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1. Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Author: Tina Pesaran, Jeffrey N. Weitzel, Clarice R. Weinberg, Chi Gao, Susan L. Neuhausen, Eric C. Polley, Alpa V. Patel, Christopher A. Haiman, Christine B. Ambrosone, Celine M. Vachon, Hongyan Huang, Sara Lindstrom, Julie R. Palmer, Esther M. John, Jill S. Dolinsky, Leslie Bernstein, Rohan Gnanaolivu, Allison W. Kurian, Steven N. Hart, Holly LaDuca, Hoda Anton-Culver, Janet E. Olson, Chunling Hu, Amal Yussuf, Song Yao, Nicole L. Larson, Peter Kraft, Jie Na, Fergus J. Couch, Nicholas J. Boddicker, Elena Martinez, Amy Trentham-Dietz, Siddhartha Yadav, Paul W. Auer, Dale R Sandler, Elizabeth C. Chao, Susan M. Domchek, Rachid Karam, Katherine L. Nathanson, James V. Lacey, Jack A. Taylor, and David E. Goldgar
Subjects: Adult, Cancer Research, Adolescent, Breast Neoplasms, Germline, Young Adult, Biomarkers, Tumor, Humans, Medicine, Genetic Predisposition to Disease, Genetic Testing, skin and connective tissue diseases, Gene, Germ-Line Mutation, Aged, Aged, 80 and over, business.industry, Cancer predisposition, Carcinoma, Ductal, Breast, ORIGINAL REPORTS, Middle Aged, Prognosis, medicine.disease, body regions, Carcinoma, Lobular, Oncology, Case-Control Studies, Invasive lobular carcinoma, cardiovascular system, Cancer research, Female, Hereditary Cancer, business, Follow-Up Studies
Abstract: PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.
Published: 2021

2. Mendelian Randomization With Repeated Measures of a Time-varying Exposure

Author: Joy Shi, Immaculata De Vivo, Miguel A. Hernán, Peter Kraft, Sonja A. Swanson, and Bernard Rosner
Subjects: Estimation, Epidemiology, business.industry, Cholesterol, HDL, Instrumental variable, Repeated measures design, Cholesterol, LDL, Mendelian Randomization Analysis, Article, Causality, Framingham Heart Study, Research Design, Statistics, Mendelian randomization, Multiple time, Humans, Medicine, Alcohol intake, Observational study, business
Abstract: Mendelian randomization (MR) is often used to estimate effects of time-varying exposures on health outcomes using observational data. However, MR studies typically use a single measurement of exposure and apply conventional instrumental variable (IV) methods designed to handle time-fixed exposures. As such, MR effect estimates for time-varying exposures are often biased, and interpretations are unclear. We describe the instrumental conditions required for IV estimation with a time-varying exposure, and the additional conditions required to causally interpret MR estimates as a point effect, a period effect or a lifetime effect depending on whether researchers have measurements at a single or multiple time points. We propose methods to incorporate time-varying exposures in MR analyses based on g-estimation of structural mean models, and demonstrate its application by estimating the period effect of alcohol intake, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol on intermediate coronary heart disease (CHD) outcomes using data from the Framingham Heart Study. We use this data example to highlight the challenges of interpreting MR estimates as causal effects, and describe other extensions of structural mean models for more complex data scenarios.
Published: 2021

3. Risk of Late-Onset Breast Cancer in Genetically Predisposed Women

Author: Lauren R. Teras, Siddhartha Yadav, Amy Trentham-Dietz, Dale P. Sandler, James M. Hodge, Elena Ma Martínez, Fergus J. Couch, Jack A. Taylor, Katie M. O'Brien, Alpa V. Patel, Christopher A. Haiman, Chunling Hu, Mia M. Gaudet, David E. Goldgar, Paul W. Auer, James V. Lacey, Nicholas J. Boddicker, Sara Lindström, Celine M. Vachon, Susan L. Neuhausen, Irene M. Ong, Kimberly A. Bertrand, Leslie Bernstein, Loic Le Marchand, Eric C. Polley, Janet E. Olson, Hongyan Huang, Christine B. Ambrosone, Tina Pesaran, Susan M. Domchek, Amal Yussuf, Nicole L. Larson, Rohan Gnanaolivu, Brian D. Carter, Song Yao, Steven N. Hart, Holly LaDuca, Rachid Karam, Jie Na, Chi Gao, Katherine L. Nathanson, Peter Kraft, Elizabeth C. Chao, Huiyan Ma, Jeffrey N. Weitzel, Julie R. Palmer, Christopher E. Scott, Charles Kooperberg, Jill S. Dolinsky, David J. Hunter, and Elizabeth S. Burnside
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Population, MEDLINE, Breast Neoplasms, Late onset, Germline, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, RAPID COMMUNICATIONS, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Age of Onset, skin and connective tissue diseases, education, Germ-Line Mutation, Aged, Aged, 80 and over, BRCA2 Protein, education.field_of_study, BRCA1 Protein, business.industry, Prognosis, medicine.disease, Checkpoint Kinase 2, Germ Cells, 030104 developmental biology, Case-Control Studies, 030220 oncology & carcinogenesis, cardiovascular system, Female, Fanconi Anemia Complementation Group N Protein, business, Follow-Up Studies
Abstract: PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.
Published: 2021

4. Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score

Author: Amy Trentham-Dietz, Katie M. O'Brien, Alpa V. Patel, Rohan Gnanaolivu, Chi Gao, Katherine L. Nathanson, Lauren R. Teras, Clarice R. Weinberg, Nicholas J. Boddicker, David J. Hunter, Julie R. Palmer, Polly A. Newcomb, Jeffrey N. Weitzel, Eric J. Jacobs, Dale P. Sandler, Jenna Lilyquist, Leslie Bernstein, Rulla M. Tamimi, Christine B. Ambrosone, Fergus J. Couch, Celine M. Vachon, Esther M. John, Christopher A. Haiman, Jack A. Taylor, Hongyan Huang, Mia M. Gaudet, David E. Goldgar, Irene M. Ong, Susan M. Domchek, Chunling Hu, Sara Lindström, Jie Na, Elizabeth S. Burnside, Susan L. Neuhausen, Janet E. Olson, Eric C. Polley, Song Yao, Peter Kraft, Huiyan Ma, Steven N. Hart, A. Heather Eliassen, and Paul L. Auer
Subjects: Adult, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, MEDLINE, Breast Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Gene, Aged, business.industry, Genetic Variation, ORIGINAL REPORTS, Middle Aged, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Polygenic risk score, business
Abstract: PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.
Published: 2021

5. Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women

Author: Kathryn J. Ruddy, Qin Wang, Joe Dennis, Stacey J. Winham, Janet E. Olson, Thomas U. Ahearn, Rachel A. Murphy, Wing-Yee Lo, David J. Hunter, Manjeet K. Bolla, Douglas F. Easton, Derrick G. Lee, Marike Gabrielson, Gareth D. Evans, Nick Orr, Reiner Hoppe, Minouk J. Schoemaker, Paul L. Auer, Michael Lush, Andrew F. Olshan, Kristan J. Aronson, Ross L. Prentice, Argyrios Ziogas, Martha S. Linet, Melissa C. Southey, Robert J. MacInnis, Michael Jones, Nicole L. Larson, Elke M van Veen, Anthony Howell, Alison M. Dunning, Christopher A. Haiman, Peter Kraft, William G. Newman, Loic Le Marchand, Lauren R. Teras, Jenny Chang-Claude, Mikael Eriksson, Irene L. Andrulis, Graham G. Giles, Heiko Becher, Montserrat Garcia-Closas, Thomas Brüning, A. Heather Eliassen, Pascal Guénel, Cari M. Kitahara, Pooja Middha Kapoor, Hoda Anton-Culver, Niclas Håkansson, Emilie Cordina-Duverger, Xiaoliang Wang, Stephen J. Chanock, Christopher J. Scott, Anthony J. Swerdlow, Ute Krüger, Sara Lindström, Roger L. Milne, Alpa V. Patel, Kristen Brantley, Annelie Augustinsson, Rulla M. Tamimi, Lynne R. Wilkens, Celine M. Vachon, Alicja Wolk, Håkan Olsson, Fergus J. Couch, Ute Hamann, Philippe Wagner, Kamila Czene, Audrey Y. Jung, Rudolf Kaaks, Claire Mulot, Laure Dossus, Angela Brooks-Wilson, Kyriaki Michailidou, Per Hall, Jonine D. Figueroa, Thérèse Truong, Charles M. Perou, Melissa A. Troester, Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, and Dennis, Joe [0000-0003-4591-1214]
Subjects: Oncology, Male, medicine.medical_specialty, Hormone Replacement Therapy, 631/208/205/2138, Hormone Replacement Therapy/adverse effects, Breast Neoplasms, Genome, Text mining, Breast cancer, SDG 3 - Good Health and Well-being, 692/699/67/2324, Risk Factors, Internal medicine, medicine, Breast Neoplasms - chemically induced - epidemiology - genetics, Humans, Breast, Breast Neoplasms/chemically induced, Medicinsk genetik, Cancer och onkologi, Multidisciplinary, business.industry, Estrogen Replacement Therapy, Hormone Replacement Therapy - adverse effects, article, Estrogen Replacement Therapy/adverse effects, Estrogen Replacement Therapy - adverse effects, medicine.disease, Cancer and Oncology, 692/699/67/1347, Female, Menopausal hormone therapy, Menopause, business, Medical Genetics, 692/499
Abstract: Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values-8 as genome-wide significant, and p-values-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values5. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.
Published: 2022
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6. Number of Retrieval Attempts Rather Than Procedure Time Is Associated With Risk of Symptomatic Intracranial Hemorrhage

