidents the adult was present (33.6% of the whole group). The most frequent stationery retrieved was rubber, counting for 209 cases (49.2%). According to the FBs types, mostly all cases reported a 3D volume and a rigid or semirigid consistency (49.3%). Looking to the outcomes, 31 (7%) children needed hospitalization and complications were seen in 38 children (8.9%). No significant associations were seen between the outcomes and the FBs' characteristics, excluded those between the consistency of the FB (rigid) and the necessity of hospitalization and the shape (2D) and the presence of complication.\n Injuries are events that in many cases can be prevented with appropriate strategies. Passive environmental strategies, including product modification by manufacturers, are the most effective. However, regulation regarding small parts of potentially dangerous objects covers products addressed to children use but objects not projected for children, such as stationary items, are excluded. Our study testifies that stationary is involved in a non-negligible percentage of FB injuries, mainly due to insertion in the ears. Frequently, injuries happen under adult supervision. These results confirm the fact that when passive preventive strategies are not practical, active strategies that promote behavior change are necessary and information about this issue should be included in all visits to family pediatricians.\n Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.\n\nZaupa, Paola\n\n\n"
},
{
"text": "\n101828\nGenome-wide analysis of genetic loci associated with Alzheimer disease.\n\nSeshadri, S\n\nFitzpatrick, AL\n\nIkram, MA\n\nDeStefano, AL\n\nGudnason, V\n\nBoada, M\n\nBis, JC\n\nSmith, AV\n\nCarassquillo, MM\n\nLambert, JC\n\nHarold, D\n\nSchrijvers, EM\n\nRamirez-Lorca, R\n\nDebette, S\n\nLongstreth, WT\n\nJanssens, AC\n\nPankratz, VS\n\nDartigues, JF\n\nHollingworth, P\n\nAspelund, T\n\nHernandez, I\n\nBeiser, A\n\nKuller, LH\n\nKoudstaal, PJ\n\nDickson, DW\n\nTzourio, C\n\nAbraham, R\n\nAntunez, C\n\nDu, Y\n\nRotter, JI\n\nAulchenko, YS\n\nHarris, TB\n\nPetersen, RC\n\nBerr, C\n\nOwen, MJ\n\nLopez-Arrieta, J\n\nVaradarajan, BN\n\nBecker, JT\n\nRivadeneira, F\n\nNalls, MA\n\nGraff-Radford, NR\n\nCampion, D\n\nAuerbach, S\n\nRice, K\n\nHofman, A\n\nJonsson, PV\n\nSchmidt, H\n\nLathrop, M\n\nMosley, TH\n\nAu, R\n\nPsaty, BM\n\nUitterlinden, AG\n\nFarrer, LA\n\nLumley, T\n\nRuiz, A\n\nWilliams, J\n\nAmouyel, P\n\nYounkin, SG\n\nWolf, PA\n\nLauner, LJ\n\nLopez, OL\n\nvan Duijn, CM\n\nBreteler, MM\n\nCHARGE Consortium\n\nGERAD1 Consortium\n\nEADI1 Consortium\n\nBeiträge in Fachzeitschriften\nISI:000277513900024\n20460622.0\n10.1001/jama.2010.574\nPMC2989531\nCONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35, 00 persons (8371 AD cases). DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14, 42 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. MAIN OUTCOME MEASURE: Presence of Alzheimer disease. RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR], .13; 95% confidence interval [CI], .06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.\n\nSchmidt, Helena\n\n\n"
},
{
"text": "\n166885\nTrophoblast retrieval and isolation from the cervix: origins of cervical trophoblasts and their potential value for risk assessment of ongoing pregnancies.