Author: Máté Elöd Maros, Caspar Brekenfeld, Gabriel Broocks, Hannes Leischner, Rosalie McDonough, Milani Deb-Chatterji, Anna Alegiani, Götz Thomalla, Jens Fiehler, Fabian Flottmann, Tobias Boeckh-Behrens, Silke Wunderlich, Arno Reich, Martin Wiesmann, Ulrike Ernemann, Till-Karsten Hauser, Christian H Nolte, Eberhard Siebert, Sarah Zweynert, Georg Bohner, Alexander Ludolph, Karl-Heinz Henn, Waltraud Pfeilschifter, Marlis Wagner, Joachim Röther, Bernd Eckert, Jörg Berrouschot, Albrecht Bormann, Christian Gerloff, Elke Hattingen, Gabor Petzold, Sven Thonke, Christopher Bangard, Christoffer Kraemer, Steffen Tiedt, Frank Wollenweber, Lars Kellert, Franziska Dorn, Moriz Herzberg, Marios Psychogios, Jan Liman, Martina Petersen, Florian Stögbauer, Peter Kraft, Mirko Pham, Michael Braun, Gerhard F. Hamann, Andreas Kastrup, Christian Roth, Klaus Gröschel, Timo Uphaus, and Volker Limmroth
Subjects: Male, Pediatrics, medicine.medical_specialty, Original Contributions, medicine.medical_treatment, infarction, Infarction, Cohort Studies, Clinical and Population Sciences, Interquartile range, Occlusion, ischemic stroke, Humans, Medicine, Stroke, Aged, Advanced and Specialized Nursing, neuroimaging, business.industry, Cerebral infarction, Endovascular Procedures, Thrombolysis, Odds ratio, Middle Aged, medicine.disease, thrombectomy, Cohort, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Intracranial Hemorrhages, intracranial hemorrhage
Abstract: Supplemental Digital Content is available in the text., Background and Purpose: Endovascular therapy is the standard of care in the treatment of acute ischemic stroke due to large-vessel occlusion. A direct association between the number of device passes and the occurrence of symptomatic intracranial hemorrhage (SICH) has been suggested. This study represents an in-depth investigation of the hypothesis that >3 retrieval attempts is associated with an increased rate of SICH in a large multicenter patient cohort. Methods: Two thousand six hundred eleven patients from the prospective German Stroke Registry were analyzed. Patients who received Endovascular therapy for acute large-vessel occlusion of the anterior circulation with known admission National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT Score, final Thrombolysis in Cerebral Infarction, and number of retrieval passes were included. The primary outcome was defined as SICH. The secondary outcome was any type of radiologically confirmed intracranial hemorrhage within the first 24 hours. Multivariate mixed-effects models were used to adjust for cluster effects of the participating centers, as well as for confounders. Results: Five hundred ninety-three patients fulfilled the inclusion criteria. The median number of retrieval passes was 2 [interquartile range, 1–3]. SICH occurred in 26 cases (4.4%), whereas intracranial hemorrhage was identified by neuroimaging in 85 (14.3%) cases. More than 3 retrieval passes was the strongest predictor for SICH (odds ratio, 3.61 [95% CI, 1.38–9.42], P=0.0089) following adjustment for age, admission National Institutes of Health Stroke Scale, admission Alberta Stroke Program Early CT Score, and Thrombolysis in Cerebral Infarction, as well as time from symptom onset to flow restoration. Baseline Alberta Stroke Program Early CT Score of 8 to 9 (odds ratio, 0.26 [95% CI, 0.07–0.89], P=0.032) or 10 (odds ratio, 0.21 [95% CI, 0.06–0.78], P=0.020) were significant protective factors against the occurrence of SICH. Conclusions: More than 3 retrieval attempts is associated with a significant increase in SICH risk, regardless of patient age, baseline National Institutes of Health Stroke Scale, or procedure time. This should be considered when deciding whether to continue a procedure, especially in patients with large baseline infarctions. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356392.
Published: 2021

7. Personalizing Breast Cancer Screening Based on Polygenic Risk and Family History

Author: A. Cecile J.W. Janssens, Jeanne S. Mandelblatt, Michael Wolfson, Douglas F. Easton, Nicolien T. van Ravesteyn, Harry J. de Koning, Peter Kraft, Amy Trentham-Dietz, Clyde B. Schechter, Jacques Simard, Jeroen J. van den Broek, Public Health, Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Adult, Risk, Cancer Research, medicine.medical_specialty, Digital mammography, Time Factors, Breast Neoplasms, Medical Overuse, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer screening, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, medicine, False positive paradox, Mammography, Humans, Mass Screening, False Positive Reactions, 030212 general & internal medicine, Family history, Overdiagnosis, Family Health, medicine.diagnostic_test, Obstetrics, business.industry, Articles, Middle Aged, Models, Theoretical, medicine.disease, Oncology, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, Polygenic risk score, Female, business, AcademicSubjects/MED00010
Abstract: Background We assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years. Methods Two established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age (30, 35, 40, 45, and 50 years) and interval (annual, hybrid, biennial, triennial). The benefits (breast cancer deaths averted, life-years gained) and harms (false-positive mammograms, overdiagnoses) were compared with those seen with 3 established screening guidelines. Results Women with a breast cancer family history who initiated biennial screening at age 40 years (vs 50 years) had a 36% (model range = 29%-40%) increase in life-years gained and 20% (model range = 16%-24%) more breast cancer deaths averted, but 21% (model range = 17%-23%) more overdiagnoses and 63% (model range = 62%-64%) more false positives. Screening tailored to PRS vs biennial screening from 50 to 74 years had smaller positive effects on life-years gained (20%) and breast cancer deaths averted (11%) but also smaller increases in overdiagnoses (10%) and false positives (26%). Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained (29%) and breast cancer deaths averted (18%). Conclusions Our results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected.
Published: 2021

8. Evaluation of a Multiethnic Polygenic Risk Score Model for Prostate Cancer

Author: Sarah S. Kalia, Adam S. Kibel, David V. Conti, Kathryn L. Penney, Anna Plym, Lorelei A. Mucci, Peter Kraft, and Christopher A. Haiman
Subjects: Oncology, 0303 health sciences, Cancer Research, education.field_of_study, medicine.medical_specialty, business.industry, Population, Odds ratio, Disease, medicine.disease, Confidence interval, Decile, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Polygenic risk score, Cumulative incidence, education, business, 030304 developmental biology
Abstract: Polygenic risk scores (PRSs) of common genetic variants have shown promise in prostate cancer risk stratification, but their validity across populations has yet to be confirmed. We evaluated a multiethnic PRS model based on 269 germline genetic risk variants (261 were available for analysis) using an independent population of 13 628 US men. The PRS was strongly associated with prostate cancer but not with any other disease. Comparing men in the top PRS decile with those at average risk (40%-60%), the odds ratio of prostate cancer was 3.89 (95% confidence interval = 3.24 to 4.68) for men of European ancestry and 3.81 (95% confidence interval = 1.48 to 10.19) for men of African ancestry. By age 85 years, the cumulative incidence of prostate cancer for European American men was 7.1% in the bottom decile and 54.1% in the top decile. This suggests that the PRS can be used to identify a substantial proportion of men at high risk for prostate cancer.
Published: 2021