\n\nMoser, G\n\nDrewlo, S\n\nHuppertz, B\n\nArmant, DR\n\nBeiträge in Fachzeitschriften\nISI:000438337700006\n29608700.0\n10.1093/humupd/dmy008\nPMC6016716\nEarly during human development, the trophoblast lineage differentiates to commence placentation. Where the placenta contacts the uterine decidua, extravillous trophoblast (EVT) cells differentiate and invade maternal tissues. EVT cells, identified by expression of HLA-G, invade into uterine blood vessels (endovascular EVT), as well as glands (endoglandular EVT), and open such luminal structures towards the intervillous space of the placenta. Endoglandular invasion diverts the contents of uterine glands to the intervillous space, while glands near the margin of the placenta that also contain endoglandular EVT cells open into the reproductive tract. Cells of the trophoblast lineage have thus been recovered from the uterine cavity and endocervical canal. An emerging non-invasive technology [trophoblast retrieval and isolation from the cervix (TRIC)] isolates and examines EVT cells residing in the cervix to explore their origin, biology and relationship to pregnancy and fetal status.\n This review explores the origins and possible uses of trophoblast cells obtained during ongoing pregnancies (weeks 5-20) by TRIC. We hypothesize that endoglandular EVT cells at the margins of the expanding placenta enter the uterine cavity and are carried together with uterine secretion products to the cervix where they can be retrieved from a Papanicolaou (Pap) smear. The advantages of TRIC for investigation of human placentation and prenatal testing will be considered. Evidence from the literature, and from archived in utero placental histological sections, is presented to support these hypotheses.\n We used 52 out of 80 publications that appeared between 1966 and 2017 and were found by searching the PubMed and Google Scholar databases. The studies described trophoblast invasion of uterine vessels and glands, as well as trophoblast cells residing in the reproductive tract. This was supplemented with literature on human placental health and disease.\n The literature describes a variety of invasive routes taken by EVT cells at the fetal-maternal interface that could displace them into the reproductive tract. Since the 1970s, investigators have attempted to recover trophoblast cells from the uterus or cervix for prenatal diagnostics. Trophoblast cells from Pap smears obtained at 5-20 weeks of gestation have been purified (>95% β-hCG positive) by immunomagnetic isolation with nanoparticles linked to anti-HLA-G (TRIC). The isolated cells contain the fetal genome, and have an EVT-like expression profile. Similar EVT-like cells appear in the lumen of uterine glands and can be observed entering the uterine cavity along the margins of the placenta, suggesting that they are the primary source of cervical trophoblast cells. Cells isolated by TRIC can be used to accurately genotype the embryo/fetus by targeted next-generation sequencing. Biomarker protein expression quantified in cervical trophoblast cells after TRIC correlates with subsequent pregnancy loss, pre-eclampsia and fetal growth restriction. A key remaining question is the degree to which EVT cells in the cervix might differ from those in the basal plate and placental bed.\n TRIC could one day provide a method of risk assessment for maternal and fetal disease, and reveal molecular pathways disrupted during the first trimester in EVT cells associated with placental maldevelopment. As perinatal interventions emerge for pregnancy disorders and inherited congenital disorders, TRIC could provide a key diagnostic tool for personalized precision medicine in obstetrics.\n\nHuppertz, Berthold\n\nMoser, Gerit\n\n\n"
},
{
"text": "\n186542\nEarly Detection of Developmental Disorders: The role of Canonical Babbling\n\nLang, S\n\nZhang, DJ\n\nPoustka, L\n\nBartl-Pokorny, KD\n\nPokorny, FB\n\nBolte, S\n\nSachse, S\n\nMani, N\n\nFox-Boyer, AV\n\nHartung, M\n\nEinspieler, C\n\nMarschik, PB\n\nBeiträge in Fachzeitschriften\nISI:000607188500004\nNone\n10.1026/0942-5403/a000324\nNone\nTheoretical Background: This article addresses early verbal capacities in children with late detected developmental disorders (LDDDs), i.?e., medical conditions that are commonly not diagnosed until toddlerhood. In particular, we focus on autism spectrum disorder (ASD), Rett syndrome (RTT), and fragile X syndrome (FXS), all associated with speech-language and socio-communicative impairments. Partly due to their generally late diagnostic age, little is known about the verbal phenomena during the first years, i.?e., the prediagnostic period, of these disorders. Canonical babbling (CB), for example, is an important preverbal milestone in early speech-language development typically achieved between 6 and 10 months of age. It is suggested that infants who fail to achieve CB within this time window will later present speech-language deficits. Objective: In this article, we review and discuss early verbal atypicalities associated with ASD, RTT, and FXS, with a special focus on CB. We aim to examine whether deviations related to CB may provide valuable cues to facilitate earlier identification of LDDDs. Method: We report on retrospective as well as prospective approaches to study early verbal development in LDDDs. Challenges and methodological issues investigating early verbal capacities in LDDDs are discussed. Results: Studies of CB in infants with ASD, and especially with RTT and FXS, are rare. Heterogeneous findings were revealed. While some studies reported a delayed onset and reduced rate of CB in infants with ASD, RTT, or FXS, others found that a proportion of infants with these disorders do achieve the CB milestone on time and they vocalize comparable ratios of CB to their typically developing peers. However, the existing studies are hard to compare due to differences in study design, measurements, and/or the definition of CB. Recently, researchers began to investigate potential differences in CB of children with LDDDs and typically developing peers at signal level, i.e., the acoustic parameters of CB, exploiting machine-learning technologies. Studies suggest that even if the CB milestone can be regarded as achieved in terms of onset time and ratio, differences may appear with respect to linguistic and acoustic qualities of vocalizations in infants with LDDDs. Discussion and Conclusion: While failing to achieve CB by 10 months of age may prove to be a sensitive sign associated with later speech-language deficits, it is not a specific marker pointing to an LDDD. Nonetheless, deviations in CB flag atypical speech-language development within the first year of life and justify intensive monitoring that may expedite the process of specific diagnosis and set out targeted interventions. This rationalizes the significance of investigating early vocalizations, including CB, aiming at an earlier identification of LDDDs. Further studies that incorporate, e.g., detailed linguistic and signal-level analyses to obtain a reliable picture of the role of preverbal development in general, and CB as age-specific pattern, in the early pathways of such disorders are urgently needed. Given that not all individuals with LDDDs, e.g., ASD, necessarily manifest speech-language deficits, studies of early verbal capacities of individuals with LDDDs ought to take the different outcomes, e.g., later language capacities, into account when interpreting the role of verbal development in the prediagnostic period in early detection of LDDDs.\n\nBartl-Pokorny, Katrin Daniela\n\nEinspieler, Christa\n\nMarschik, Dajie\n\nMarschik, Peter\n\nPokorny, Florian\n\n\n"
},
{