9. Tandem Lesions in Anterior Circulation Stroke

Author: Katharina Feil, Moriz Herzberg, Franziska Dorn, Steffen Tiedt, Clemens Küpper, Dennis C. Thunstedt, Panagiotis Papanagiotou, Lukas Meyer, Andreas Kastrup, Konstantinos Dimitriadis, Thomas Liebig, Marianne Dieterich, Lars Kellert, Tobias Boeckh-Behrens, Silke Wunderlich, Alexander Ludolph, Karl-Heinz Henn, Arno Reich, Anastasios Mpotsaris, Martin Wiesmann, Ulrike Ernemann, Sven Poli, Christian H. Nolte, Eberhard Siebert, Sarah Zweynert, Georg Bohner, Laszlo Solymosi, Gabor Petzold, Waltraud Pfeilschifter, Fee Keil, Joachim Röther, Bernd Eckert, Jörg Berrouschot, Albrecht Bormann, Anna Alegiani, Jens Fiehler, Christian Gerloff, Götz Thomalla, Sven Thonke, Christopher Bangard, Christoffer Kraemer, Martin Dichgans, Marios Psychogios, Jan Liman, Martina Petersen, Florian Stögbauer, Peter Kraft, Mirko Pham, Michael Braun, Gerhard F. Hamann, Christian Roth, Klaus Gröschel, Timo Uphaus, and Volker Limmroth
Subjects: Carotid Artery Diseases, Male, medicine.medical_specialty, medicine.medical_treatment, 030204 cardiovascular system & hematology, Lesion, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, Germany, medicine.artery, Occlusion, medicine, Humans, Registries, Stroke, Aged, Thrombectomy, Advanced and Specialized Nursing, business.industry, Cerebral infarction, Endovascular Procedures, Thrombolysis, Middle Aged, medicine.disease, Cerebrovascular Disorders, Stenosis, Female, Neurology (clinical), Radiology, medicine.symptom, Internal carotid artery, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: Background and Purpose: Tandem lesions in the anterior circulation account for up to 30% of all large vessel occlusion strokes. The optimal periprocedural approach in these lesions is still a matter of debate. Methods: Data from the German Stroke Registry—Endovascular Treatment between June 2015 and December 2019 were analyzed. The German Stroke Registry—Endovascular Treatment is an academic, independent, prospective, multicenter, observational registry study with 25 participating stroke centers from all over Germany enrolling consecutive mechanical thrombectomy patients. Tandem lesions were defined as a combination of a relevant extracranial internal carotid artery (ICA) pathology (ipsilateral stenosis >70% or occlusion) and concomitant intracranial large vessel occlusion. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction score of 2b-3. The modified Rankin Scale score of 0 to 2 at 3 months indicated good outcome. The aim of this study was to investigate the safety and efficacy of different technical strategies in tandem lesions. Results: Out of 6635 patients, 874 (13.2%) presented with tandem lesions. Of these, 607 (69.5%) underwent acute treatment of the extracranial ICA. Acute treatment of the extracranial ICA lesion led to a higher probability of successful reperfusion (odds ratio, 40.63 [95% CI, 30.03–70.06]) compared with patients who did not undergo acute treatment of the extracranial ICA lesion and was associated with good clinical outcome (39.5% versus 29.3%, P P P =0.035) and intravenous thrombolysis (odds ratio, 10.58 [95% CI, 10.04–20.4]; P =0.033). Intracranial-first approach (n=227) compared with extracranial-first approach (n=267) resulted in a shorter time to flow restoration (53.5 versus 72.0 minutes, P P =0.24) without differences in periprocedural complications. Conclusions: In tandem lesions in the anterior circulation, acute treatment of the extracranial ICA lesion is associated with better clinical outcome and lower mortality. The intracranial-first approach might provide advantages.
Published: 2021

10. Breast cancer risk factors and survival by tumor subtype

Author: Päivi Auvinen, Hoda Anton-Culver, Stig E. Bojesen, Gad Rennert, Christos Petridis, Taru A. Muranen, Lukas Schwentner, Jenny Chang-Claude, Chen-Yang Shen, Melissa A. Troester, Sara Y. Brucker, Miriam Dwek, Jingmei Li, Nadia Obi, Montserrat Garcia-Closas, Soo Hwang Teo, Pascal Guénel, Hidemi Ito, Sabine Behrens, Rulla M. Tamimi, Melissa C. Southey, Michelle D. Holmes, Christopher A. Haiman, Henrik Flyger, Roger L. Milne, Per Hall, Jyh-Cherng Yu, Thomas U. Ahearn, William G. Newman, D. Gareth Evans, Dong-Young Noh, Qin Wang, Robert Winqvist, Tjoung-Won Park-Simon, Angela Cox, Dimitrios Mavroudis, Federico Canzian, Celine M. Vachon, Annelie Augustinsson, Shivaani Mariapun, Keitaro Matsuo, Mia M. Gaudet, Anna Jakubowska, Loic Le Marchand, Rob A. E. M. Tollenaar, Paul D.P. Pharoah, Mikael Hartman, Jane Heyworth, Alison M. Dunning, Daniele Campa, Keun-Young Yoo, Anna Morra, Sileny Han, Anna H. Wu, David J. Hunter, Laura E. Beane Freeman, Mehdi Manoochehri, Volker Arndt, Elinor J. Sawyer, Peter A. Fasching, Alicja Wolk, Xiao-Ou Shu, José A. García-Sáenz, Hermann Brenner, Børge G. Nordestgaard, Pooja Middha Kapoor, Diether Lambrechts, Kamila Czene, Marjanka K. Schmidt, Nadege Presneau, Stephen J. Chanock, Mervi Grip, Ignacio Briceño, Stella Koutros, Nicola J. Camp, Kathleen M. Egan, Wei Zheng, Reiner Hoppe, Simon S. Cross, James V. Lacey, Manjeet K. Bolla, Cari M. Kitahara, Annika Lindblom, Carl Blomqvist, William J. Tapper, Diana Torres, Jan Lubinski, Milena Jakimovska, Vessela N. Kristensen, Jose E. Castelao, Graham G. Giles, Andrew F. Olshan, John L. Hopper, A. Heather Eliassen, Valerie Rhenius, Christopher G. Scott, Agnes Jager, Thilo Dörk, Justin A. Williams, Ian Tomlinson, Emmanouil Saloustros, Ji Yeob Choi, Dijana Plaseska-Karanfilska, Thérèse Truong, Audrey Y. Jung, Daehee Kang, Argyrios Ziogas, Peter Kraft, Arto Mannermaa, Rudolf Kaaks, Heiko Becher, Wolfgang Janni, Niclas Håkansson, Steven N. Hart, Xiaohong R. Yang, Håkan Olsson, Fergus J. Couch, Renske Keeman, Ute Hamann, Atocha Romero, Daniel O. Stram, Andreas Schneeweiss, Susan M. Gapstur, Michael Lush, Diana Eccles, Sara Margolin, Hedy S. Rennert, Muhammad Usman Rashid, Mitul Shah, Matthias W. Beckmann, Sophia S. Wang, Douglas F. Easton, Manuela Gago-Dominguez, Christine L. Clarke, and Medical Oncology
Subjects: 0301 basic medicine, Oncology, Adult, medicine.medical_specialty, Epidemiology, Estrogen receptor, Breast Neoplasms, Article, 03 medical and health sciences, Aged, Cause of Death, Female, Humans, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Prospective Studies, Risk Factors, Survival Analysis, Life Style, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, business.industry, Proportional hazards model, Cancer, medicine.disease, Confidence interval, 3. Good health, Tumor Subtype, 030104 developmental biology, Clinical research, 030220 oncology & carcinogenesis, business, Body mass index
Abstract: Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
Published: 2021

11. Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author: Mengmeng Du, Rachael Z. Stolzenberg-Solomon, Herbert Yu, Paige M. Bracci, Antonia Trichopoulou, Anne Tjønneland, Eric J. Duell, Bas Bueno-de-Mesquita, Alison P. Klein, Graham G. Giles, Fangcheng Yuan, Howard D. Sesso, Federico Canzian, Sonja I. Berndt, I-Min Lee, Ghislaine Scelo, Lynne R. Wilkens, Jean Wactawski-Wende, Nicolas Wentzensen, Kari G. Rabe, Laufey T. Amundadottir, Eric J. Jacobs, Victoria L. Stevens, Phyllis J. Goodman, Harvey A. Risch, Edward Giovannucci, Evelina Mocci, Stephen K. Van Den Eeden, Stephen J. Chanock, Ann L. Oberg, Gloria M. Petersen, Rayjean J. Hung, Robert C. Kurtz, Xiao-Ou Shu, Charles Kooperberg, Charles S. Fuchs, Nilanjan Chatterjee, Nathaniel Rothman, Ulrike Peters, Núria Malats, Kimmie Ng, Ian M. Thompson, Roger L. Milne, William Wheeler, Paul Brennan, Emily White, J. Michael Gaziano, Steven Gallinger, Prosenjit Kundu, Wei Zheng, Miquel Porta, Brian M. Wolpin, Kala Visvanathan, Loic Le Marchand, Elio Riboli, Oliver Strobel, Michael Goggins, Daniele Campa, Salvatore Panico, Rachel E. Neale, Laura E. Beane Freeman, Gabriella Andreotti, Debra T. Silverman, Ana Babic, Erica J. Childs, Donghui Li, Julie E. Buring, Patricia Hartge, Manal M. Hassan, Alan A. Arslan, Robert N. Hoover, Amanda L. Blackford, Anne Zeleniuch-Jacquotte, Demetrius Albanes, William R. Bamlet, Peter Kraft, and Elizabeth A. Holly
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Pancreatic ductal adenocarcinoma, Genotype, Quantitative Trait Loci, Polymorphism, Single Nucleotide, Article, Chromosomes, Germline, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Pancreatic cancer, Internal medicine, medicine, Humans, SNP, Genetic Predisposition to Disease, Polymorphism, Genetic association, business.industry, Cyclin T, Carcinoma, Smoking, Membrane Proteins, Colocalization, Single Nucleotide, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Pancreatic Ductal, Chromosomes, Human, Pair 2, 030220 oncology & carcinogenesis, Pair 2, Expression quantitative trait loci, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study, business, Human
Abstract: Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
Published: 2021