"text": "\n128816\nGWAS of 126,559 individuals identifies genetic variants associated with educational attainment.\n\nRietveld, CA\n\nMedland, SE\n\nDerringer, J\n\nYang, J\n\nEsko, T\n\nMartin, NW\n\nWestra, HJ\n\nShakhbazov, K\n\nAbdellaoui, A\n\nAgrawal, A\n\nAlbrecht, E\n\nAlizadeh, BZ\n\nAmin, N\n\nBarnard, J\n\nBaumeister, SE\n\nBenke, KS\n\nBielak, LF\n\nBoatman, JA\n\nBoyle, PA\n\nDavies, G\n\nde Leeuw, C\n\nEklund, N\n\nEvans, DS\n\nFerhmann, R\n\nFischer, K\n\nGieger, C\n\nGjessing, HK\n\nHägg, S\n\nHarris, JR\n\nHayward, C\n\nHolzapfel, C\n\nIbrahim-Verbaas, CA\n\nIngelsson, E\n\nJacobsson, B\n\nJoshi, PK\n\nJugessur, A\n\nKaakinen, M\n\nKanoni, S\n\nKarjalainen, J\n\nKolcic, I\n\nKristiansson, K\n\nKutalik, Z\n\nLahti, J\n\nLee, SH\n\nLin, P\n\nLind, PA\n\nLiu, Y\n\nLohman, K\n\nLoitfelder, M\n\nMcMahon, G\n\nVidal, PM\n\nMeirelles, O\n\nMilani, L\n\nMyhre, R\n\nNuotio, ML\n\nOldmeadow, CJ\n\nPetrovic, KE\n\nPeyrot, WJ\n\nPolasek, O\n\nQuaye, L\n\nReinmaa, E\n\nRice, JP\n\nRizzi, TS\n\nSchmidt, H\n\nSchmidt, R\n\nSmith, AV\n\nSmith, JA\n\nTanaka, T\n\nTerracciano, A\n\nvan der Loos, MJ\n\nVitart, V\n\nVölzke, H\n\nWellmann, J\n\nYu, L\n\nZhao, W\n\nAllik, J\n\nAttia, JR\n\nBandinelli, S\n\nBastardot, F\n\nBeauchamp, J\n\nBennett, DA\n\nBerger, K\n\nBierut, LJ\n\nBoomsma, DI\n\nBültmann, U\n\nCampbell, H\n\nChabris, CF\n\nCherkas, L\n\nChung, MK\n\nCucca, F\n\nde Andrade, M\n\nDe Jager, PL\n\nDe Neve, JE\n\nDeary, IJ\n\nDedoussis, GV\n\nDeloukas, P\n\nDimitriou, M\n\nEiríksdóttir, G\n\nElderson, MF\n\nEriksson, JG\n\nEvans, DM\n\nFaul, JD\n\nFerrucci, L\n\nGarcia, ME\n\nGrönberg, H\n\nGuðnason, V\n\nHall, P\n\nHarris, JM\n\nHarris, TB\n\nHastie, ND\n\nHeath, AC\n\nHernandez, DG\n\nHoffmann, W\n\nHofman, A\n\nHolle, R\n\nHolliday, EG\n\nHottenga, JJ\n\nIacono, WG\n\nIllig, T\n\nJärvelin, MR\n\nKähönen, M\n\nKaprio, J\n\nKirkpatrick, RM\n\nKowgier, M\n\nLatvala, A\n\nLauner, LJ\n\nLawlor, DA\n\nLehtimäki, T\n\nLi, J\n\nLichtenstein, P\n\nLichtner, P\n\nLiewald, DC\n\nMadden, PA\n\nMagnusson, PK\n\nMäkinen, TE\n\nMasala, M\n\nMcGue, M\n\nMetspalu, A\n\nMielck, A\n\nMiller, MB\n\nMontgomery, GW\n\nMukherjee, S\n\nNyholt, DR\n\nOostra, BA\n\nPalmer, LJ\n\nPalotie, A\n\nPenninx, BW\n\nPerola, M\n\nPeyser, PA\n\nPreisig, M\n\nRäikkönen, K\n\nRaitakari, OT\n\nRealo, A\n\nRing, SM\n\nRipatti, S\n\nRivadeneira, F\n\nRudan, I\n\nRustichini, A\n\nSalomaa, V\n\nSarin, AP\n\nSchlessinger, D\n\nScott, RJ\n\nSnieder, H\n\nSt Pourcain, B\n\nStarr, JM\n\nSul, JH\n\nSurakka, I\n\nSvento, R\n\nTeumer, A\n\nLifeLines Cohort Study\n\nTiemeier, H\n\nvan Rooij, FJ\n\nVan Wagoner, DR\n\nVartiainen, E\n\nViikari, J\n\nVollenweider, P\n\nVonk, JM\n\nWaeber, G\n\nWeir, DR\n\nWichmann, HE\n\nWiden, E\n\nWillemsen, G\n\nWilson, JF\n\nWright, AF\n\nConley, D\n\nDavey-Smith, G\n\nFranke, L\n\nGroenen, PJ\n\nHofman, A\n\nJohannesson, M\n\nKardia, SL\n\nKrueger, RF\n\nLaibson, D\n\nMartin, NG\n\nMeyer, MN\n\nPosthuma, D\n\nThurik, AR\n\nTimpson, NJ\n\nUitterlinden, AG\n\nvan Duijn, CM\n\nVisscher, PM\n\nBenjamin, DJ\n\nCesarini, D\n\nKoellinger, PD\n\nBeiträge in Fachzeitschriften\nISI:000320647000046\n23722424.0\n10.1126/science.1235488\nPMC3751588\nA genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101, 69 individuals and a replication sample of 25, 90. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.\n\nKoini, Marisa\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n16414\nLow BMD is less predictive than reported falls for future limb fractures in women across Europe: results from the European Prospective Osteoporosis Study.\n\nKaptoge, S\n\nBenevolenskaya, LI\n\nBhalla, AK\n\nCannata, JB\n\nBoonen, S\n\nFalch, JA\n\nFelsenberg, D\n\nFinn, JD\n\nNuti, R\n\nHoszowski, K\n\nLorenc, R\n\nMiazgowski, T\n\nJajic, I\n\nLyritis, G\n\nMasaryk, P\n\nNaves-Diaz, M\n\nPoor, G\n\nReid, DM\n\nScheidt-Nave, C\n\nStepan, JJ\n\nTodd, CJ\n\nWeber, K\n\nWoolf, AD\n\nRoy, DK\n\nLunt, M\n\nPye, SR\n\nO'neill, TW\n\nSilman, AJ\n\nReeve, J\n\nBeiträge in Fachzeitschriften\nISI:000228196900003\n15777673.0\n10.1016/j.bone.2004.11.012\nNone\nWe have previously shown that center- and sex-specific fall rates explained one-third of between-center variation in upper limb fractures across Europe. In this current analysis, our aim was to determine how much of the between-center variation in fractures could be attributed to repeated falling, bone mineral density (BMD), and other risk factors in individuals, and to compare the relative contributions of center-specific BMD vs. center-specific fall rates. A clinical history of fracture was assessed prospectively in 2451 men and 2919 women aged 50-80 from 20 centers participating in the European Prospective Osteoporosis Study (EPOS) using standardized questionnaires (mean follow-up = 3 years). Bone mineral density (BMD, femoral neck, trochanter, and/or spine) was measured in 2103 men and 2565 women at these centers. Cox regression was used to model the risk of incident fracture as a function of the person-specific covariates: age, BMD, personal fracture history (PFH), family hip fracture history (FAMHIP), time spent walking/cycling, number of 'all falls' and falls not causing fracture ('fracture-free') during follow-up, alcohol consumption, and body mass index. Center effects were modeled by inclusion of multiplicative gamma-distributed random effects, termed center-shared frailty (CSF), with mean 1 and finite variance theta (theta) acting on the hazard rate. The relative contributions of center-specific fall risk and center-specific BMD on the incidence of limb fractures were evaluated as components of CSF. In women, the risk of any incident nonspine fracture (n = 190) increased with age, PFH, FAMHIP, > or =1 h/day walking/cycling, and number of 'all falls' during follow-up (all P < 0.074). 'Fracture-free' falls (P = 0.726) and femoral neck BMD did not have a significant effect at the individual level, but there was a significant center-shared frailty effect (theta = 0.271, P = 0.001) that was reduced by 4% after adjusting for mean center BMD and reduced by 19% when adjusted for mean center fall rate. Femoral trochanter BMD was a significant determinant of lower limb fractures (n = 53, P = 0.014) and the center-shared frailty effect was significant for upper limb fractures (theta = 0.271, P = 0.011). This upper limb fracture center effect was unchanged after adjusting for mean center BMD but was reduced by 36% after adjusting for center mean fall rates. In men, risk of any nonspine fracture (n = 75) increased with PFH, fall during follow-up (P < 0.026), and with a decrease in trochanteric BMD [RR 1.38 (1.08, 1.79) per 1 SD decrease]. There was no center effect evident (theta = 0.081, P = 0.096). We conclude that BMD alone cannot be validly used to discriminate between the risk of upper limb fractures across populations without taking account of population-specific variations in fall risk and other factors. These variations might reflect shared environmental or possibly genetic factors that contribute quite substantially to the risk of upper limb fractures in women.\n\nWeber, Kurt\n\n\n"
},
{
"text": "\n2919\nPostoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91.\n\nKortmann, RD\n\nKühl, J\n\nTimmermann, B\n\nMittler, U\n\nUrban, C\n\nBudach, V\n\nRichter, E\n\nWillich, N\n\nFlentje, M\n\nBerthold, F\n\nSlavc, I\n\nWolff, J\n\nMeisner, C\n\nWiestler, O\n\nSörensen, N\n\nWarmuth-Metz, M\n\nBamberg, M\n\nBeiträge in Fachzeitschriften\nISI:000084950700004\n10661332.0\n10.1016/S0360-3016(99)00369-7\nNone\nPURPOSE: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT '91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. METHODS AND MATERIALS: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine ("Philadelphia protocol"). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). RESULTS: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4-62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70+/-0.08; for patients with residual disease: 0.72+/-0.06; without residual disease: 0.68+/-0.09; M0: 0.72+/-0.04; M1: 0.65+/-0.12; and M2/3: 0.30+/-0.15. For all randomized patients without M2/3 disease: 0.65+/-0.05 (arm I) and 0.78+/-0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60+/-0.13 and 0.64+/-0.14, respectively, but patients between 6 and 18 years: 0.62+/-0.09 and 0.84+/-0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). CONCLUSIONS: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.\n\nUrban, Ernst-Christian\n\n\n"
},
{
"text": "\n139751\nSeventy-five genetic loci influencing the human red blood cell.\n\nvan der Harst, P\n\nZhang, W\n\nMateo Leach, I\n\nRendon, A\n\nVerweij, N\n\nSehmi, J\n\nPaul, DS\n\nElling, U\n\nAllayee, H\n\nLi, X\n\nRadhakrishnan, A\n\nTan, ST\n\nVoss, K\n\nWeichenberger, CX\n\nAlbers, CA\n\nAl-Hussani, A\n\nAsselbergs, FW\n\nCiullo, M\n\nDanjou, F\n\nDina, C\n\nEsko, T\n\nEvans, DM\n\nFranke, L\n\nGögele, M\n\nHartiala, J\n\nHersch, M\n\nHolm, H\n\nHottenga, JJ\n\nKanoni, S\n\nKleber, ME\n\nLagou, V\n\nLangenberg, C\n\nLopez, LM\n\nLyytikäinen, LP\n\nMelander, O\n\nMurgia, F\n\nNolte, IM\n\nO'Reilly, PF\n\nPadmanabhan, S\n\nParsa, A\n\nPirastu, N\n\nPorcu, E\n\nPortas, L\n\nProkopenko, I\n\nRied, JS\n\nShin, SY\n\nTang, CS\n\nTeumer, A\n\nTraglia, M\n\nUlivi, S\n\nWestra, HJ\n\nYang, J\n\nZhao, JH\n\nAnni, F\n\nAbdellaoui, A\n\nAttwood, A\n\nBalkau, B\n\nBandinelli, S\n\nBastardot, F\n\nBenyamin, B\n\nBoehm, BO\n\nCookson, WO\n\nDas, D\n\nde Bakker, PI\n\nde Boer, RA\n\nde Geus, EJ\n\nde Moor, MH\n\nDimitriou, M\n\nDomingues, FS\n\nDöring, A\n\nEngström, G\n\nEyjolfsson, GI\n\nFerrucci, L\n\nFischer, K\n\nGalanello, R\n\nGarner, SF\n\nGenser, B\n\nGibson, QD\n\nGirotto, G\n\nGudbjartsson, DF\n\nHarris, SE\n\nHartikainen, AL\n\nHastie, CE\n\nHedblad, B\n\nIllig, T\n\nJolley, J\n\nKähönen, M\n\nKema, IP\n\nKemp, JP\n\nLiang, L\n\nLloyd-Jones, H\n\nLoos, RJ\n\nMeacham, S\n\nMedland, SE\n\nMeisinger, C\n\nMemari, Y\n\nMihailov, E\n\nMiller, K\n\nMoffatt, MF\n\nNauck, M\n\nNovatchkova, M\n\nNutile, T\n\nOlafsson, I\n\nOnundarson, PT\n\nParracciani, D\n\nPenninx, BW\n\nPerseu, L\n\nPiga, A\n\nPistis, G\n\nPouta, A\n\nPuc, U\n\nRaitakari, O\n\nRing, SM\n\nRobino, A\n\nRuggiero, D\n\nRuokonen, A\n\nSaint-Pierre, A\n\nSala, C\n\nSalumets, A\n\nSambrook, J\n\nSchepers, H\n\nSchmidt, CO\n\nSilljé, HH\n\nSladek, R\n\nSmit, JH\n\nStarr, JM\n\nStephens, J\n\nSulem, P\n\nTanaka, T\n\nThorsteinsdottir, U\n\nTragante, V\n\nvan Gilst, WH\n\nvan Pelt, LJ\n\nvan Veldhuisen, DJ\n\nVölker, U\n\nWhitfield, JB\n\nWillemsen, G\n\nWinkelmann, BR\n\nWirnsberger, G\n\nAlgra, A\n\nCucca, F\n\nd'Adamo, AP\n\nDanesh, J\n\nDeary, IJ\n\nDominiczak, AF\n\nElliott, P\n\nFortina, P\n\nFroguel, P\n\nGasparini, P\n\nGreinacher, A\n\nHazen, SL\n\nJarvelin, MR\n\nKhaw, KT\n\nLehtimäki, T\n\nMaerz, W\n\nMartin, NG\n\nMetspalu, A\n\nMitchell, BD\n\nMontgomery, GW\n\nMoore, C\n\nNavis, G\n\nPirastu, M\n\nPramstaller, PP\n\nRamirez-Solis, R\n\nSchadt, E\n\nScott, J\n\nShuldiner, AR\n\nSmith, GD\n\nSmith, JG\n\nSnieder, H\n\nSorice, R\n\nSpector, TD\n\nStefansson, K\n\nStumvoll, M\n\nTang, WH\n\nToniolo, D\n\nTönjes, A\n\nVisscher, PM\n\nVollenweider, P\n\nWareham, NJ\n\nWolffenbuttel, BH\n\nBoomsma, DI\n\nBeckmann, JS\n\nDedoussis, GV\n\nDeloukas, P\n\nFerreira, MA\n\nSanna, S\n\nUda, M\n\nHicks, AA\n\nPenninger, JM\n\nGieger, C\n\nKooner, JS\n\nOuwehand, WH\n\nSoranzo, N\n\nChambers, JC\n\nBeiträge in Fachzeitschriften\nISI:000312488200044\n23222517.0\n10.1038/nature11677\nPMC3623669\nAnaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135, 67 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n28\n30 degree trunk elevation of the patient and quality of lumbar epidural anesthesia. Effects of elevation in operations on the lower extremities].