12. A Population-Based Study of Genes Previously Implicated in Breast Cancer

Author: Janet E. Olson, Elizabeth S. Burnside, Chi Gao, Heather Eliassen, Paul L. Auer, Chunling Hu, Argyrios Ziogas, Brian D. Carter, James M. Hodge, Lynn Rosenberg, Jack A. Taylor, Rohan Gnanaolivu, Amy Trentham-Dietz, Mia M. Gaudet, Katherine L. Nathanson, David E. Goldgar, Irene M. Ong, Susan M. Gapstur, Katie M. O'Brien, Alpa V. Patel, Charles Kooperberg, Rulla M. Tamimi, David J. Hunter, Christine B. Ambrosone, Celine M. Vachon, Nicholas J. Boddicker, Hoda Anton-Culver, Esther M. John, Song Yao, Jeffrey N. Weitzel, Dale P. Sandler, Christopher G. Scott, Susan L. Neuhausen, Eric C. Polley, Josh Klebba, Jenna Lilyquist, Polly A. Newcomb, Kimberly A. Bertrand, Raed Samara, Kun Y. Lee, Susan M. Domchek, Steven N. Hart, Elisa V. Bandera, Huiyan Ma, Leslie Bernstein, Sara Lindstroem, Sonya Reid, Christopher A. Haiman, Loic Le Marchand, Hongyan Huang, Tuya Pal, Peter Kraft, Eric J. Jacobs, Siddhartha Yadav, Julie R. Palmer, Allison W. Kurian, Fergus J. Couch, Tricia Lindstrom, Clarice R. Weinberg, and Jie Na
Subjects: 030204 cardiovascular system & hematology, Bioinformatics, Medical and Health Sciences, Germline, 0302 clinical medicine, 80 and over, Odds Ratio, 2.1 Biological and endogenous factors, 030212 general & internal medicine, Aetiology, skin and connective tissue diseases, Cancer, Aged, 80 and over, screening and diagnosis, education.field_of_study, General Medicine, Middle Aged, Detection, Female, Risk assessment, Sequence Analysis, Adult, Risk, Population, Breast Neoplasms, Article, Young Adult, 03 medical and health sciences, Breast cancer, Clinical Research, General & Internal Medicine, Breast Cancer, Genetic variation, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, education, Gene, Aged, business.industry, Prevention, Case-control study, Genetic Variation, DNA, Sequence Analysis, DNA, Odds ratio, medicine.disease, 4.1 Discovery and preclinical testing of markers and technologies, Case-Control Studies, Mutation, business
Abstract: BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case–control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor–positive breast cancer. Pathogenic variants in 16 candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)
Published: 2021

13. The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice

Author: Michael Bieber, Maximilian Franke, Peter Kraft, Guido Stoll, Michael K. Schuhmann, and Alexander N.R. Weber
Subjects: 0301 basic medicine, Inflammasomes, Immunology, Ischemia, Caspase 1, Pharmacology, Blood–brain barrier, Brain Ischemia, Mice, 03 medical and health sciences, Behavioral Neuroscience, AIM2, 0302 clinical medicine, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Stroke, Neuroinflammation, Inflammation, integumentary system, Endocrine and Autonomic Systems, business.industry, Infarction, Middle Cerebral Artery, Inflammasome, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Reperfusion Injury, business, Reperfusion injury, 030217 neurology & neurosurgery, medicine.drug
Abstract: Purpose Cerebral ischemia induces a profound neuro-inflammatory response, but the underlying molecular mechanisms are poorly understood. Inflammasomes (NLRP1, NLRP3, NLRC4, AIM2) are intracellular multi-protein complexes which can induce sets of pro-inflammatory cyto- and chemokines, and thereby guide inflammation. We, here, assessed the functional role of NLRP3 in ischemia/reperfusion (I/R) injury in a mouse model of transient cerebral ischemia. Methods Ischemic stroke was induced in C57Bl/6 mice by 60 min transient middle cerebral artery occlusion (tMCAO) and 3, 7 or 23 h of reperfusion, a paradigm of I/R injury. The expression patterns of inflammasomes in the ischemic hemispheres were evaluated by semiquantitative real-time PCR and Western Blot analysis accompanied by protein localization using immunocytochemistry. Finally, animals were treated with the inflammasome inhibitors Sulforaphane, Genipin, MCC950 or vehicle, directly before or upon recanalization after tMCAO. Stroke outcome was assessed, including infarct size and functional deficits, local inflammatory response, neuronal survival as well as blood–brain barrier function on day 1 after tMCAO. Results After tMCAO the relative gene expression levels of NLRP3 increased 20-30x within 1 day in the ischemic hemisphere which translated into an increased expression of NLRP3 in neurons. Accordingly, the gene expression levels of the NLRP3-modulator, Bruton’s Tyrosine Kinase (BTK), and the NLRP3-inducible cytokine IL-1β significantly rose. Lesser or non-significant changes were seen for the other inflammasomes. Application of inflammasome inhibitors covering all inflammasomes or specifically NLRP3 significantly reduced infarct volumes when given before or after tMCAO and was accompanied by clear evidence for reduced activation of caspase 1. This stroke attenuating effect coincided with less immune cell infiltration in the ischemic hemisphere and preservation of the blood–brain barrier integrity. Conclusions Our data show that induction of the NLRP3 inflammasome in neurons drives neuroinflammation in acute ischemic stroke. Early blockade of NLRP3 protects from I/R injury by mitigating inflammation and stabilizing the blood–brain barrier.
Published: 2021

14. A Genome‐Wide Association Study of Childhood Body Fatness

Author: Peter Kraft, David Nana Adjei, William J. Gordon, Lu Wang, Erica T. Warner, Rulla M. Tamimi, Sara Lindström, Constance Turman, and Lai Jiang
Subjects: Adult, Male, Pediatric Obesity, medicine.medical_specialty, Waist, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), 030209 endocrinology & metabolism, Genome-wide association study, Polymorphism, Single Nucleotide, Article, Childhood obesity, Body Mass Index, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, FHIT, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, 1000 Genomes Project, Adiposity, Aged, Nutrition and Dietetics, business.industry, Body fatness, Middle Aged, medicine.disease, Genetic architecture, Phenotype, Menarche, Female, business, Genome-Wide Association Study
Abstract: OBJECTIVE This study aimed to uncover genetic contributors to adiposity in early life. METHODS A genome-wide association study of childhood body fatness in 34,401 individuals within the Nurses' Health Studies and the Health Professionals Follow-up Study was conducted. Data were imputed to the 1000 Genomes Phase 3 version 5 reference panel. RESULTS A total of 1,354 single-nucleotide polymorphisms (P
Published: 2021

15. Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk

Author: Núria Malats, Paul Brennan, Veronica Wendy Setiawan, Yaohua Yang, Jirong Long, Thilo Hackert, Xiaoliang Wang, Charles Kooperberg, Michael Goggins, Manal M. Hassan, I-Min Lee, Elizabeth A. Holly, Graham G. Giles, Roger L. Milne, Brian M. Wolpin, Miquel Porta, Verena Katske, Sonja I. Berndt, Herbert Yu, Laura E. Beane Freeman, Kari G. Rabe, Jean Wactawski-Wende, Robert N. Hoover, Stephen J. Chanock, Paige M. Bracci, Fei Ye, Ann L. Oberg, Wei Zheng, Anne Zeleniuch-Jacquotte, Lauren K. Brais, Samuel O. Antwi, Pilar Amiano, Nicolas Wentzensen, J. Michael Gaziano, Dalia Ghoneim, Jingjing Zhu, Rachel E. Neale, Charles S. Fuchs, Nathaniel Rothman, Ghislaine Scelo, Philip C Haycock, Alison P. Klein, Neil Murphy, Harvey A. Risch, Nikhil K. Khankari, Lynne R. Wilkens, Laufey T. Amundadottir, Peter Kraft, Mengmeng Du, Eric J. Jacobs, Federico Canzian, Ian M. Thompson, Alan A. Arslan, Howard D. Sesso, Emily White, Eric J. Duell, Gloria M. Petersen, Phyllis J. Goodman, Stolzenberg-Solomon R, Xiao-Ou Shu, Harvey J. Murff, Priya Duggal, Kathy J. Helzlsouer, Steven Gallinger, Demetrius Albanes, Bas Bueno-de-Mesquita, William R. Bamlet, Kai Yu, Gabriella Andreotti, Lang Wu, Peter T. Campbell, Robert C. Kurtz, Debra T. Silverman, Ana Babic, Julie E. Buring, Kala Visvanathan, and Loic Le Marchand
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Linoleic acid, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Fatty Acids, Omega-6, Internal medicine, Pancreatic cancer, Mendelian randomization, Humans, Medicine, Aged, chemistry.chemical_classification, business.industry, Mendelian Randomization Analysis, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Pancreatic Neoplasms, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Cohort, Female, business, Polyunsaturated fatty acid
Abstract: Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case–Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98–1.02; arachidonic acid OR = 1.00, 95% CI = 0.99–1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87–1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
Published: 2020

16. DIFF: a relational interface for large-scale data explanation

Author: Sahaana Suri, Eric Xu, Edward Gan, Peter Kraft, Asvin Ananthanarayan, Xi Wu, Firas Abuzaid, John Te-Jui Sheu, Matei Zaharia, Erik Meijer, Peter Bailis, Atul Shenoy, and Jeffrey F. Naughton
Subjects: SQL, Information retrieval, Computer science, Interface (Java), business.industry, Relational database, General Engineering, Complex event processing, 02 engineering and technology, Set (abstract data type), Logical conjunction, Analytics, Hardware and Architecture, 020204 information systems, 0202 electrical engineering, electronic engineering, information engineering, 020201 artificial intelligence & image processing, Use case, business, computer, computer.programming_language, Information Systems
Abstract: A range of explanation engines assist data analysts by performing feature selection over increasingly high-volume and high-dimensional data, grouping and highlighting commonalities among data points. While useful in diverse tasks such as user behavior analytics, operational event processing, and root cause analysis, today's explanation engines are designed as standalone data processing tools that do not interoperate with traditional, SQL-based analytics workflows; this limits the applicability and extensibility of these engines. In response, we propose the DIFF operator, a relational aggregation operator that unifies the core functionality of these engines with declarative relational query processing. We implement both single-node and distributed versions of the DIFF operator in MB SQL, an extension of MacroBase, and demonstrate how DIFF can provide the same semantics as existing explanation engines while capturing a broad set of production use cases in industry, including at Microsoft and Facebook. Additionally, we illustrate how this declarative approach to data explanation enables new logical and physical query optimizations. We evaluate these optimizations on several real-world production applications, and find that DIFF in MB SQL can outperform state-of-the-art engines by up to an order of magnitude.
Published: 2020

17. A demonstration of willump

Author: Peter Bailis, Matei Zaharia, Deepak Narayanan, Daniel Kang, Shoumik Palkar, and Peter Kraft
Subjects: Speedup, Computer science, business.industry, General Engineering, Inference, Feature computation, Machine learning, computer.software_genre, Bottleneck, Very large database, End-to-end principle, Leverage (statistics), Artificial intelligence, business, computer
Abstract: Systems for ML inference are widely deployed today, but they typically optimize ML inference workloads using techniques designed for conventional data serving workloads and miss critical opportunities to leverage the statistical nature of ML. In this demo, we present Willump, an optimizer for ML inference that introduces statistically-motivated optimizations targeting ML applications whose performance bottleneck is feature computation. Willump automatically cascades feature computation for classification queries: Willump classifies most data inputs using only high-value, low-cost features selected by a cost model, improving query performance by up to 5 x without statistically significant accuracy loss. In this demo, we use interactive and easily-downloadable Jupyter notebooks to show VLDB attendees which applications Willump can speed up, how to use Willump, and how Willump produces such large performance gains.
Published: 2020

18. Development of a German telephone version of the IQCODE (The Informant Questionnaire on Cognitive Decline in the Elderly) within a cohort of relatives of ischemic stroke patients

Author: Daniel Mackenrodt, Christoph Kleinschnitz, Viktoria Rücker, Peter U. Heuschmann, Uwe Malzahn, Silke Wiedmann, Peter Kraft, Sabrina Engelhardt, and Stefan Störk
Subjects: Gynecology, 050103 clinical psychology, Validation study, medicine.medical_specialty, business.industry, 05 social sciences, Medizin, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Neurology, Cognitive Changes, Medicine, 0501 psychology and cognitive sciences, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Zusammenfassung Hintergrund Eine validierte telefonische Fassung der deutschen Version des Fragebogens „Informant Questionnaire on Cognitive Decline in the Elderly“ (IQCODE) zur Erfassung kognitiver Veränderungen von Schlaganfall-Patienten über einen Zeitraum von 10 Jahren vor Schlaganfall durch Befragung Angehöriger liegt bislang nicht vor. Eine deutsche telefonische Kurzversion existiert ebenfalls nicht. Methoden 60 Angehörige von 60 Patientinnen und Patienten mit ischämischem Schlaganfall wurden mit der persönlichen und der telefonischen 26-Item-Version des IQCODE in randomisierter Reihenfolge befragt. Als Maß zur Quantifizierung der Reliabilität beider IQCODE-Versionen wurde ein gewichtetes Kappa berechnet (Fleiss-Cohen Gewichte). Mithilfe von Varianzinflationsfaktoren wurde eine telefonische Kurzversion des IQCODE entwickelt und diese Version mit der 26-Item-Telefonversion mittels Spearman‘s Korrelationskoeffizienten verglichen. Ergebnisse Das gewichtete Kappa der telefonischen Befragung gegenüber der persönlichen betrug 0,84 (95 % Konfidenzintervall 0,72–0,97). Die neu entwickelte Kurzversion des telefonbasierten IQCODE umfasste 10 Items. Der Korrelationskoeffizient zwischen der Kurz- und der Langversion betrug 0,97 (95 % Konfidenzintervall 0,96–0,99). Schlussfolgerung Die telefonische Version des deutschsprachigen 26-Item IQCODE zeigte im Vergleich zur persönlichen Befragung exzellente Übereinstimmungswerte. Die telefonische 10-Item-Kurzversion zeigte eine exzellente Übereinstimmung mit der telefonischen Langversion. Somit stehen nun auch für den deutschen Sprachraum vereinfachte Werkzeuge für die effiziente Befragung großer Kollektive zur Verfügung.
Published: 2020

19. Validating Breast Cancer Risk Prediction Models in the Korean Cancer Prevention Study-II Biobank

Author: Jihye Kim, Peter Kraft, Chi Gao, Sun Ha Jee, Seho Park, and Yon Ho Jee
Subjects: 0301 basic medicine, Epidemiology, Breast Neoplasms, Validation Studies as Topic, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Republic of Korea, medicine, Humans, Risk factor, Biological Specimen Banks, Cancer prevention, business.industry, Incidence (epidemiology), Mortality rate, Absolute risk reduction, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Relative risk, Cohort, Female, business, Demography
Abstract: Background: Risk prediction models may be useful for precision breast cancer screening. We aimed to evaluate the performance of breast cancer risk models developed in European-ancestry studies in a Korean population. Methods: We compared discrimination and calibration of three multivariable risk models in a cohort of 77,457 women from the Korean Cancer Prevention Study (KCPS)-II. The first incorporated U.S. breast cancer incidence and mortality rates, U.S. risk factor distributions, and RR estimates from European-ancestry studies. The second recalibrated the first by using Korean incidence and mortality rates and Korean risk factor distributions, while retaining the European-ancestry RR estimates. Finally, we derived a Korea-specific model incorporating the RR estimates from KCPS. Results: The U.S. European-ancestry breast cancer risk model was well calibrated among Korean women Conclusions: The poor performance of the U.S. European-ancestry breast cancer risk model among older Korean women highlights the importance of tailoring absolute risk models to specific populations. Recalibrating the model using Korean incidence and mortality rates and risk factor distributions greatly improved performance. Impact: The data will provide valuable information to plan and evaluate actions against breast cancer focused on primary prevention and early detection in Korean women.
Published: 2020

20. Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women

Author: Loic LeMarchand, Esther M. John, Song Yao, Mia M. Gaudet, Chi Gao, Tuya Pal, Julie R. Palmer, Kimberly A. Bertrand, Payal D. Shah, Rohan Gnanaolivu, Katherine L. Nathanson, Chunling Hu, Susan M. Domchek, Peter Kraft, Jie Na, Leslie Bernstein, Fergus J. Couch, David E Goldgar, Eric C. Polley, Elisa V. Bandera, Dale P. Sandler, Christine B. Ambrosone, Jeffrey N. Weitzel, Amy Trentham-Dietz, Siddhartha Yadav, Steven N. Hart, William Yang, Kun Y. Lee, Christopher A. Haiman, Traci N. Bethea, Hongyan Huang, and Hoda Anton-Culver
Subjects: Oncology, 0303 health sciences, Cancer Research, medicine.medical_specialty, education.field_of_study, medicine.diagnostic_test, business.industry, PALB2, Population, Estrogen receptor, Cancer, Gene mutation, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, medicine, business, education, CHEK2, 030304 developmental biology, Genetic testing
Abstract: Background The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. Methods Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. Results Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. Conclusions The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.
Published: 2020

21. Sex-Stratified Polygenic Risk Score Identifies Individuals at Increased Risk of Basal Cell Carcinoma

Author: Peter Kraft, Maryam M. Asgari, Joanne E. Sordillo, and Michelle Roberts
Subjects: Adult, Male, Risk, 0301 basic medicine, Multifactorial Inheritance, Percentile, Skin Neoplasms, animal structures, Single-nucleotide polymorphism, Genome-wide association study, Dermatology, Polymorphism, Single Nucleotide, Biochemistry, Article, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Humans, Medicine, Genetic Predisposition to Disease, Genetic variability, skin and connective tissue diseases, neoplasms, Molecular Biology, Genetic association, Sex Characteristics, integumentary system, business.industry, Incidence, fungi, Cell Biology, Odds ratio, 030104 developmental biology, Carcinoma, Basal Cell, Genetic Loci, 030220 oncology & carcinogenesis, Relative risk, Female, Population Risk, business, Demography
Abstract: The incidence of basal cell carcinoma (BCC) is higher among men than women. Susceptibility loci for BCC have been identified through genome-wide association studies, and two previous studies have found polygenic risk scores (PRS) to be significantly associated with the risk of BCC. However, to our knowledge, sex-stratified PRS analyses examining the genetic contribution to BCC risk among men and women have not been previously reported. To quantify the contribution of genetic variability on the BCC risk by sex, we derived a polygenic risk score and estimated the genetic relative risk distribution for men and women. Using 29 published single nucleotide polymorphisms, we found that the estimated relative risk of BCC increases with higher percentiles of the polygenic risk score. For men, the estimated risk of BCC is twice the average population risk at the 88th percentile, while for women, this occurs at the 99th percentile. Our findings indicate that there is a significant impact of genetic variation on the risk of developing BCC and that this impact may be greater for men than for women. Polygenic risk scores may be clinically useful tools for risk stratification, particularly in combination with other known risk factors for BCC development.
Published: 2020