\n\nPonhold, H\n\nKulier, AH\n\nRehak, PH\n\nBeiträge in Fachzeitschriften\nISI:A1993MJ85500005\n8279691.0\nNone\nNone\nThe spread and intensity of lumbar epidural anaesthesia are unpredictable. Moreover, segments L5 and S1 are frequently missed. In this study the effect of 30 degrees trunk elevation on the spread and intensity of lumbar epidural sensory and motor blockade and on the cardiovascular system were studied. METHODS. After oral premedication with 7.5 mg midazolam, 30 patients 20 to 40 years of age, ASA 1-2, were randomly allocated to one of two groups according to their body position during injection of 20 ml 2% lidocaine (3 + 8 + 9 ml) into a lumbar epidural catheter (L2/3 or L3/4) and during the following 30 min: supine horizontal position or supine 30 degrees trunk elevation with 30 degrees leg elevation (hammock position). The patients received 500 ml Ringer solution before the epidural injection, followed by more Ringer solution. Systolic and diastolic blood pressures and heart rate were monitored noninvasively every 5 min; 30 min after the epidural injection the spread of analgesia (dullness of pinprick) and anaesthesia (no sensation of pinprick) as well as motor block according to Bromage were tested. A spread of anaesthetic segments including T12 to L3 was considered adequate for hip surgery, L3 to L5 for knee surgery, and L3 to S2 for foot surgery. Student's t-test, ANOVA, chi-square (Wilcoxon), and Mann-Whitney tests were used for statistical analysis. P < 0.05 was considered statistically significant. RESULTS. The median cephalad level of analgesia was lower in patients with the hammock position than those with the horizontal position (L1 vs T10; P < 0.05). There was no significant difference in the cranial level of anaesthesia (L2 vs L1) (Table 2). No significant difference was seen in the number of patients having adequate anaesthesia for hip surgery. Anaesthesia in the segments L5 and S1 was seen in 2/15 patients in the horizontal position and 8/15 patients in the hammock position (P < 0.05). The hammock position resulted in a higher percentage of patients having adequate anaesthesia for knee surgery (60% vs 13%; P < 0.05) and foot surgery (53% vs 13%; P < 0.05) (Table 3). Motor block was more profound in patients in the hammock position (Table 4). Blood pressure and heart rate did not change significantly in patients in the horizontal position (Fig. 1); there was a decrease in both systolic (7 mmHg) and diastolic (5 mmHg) blood pressures in patients in the hammock position. Heart rate did not change significantly (Fig. 2). No patient needed vasopressor support; the body position could be maintained in all patients during the observation period. One or two epidural reinjections according to the spread of anaesthesia 30 min after the first injection and to the scheduled operation resulted in adequate anaesthesia in every patient. DISCUSSION. More patients in the hammock position developed adequate anaesthesia in the relevant segments for knee and foot operations than patients in the horizontal position. These included the frequently missed segments L5 and S1. Patients in the hammock position had a clinically insignificant drop in systolic and diastolic blood pressure. In contrast to the young and healthy patients in this study, more severe cardiovascular changes might result in geriatric and/or ill patients subjected to a hammock position. For this reason, use of the technique in geriatric and/or ill patients requires special attention.\n\n\n"
}
]
}