22. Abstract P5-08-07: Tobacco use, alcohol consumption, and breast cancer somatic genomic alterations

Author: Christine B. Ambrosone, Jun Wang, Fergus J. Couch, Adam Brufsky, Peter Kraft, Tari A. King, A. Heather Eliassen, Susan E. Hankinson, Victor P. Andrade, Francesmary Modugno, Rulla M. Tamimi, Celine M. Vachon, Ludmil B. Alexandrov, and Yujing J. Heng
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Estrogen receptor, MAP3K1, medicine.disease, medicine.disease_cause, Breast Cancer Risk Factor, Germline mutation, Breast cancer, Internal medicine, medicine, Copy-number variation, Carcinogenesis, business, Exome sequencing
Abstract: Background: Understanding the molecular influence of epidemiological risk factors can provide insights into breast cancer etiology and progression, and lead to better prevention efforts and treatment guidelines. The link between modifiable breast cancer risk factors and tumor genomic alterations remains unexplored. This study evaluated the association of tobacco use and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30) (1-3), and nine breast cancer driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) (4,5), in a subset of The Cancer Genome Atlas (TCGA). Method: Clinical and genomic data were retrieved from the TCGA database, and breast cancer risk factor information was collected from four TCGA sites; in all, 219 female breast cancer cases were included. Pre-diagnostic tobacco use was defined as never or ever; alcohol consumption was defined as drinkers or non-drinkers. Total SCNV was obtained by summing all segments with ≥|0.2|. TSMB was calculated by summing all significant mutations for each case. SBS signatures were computed using whole exome sequencing data. Analyses were conducted in all tumors (i.e., pooled) and by stratifying according to estrogen receptor (ER) status using multivariate regression, adjusting for co-variables. Results: Tobacco users had higher TSMB compared to non-users (p Conclusion: This study provides preliminary evidence that tobacco use and alcohol consumption can influence breast tumor biology, in particular, DNA alterations. Future larger epidemiological studies are required to confirm these findings. References 1. Vineis P, et al. Mutational signatures associated with tobacco smoking in human cancer. Science. 2016;354(6312):618-22. 2. Alexandrov LB, et al. Clock-like mutational processes in human somatic cells. Nat Genet. 2015;47(12):1402-7. 3. Petljak M, Alexandrov LB. Understanding mutagenesis through delineation of mutational signatures in human cancer. Carcinogenesis. 2016;37(6):531-40. 4. Heng YJ, et al. The molecular basis of breast cancer pathologic phenotypes. J Pathol. 2017 Nov;241(3):375-91. 5. Ciriello G, et al. Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. Cell. 2015 Oct 10;163(2):506-19. Citation Format: Yujing J Heng, Susan E Hankinson, Jun Wang, Ludmil B Alexandrov, Christine B Ambrosone, Victor Piana de Andrade, Adam M Brufsky, Fergus J Couch, Tari A King, Francesmary Modugno, Celine M Vachon, A. Heather Eliassen, Rulla M Tamimi, Peter Kraft. Tobacco use, alcohol consumption, and breast cancer somatic genomic alterations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-07.
Published: 2020

23. Allergy, asthma, and the risk of breast and prostate cancer: a Mendelian randomization study

Author: Konstantinos K. Tsilidis, Peter Kraft, Sarah J Lewis, Sara Lindström, Richard M. Martin, Zhaozhong Zhu, Niki Dimou, Xia Jiang, Pegasus consortia, Carolina Bonilla, and Practical, Cruk, Bpc , Caps
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Allergy, Breast Neoplasms, Disease, Polymorphism, Single Nucleotide, Prostate cancer, Breast cancer, Internal medicine, Mendelian randomization, Odds Ratio, medicine, Humans, Asthma, business.industry, Prostatic Neoplasms, Malignancy, Cancer, Odds ratio, Mendelian Randomization Analysis, medicine.disease, Case-Control Studies, Hay fever, Female, Disease Susceptibility, business, Genome-Wide Association Study, Bristol Population Health Science Institute, Causal inference
Abstract: Purpose The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer. Methods We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (ncase = 180,129), asthma (ncase = 14,085), breast (ncase = 122,977), and prostate cancer (ncase = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease. Results We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96–1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95–1.04), p = 0.71], ER− [1.05 (0.99–1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94–1.05), p = 0.93] or advanced subtype [0.97 (0.90–1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy. Conclusion Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).
Published: 2020

24. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany—Updated series of 120 cases

Author: Sebastian Edelbusch, Christian H. Nolte, Olav Schwarte, Robert Wruck, Oliver Sauer, Gabriele Schackert, Yasser Abdalla, Valentin Held, Joachim Röther, Bettina von Sarnowksi, Claus G. Haase, Hans-Christoph Diener, Jan Latta, Rüdiger J. Seitz, Michael Daffertshofer, Silke Wunderlich, Karsten Witt, Torsten Rehfeldt, Eckhart Sindern, Peter Kühnlein, Elke Leinisch, Tobias Neumann-Haefelin, Raluca Rossi, Ulrich Pulkowski, Yogesh P Shah, Rolf Kern, Kristina Szabo, Lothar Burghaus, Peter D. Schellinger, Gebhard Becks, Martin Köhrmann, Mark Obermann, Ramona Schuppner, Christoph Leithner, Sebastian Senger, A. Lenz, Peer Patzschke, Jörg Berthel, Christoph C. Eschenfelder, Paul Sparenberg, Peter Kraft, Jan C. Purrucker, Albrecht Günther, Niklas Schäfer, Hazem El-Sabassy, Martin Grond, Rüdiger Gerlach, Karin Weissenborn, Sven Poli, Stefan Schwab, Thomas Kerz, Peter Wienecke, Carl-Albrecht Haensch, Peter A. Ringleb, Andreas Harloff, Felix J. Bode, Christian Urbanek, Pawel Kermer, Jürgen Eggers, Alexej Abraham, Maren Hieber, Joseph G Heckmann, Wolfgang Müllges, Thorsten Steiner, Someieh Partowi, Klaus Gröschel, Jörg Berrouschot, Florian Große-Dresselhaus, Hakan Cangür, Andreas Schneider, Andreas Kauert, Katharina Althaus, and Mathias Mäurer
Subjects: medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, Medizin, Antibodies, Monoclonal, Humanized, Antithrombins, Brain Ischemia, Dabigatran, Germany, Internal medicine, medicine, Humans, Thrombolytic Therapy, ddc:610, Ischemic Stroke, Retrospective Studies, Intracerebral hemorrhage, business.industry, Anticoagulant, Warfarin, Idarucizumab, Atrial fibrillation, Thrombolysis, Vitamin K antagonist, medicine.disease, Stroke, Neurology, Cardiology, business, Intracranial Hemorrhages, medicine.drug
Abstract: Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. Results One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0–3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. Conclusion Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.
Published: 2020

25. A Mendelian randomization analysis of circulating lipid traits and breast cancer risk

Author: Peter Kraft, Yingchang Lu, Ryan J. Delahanty, Marjanka K. Schmidt, Alicia Beeghly-Fadiel, Douglas F. Easton, Nikhil K. Khankari, Joe Dennis, Jacques Simard, Drakoulis Yannoukakos, Paul D.P. Pharoah, Qin Wang, Kyriaki Michailidou, Alison M. Dunning, Georgia Chenevix-Trench, David J. Hunter, Wei Zheng, Roger L. Milne, Manjeet K. Bolla, Xiao-Ou Shu, Hall Per, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, HDL, Epidemiology, LOCI, Breast Neoplasms, Genome-wide association study, Logistic regression, Polymorphism, Single Nucleotide, lipids, 03 medical and health sciences, Breast cancer, PLEIOTROPIC GENETIC-VARIANTS, 0302 clinical medicine, Risk Factors, COLON, Internal medicine, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, genetics, SERUM-CHOLESTEROL, Triglycerides, METAANALYSIS, business.industry, MORTALITY, GENOME-WIDE, cholesterol, Mendelian Randomization Analysis, General Medicine, Odds ratio, medicine.disease, 3142 Public health care science, environmental and occupational health, Confidence interval, instrumental variable, 3. Good health, ASSOCIATION ANALYSIS, 030104 developmental biology, 030220 oncology & carcinogenesis, HIGH-DENSITY-LIPOPROTEINS, lipids (amino acids, peptides, and proteins), Risk assessment, business, Genome-Wide Association Study
Abstract: Background Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. Methods Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. Results Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08–1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. Conclusions This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.
Published: 2019

26. Diagnostik und Akuttherapie des ischämischen Schlaganfalls

Author: Mirjam Dreikorn, Christoph Kleinschnitz, Sami Nasri, Peter Kraft, and Martin Köhrmann
Subjects: Gynecology, medicine.medical_specialty, business.industry, medicine, business
Abstract: Ischamische Schlaganfalle (IS) machen 85 – 90 % aller Schlaganfalle aus. IS und hamorrhagische Schlaganfalle konnen anhand der klinischen Untersuchung nicht differenziert werden. Der zunehmende Einsatz der mechanischen Thrombektomie wirft die Frage einer prahospitalen Triagierung von Patienten mit IS auf. Das Stroke-Unit-Konzept sowie die multimodale Bildgebung sind heute wesentliche Bestandteile der modernen Schlaganfallversorgung. Weiterhin bleibt die systemische Thrombolyse eine hocheffektive Behandlungsoption beim akuten IS, ist allerdings bei Kontraindikationen nicht immer einsetzbar.
Published: 2019

27. Polygenic Risk Scores for Prediction of Breast Cancer in Korean women

Author: Weang Kee Ho, Yon Ho Jee, Douglas F. Easton, Sohee Park, Soo-Hwang Teo, Keum Ji Jung, and Peter Kraft
Subjects: Cancer prevention, Breast cancer, business.industry, Relative risk, Incidence (epidemiology), Cohort, Absolute risk reduction, medicine, Area under the curve, Risk factor, medicine.disease, business, Demography
Abstract: BackgroundPolygenic risk scores (PRSs) developed using European and Asian GWAS have been shown to have good discrimination in Asian women. However, prospective calibration of absolute risk prediction models based on a PRS or PRS combined with lifestyle clinical and environmental factors in Asian women is limited. We evaluate the discrimination and calibration of several breast cancer PRSs among Korean women; these PRSs were developed using Asian and/or European training samples and include between 11 and 947,621 variants.MethodsFor each PRS, we compared discrimination (area under the curve [AUC]) and calibration (expected-to-observed ratio [E/O]) of three absolute risk models among 41,031 women from the Korean Cancer Prevention Study (KCPS)-II Biobank: (i) a model using incidence, mortality, and risk factor distributions (reference inputs) among U.S. women and European relative risks; (ii) a recalibrated model, using Korean reference but European relative risks; and (iii) a fully Korean-based model using Korean reference and relative risk estimates from KCPS.ResultsAll Asian and European PRS improved discrimination over lifestyle, clinical and environmental (Qx) factors in Korean women; a PRS trained using both European and Asian GWAS results led to the greatest improvement (Qx: AUC=0.65, Qx+PRS: AUC=0.72). U.S.- based absolute risk models overestimated the risks for women age ≥50 years, and this overestimation was larger for models that only included PRS (E/O=1.2 for women ConclusionsIncorporation of Asian and European PRS can improve discrimination in Korean women and may be useful for the risk-stratified interventions.Key Messages⍰Prospective validation of absolute risk prediction models combining lifestyle and polygenic risk scores in Asian women is limited.⍰We evaluated the calibration and discrimination of five PRSs developed using Asian and/or European training samples; two PRS were restricted to genome-wide significant SNPs, two included sub-genome-wide significant SNPs, and a multi-ancestry PRS using both European and Asian GWAS results.⍰Incorporation of PRS previously developed in Asian and European-ancestry populations can improve discrimination in Korean women.⍰Calibration improved for risk models that incorporate age-specific incidence rates from the target population relative to models that use external incidence rates⍰Our finding suggests that PRS may be useful for prioritizing individuals for targeted intervention on their lifestyle such as alcohol intake and obesity.⍰Further studies are needed to evaluate the value of incorporating PRS into risk models in ancestrally diverse populations.
Published: 2021

28. Solving Large-Scale Granular Resource Allocation Problems Efficiently with POP

Author: Peter Kraft, Stephen Boyd, Firas Abuzaid, Matei Zaharia, Akshay Agrawal, Fiodar Kazhamiaka, Srikanth Kandula, and Deepak Narayanan
Subjects: FOS: Computer and information sciences, Mathematical optimization, Optimization problem, Heuristic (computer science), Computer science, business.industry, Load balancing (computing), Scheduling (computing), Computer Science - Distributed, Parallel, and Cluster Computing, Traffic engineering, Resource allocation, Fraction (mathematics), Distributed, Parallel, and Cluster Computing (cs.DC), Heuristics, business
Abstract: Resource allocation problems in many computer systems can be formulated as mathematical optimization problems. However, finding exact solutions to these problems using off-the-shelf solvers is often intractable for large problem sizes with tight SLAs, leading system designers to rely on cheap, heuristic algorithms. We observe, however, that many allocation problems are granular: they consist of a large number of clients and resources, each client requests a small fraction of the total number of resources, and clients can interchangeably use different resources. For these problems, we propose an alternative approach that reuses the original optimization problem formulation and leads to better allocations than domain-specific heuristics. Our technique, Partitioned Optimization Problems (POP), randomly splits the problem into smaller problems (with a subset of the clients and resources in the system) and coalesces the resulting sub-allocations into a global allocation for all clients. We provide theoretical and empirical evidence as to why random partitioning works well. In our experiments, POP achieves allocations within 1.5% of the optimal with orders-of-magnitude improvements in runtime compared to existing systems for cluster scheduling, traffic engineering, and load balancing., Comment: Accepted to SOSP 2021 (extended version)
Published: 2021

29. Treatment with Edoxaban Attenuates Acute Stroke Severity in Mice by Reducing Blood–Brain Barrier Damage and Inflammation

Author: Mirko Pham, Kathrin I. Foerster, Michael Bieber, Peter Kraft, Walter E. Haefeli, and Michael K. Schuhmann
Subjects: Pyridines, blood–brain barrier, Severity of Illness Index, Brain Ischemia, Phenprocoumon, chemistry.chemical_compound, Mice, thrombo-inflammation, Edoxaban, Medicine, NOAC, Biology (General), Spectroscopy, Atrial fibrillation, Infarction, Middle Cerebral Artery, General Medicine, Computer Science Applications, Stroke, Chemistry, medicine.anatomical_structure, Blood-Brain Barrier, Cardiology, medicine.symptom, tMCAO, medicine.drug, medicine.medical_specialty, QH301-705.5, Ischemia, Inflammation, Blood–brain barrier, Catalysis, Article, Inorganic Chemistry, Internal medicine, Animals, Humans, ddc:610, Physical and Theoretical Chemistry, QD1-999, Molecular Biology, Intracerebral hemorrhage, business.industry, Organic Chemistry, medicine.disease, Disease Models, Animal, Thiazoles, hemorrhagic transformation, chemistry, edoxaban, business, experimental stroke, Reperfusion injury
Abstract: Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood–brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.
Published: 2021
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30. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Author: Götz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell, Bastian Cheng, Leonid Churilov, Martin Ebinger, Matthias Endres, Jochen B Fiebach, Mayumi Fukuda-Doi, Manabu Inoue, Timothy J Kleinig, Lawrence L Latour, Robin Lemmens, Christopher R Levi, Didier Leys, Kaori Miwa, Carlos A Molina, Keith W Muir, Norbert Nighoghossian, Mark W Parsons, Salvador Pedraza, Peter D Schellinger, Stefan Schwab, Claus Z Simonsen, Shlee S Song, Vincent Thijs, Danilo Toni, Chung Y Hsu, Nils Wahlgren, Haruko Yamamoto, Nawaf Yassi, Sohei Yoshimura, Steven Warach, Werner Hacke, Kazunori Toyoda, Geoffrey A Donnan, Stephen M Davis, Christian Gerloff, Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L. Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bharath Cheripelli, Tae-Hee Cho, Chi-un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B. Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M. Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K. Mueller, Keith W. Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H. Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H. Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z. Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Keizo Yasui, Toshiro Yonehara, Shinichi Yoshimura, K. Aarnio, F. Alemseged, C. Anderson, T. Ang, M.L. Archer, J. Attia, P. Bailey, A. Balabanski, A. Barber, P.A. Barber, J. Bernhardt, A. Bivard, D. Blacker, C.F. Bladin, A. Brodtmann, D. Cadilhac, B.C.V. Campbell, L. Carey, S. Celestino, L. Chan, W.H. Chang, A. ChangI, C.H. Chen, C.-I. Chen, H.F. Chen, T.C. Chen, W.H. Chen, Y.Y. Chen, C.A. Cheng, E. Cheong, Y.W. Chiou, P.M. Choi, H.J. Chu, C.S. Chuang, T.C. Chung, L. Churilov, B. Clissold, A. Connelly, S. Coote, B. Coulton, E. Cowley, J. Cranefield, S. Curtze, C. D'Este, S.M. Davis, S. Day, P.M. Desmond, H.M. Dewey, C. Ding, G.A. Donnan, R. Drew, S. Eirola, D. Field, T. Frost, C. Garcia-Esperon, K. George, R. Gerraty, R. Grimley, Y.C. Guo, G. Hankey, J. Harvey, S.C. Ho, K. Hogan, D. Howells, P.M. Hsiao, C.H. Hsu, C.T. Hsu, C.-S. Hsu, J.P. Hsu, Y.D. Hsu, Y.T. Hsu, C.J. Hu, C.C. Huang, H.Y. Huang, M.Y. Huang, S.C. Huang, W.S. Huang, D. Jackson, J.S. Jeng, S.K. Jiang, L. Kaauwai, O. Kasari, J. King, T.J. Kleinig, M. Koivu, J. Kolbe, M. Krause, C.W. Kuan, W.L. Kung, C. Kyndt, C.L. Lau, A. Lee, C.Y. Lee, J.T. Lee, Y. Lee, Y.C. Lee, C. Levi, C.R. Levi, L.M. Lien, J.C. Lim, C.C. Lin, C.H. Lin, C.M. Lin, D. Lin, C.H. Liu, J. Liu, Y.C. Lo, P.S. Loh, E. Low, C.H. Lu, C.J. Lu, M.K. Lu, J. Ly, H. Ma, L. Macaulay, R. Macdonnell, E. Mackey, M. Macleod, J. Mahadevan, V. Maxwell, R. McCoy, A. McDonald, S. McModie, A. Meretoja, S. Mishra, P.J. Mitchell, F. Miteff, A. Moore, C. Muller, F. Ng, F.C. Ng, J-L. Ng, W. O'Brian, V. O'Collins, T.J. Oxley, M.W. Parsons, S. Patel, G.S. Peng, L. Pesavento, T. Phan, E. Rodrigues, Z. Ross, A. Sabet, M. Sallaberger, P. Salvaris, D. Shah, G. Sharma, G. Sibolt, M. Simpson, S. Singhal, B. Snow, N. Spratt, R. Stark, J. Sturm, M.C. Sun, Y. Sun, P.S. Sung, Y.F. Sung, M. Suzuki, M. Tan, S.C. Tang, T. Tatlisumak, V. Thijs, M. Tiainen, C.H. Tsai, C.K. Tsai, C.L. Tsai, H.T. Tsai, L.K. Tsai, C.H. Tseng, L.T. Tseng, J. Tsoleridis, H. Tu, H.T-H. Tu, W. Vallat, J. Virta, W.C. Wang, Y.T. Wang, M. Waters, L. Weir, T. Wijeratne, C. Williams, W. Wilson, A.A. Wong, K. Wong, T.Y. Wu, Y.H. Wu, B. Yan, F.C. Yang, Y.W. Yang, N. Yassi, H.L. Yeh, J.H. Yeh, S.J. Yeh, C.H. Yen, D. Young, C.L. Ysai, W.W. Zhang, H. Zhao, L. Zhao, Katharina Althaus-Knaurer, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A. Dixit, Geoffrey Donnan, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R. Lees, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Peter Schellinger, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Rüdiger von Kummer, Joanna Wardlaw, Rebecca A. Betensky, Gregoire Boulouis, Raphael A. Carandang, William A. Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L. Ford, John Hallenbeck, Gordon J. Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Michael H. Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H. Schwamm, Eric Searls, Shlee S. Song, Sidney Starkman, Albert J. Yoo, Ramin Zand, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Monash University [Melbourne], National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], University of Heidelberg, Medical Faculty, Massachusetts General Hospital [Boston], University of Melbourne, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Royal Adelaide Hospital [Adelaide Australia], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Flanders Make [Leuven], Flanders Make, University of Newcastle [Australia] (UoN), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vall d'Hebron University Hospital [Barcelona], University of Glasgow, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Ruhr-Universität Bochum [Bochum], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Aarhus University Hospital, Cedars-Sinai Medical Center, Florey Institute of Neuroscience and Mental Health [Melbourne, Victoria, Australia], Austin Health, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], China Medical University Hospital [Taichung], Karolinska Institutet [Stockholm], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Texas at Austin [Austin], Collaborators Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators: Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Florent Boutitie, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bastian Cheng, Bharath Cheripelli, Tae-Hee Cho, Chi-Un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria Del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Martin Ebinger, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Matthias Endres, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Christian Gerloff, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Robin Lemmens, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-Cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K Mueller, Keith W Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Norbert Nighoghossian, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Peter Ringleb, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Vincent Thijs, Götz Thomalla, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Mayumi Fukuda-Doi, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Manabu Inoue, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Masatoshi Koga, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Kaori Miwa, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Kazunori Toyoda, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Haruko Yamamoto, Keizo Yasui, Toshiro Yonehara, Sohei Yoshimura, Shinichi Yoshimura, K Aarnio, F Alemseged, C Anderson, T Ang, M L Archer, J Attia, P Bailey, A Balabanski, A Barber, P A Barber, J Bernhardt, A Bivard, D Blacker, C F Bladin, A Brodtmann, D Cadilhac, B C V Campbell, L Carey, S Celestino, L Chan, W H Chang, A ChangI, C H Chen, C-I Chen, H F Chen, T C Chen, W H Chen, Y Y Chen, C A Cheng, E Cheong, Y W Chiou, P M Choi, H J Chu, C S Chuang, T C Chung, L Churilov, B Clissold, A Connelly, S Coote, B Coulton, E Cowley, J Cranefield, S Curtze, C D'Este, S M Davis, S Day, P M Desmond, H M Dewey, C Ding, G A Donnan, R Drew, S Eirola, D Field, T Frost, C Garcia-Esperon, K George, R Gerraty, R Grimley, Y C Guo, G Hankey, J Harvey, S C Ho, K Hogan, D Howells, P M Hsiao, C H Hsu, C T Hsu, C-S Hsu, J P Hsu, Y D Hsu, Y T Hsu, C J Hu, C C Huang, H Y Huang, M Y Huang, S C Huang, W S Huang, D Jackson, J S Jeng, S K Jiang, L Kaauwai, O Kasari, J King, T J Kleinig, M Koivu, J Kolbe, M Krause, C W Kuan, W L Kung, C Kyndt, C L Lau, A Lee, C Y Lee, J T Lee, Y Lee, Y C Lee, C Levi, C R Levi, L M Lien, J C Lim, C C Lin, C H Lin, C M Lin, D Lin, C H Liu, J Liu, Y C Lo, P S Loh, E Low, C H Lu, C J Lu, M K Lu, J Ly, H Ma, L Macaulay, R Macdonnell, E Mackey, M Macleod, J Mahadevan, V Maxwell, R McCoy, A McDonald, S McModie, A Meretoja, S Mishra, P J Mitchell, F Miteff, A Moore, C Muller, F Ng, F C Ng, J-L Ng, W O'Brian, V O'Collins, T J Oxley, M W Parsons, S Patel, G S Peng, L Pesavento, T Phan, E Rodrigues, Z Ross, A Sabet, M Sallaberger, P Salvaris, D Shah, G Sharma, G Sibolt, M Simpson, S Singhal, B Snow, N Spratt, R Stark, J Sturm, M C Sun, Y Sun, P S Sung, Y F Sung, M Suzuki, M Tan, S C Tang, T Tatlisumak, V Thijs, M Tiainen, C H Tsai, C K Tsai, C L Tsai, H T Tsai, L K Tsai, C H Tseng, L T Tseng, J Tsoleridis, H Tu, H T-H Tu, W Vallat, J Virta, W C Wang, Y T Wang, M Waters, L Weir, T Wijeratne, C Williams, W Wilson, A A Wong, K Wong, T Y Wu, Y H Wu, B Yan, F C Yang, Y W Yang, N Yassi, H L Yeh, J H Yeh, S J Yeh, C H Yen, D Young, C L Ysai, W W Zhang, H Zhao, L Zhao, Katharina Althaus-Knaurer, Martin Bendszus, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A Dixit, Geoffrey Donnan, Rainer Dziewas, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Werner Hacke, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R Lees, Didier Leys, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Catherine Oppenheim, Sven Poli, Peter Ringleb, Peter Schellinger, Stefan Schwab, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Danilo Toni, Roland Veltkamp, Rüdiger von Kummer, Nils Wahlgren, Joanna Wardlaw, Rebecca A Betensky, Gregoire Boulouis, Raphael A Carandang, William A Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L Ford, John Hallenbeck, Gordon J Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Arne Lauer, Michael H Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H Schwamm, Eric Searls, Shlee S Song, Sidney Starkman, Steven Warach, Ona Wu, Albert J Yoo, Ramin Zand, University of Newcastle [Callaghan, Australia] (UoN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CarMeN, laboratoire, Yperzeele, Laetitia, Evaluation of Unknown Onset Stroke Thrombolysis trials (EOS) investigators, UCL - SSS/IONS - Institute of NeuroScience, UCL - (MGD) Service de neurologie, Supporting clinical sciences, UZB Other, Physical Medicine and Rehabilitation, Clinical sciences, Neuroprotection & Neuromodulation, Radiology and Nuclear Medicine, ANS - Neurovascular Disorders, Neurology, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Center of Experimental and Molecular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation
Subjects: medicine.medical_treatment, [SDV]Life Sciences [q-bio], Ischemic Stroke/*diagnostic imaging/*drug therapy, Tomography, X-Ray Computed/methods, Fibrinolytic Agents/adverse effects/*therapeutic use, 030204 cardiovascular system & hematology, Ischemic Stroke/diagnostic imaging, surgery, 0302 clinical medicine, Modified Rankin Scale, 030212 general & internal medicine, 10. No inequality, Infusions, Intravenous, Stroke, Tomography, Time-to-Treatment, General Medicine, Thrombolysis, X-Ray Computed/methods, Tissue Plasminogen Activator/adverse effects, 3. Good health, [SDV] Life Sciences [q-bio], Diffusion Magnetic Resonance Imaging/methods, Treatment Outcome, Meta-analysis, Tissue Plasminogen Activator, Intravenous, medicine.medical_specialty, Infusions, Intravenous thrombolysis, Neuroimaging, Neuroscience(all), Placebo, Tissue Plasminogen Activator/adverse effects/*therapeutic use, 03 medical and health sciences, Fibrinolytic Agents, Internal medicine, medicine, Humans, ddc:610, Ischemic Stroke, business.industry, neurology, Fibrinolytic Agents/adverse effects, Odds ratio, Recovery of Function, medicine.disease, Clinical research, Diffusion Magnetic Resonance Imaging, Human medicine, business, Tomography, X-Ray Computed, Fibrinolytic agent
Abstract: International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.
Published: 2020

31. Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial

Author: Albert C Ludolph, Joachim Schuster, Johannes Dorst, Luc Dupuis, Jens Dreyhaupt, Jochen H Weishaupt, Jan Kassubek, Ulrike Weiland, Susanne Petri, Thomas Meyer, Julian Grosskreutz, Berthold Schrank, Matthias Boentert, Alexander Emmer, Andreas Hermann, Daniel Zeller, Johannes Prudlo, Andrea S Winkler, Torsten Grehl, Michael T Heneka, Siw Wollebæk Johannesen, Bettina Göricke, Andreas Funke, Dagmar Kettemann, Robert Meyer, Kai Gruhn, Peter Schwenkreis, Philipp Stude, Delia Kurzwelly, Alexander Storch, Nicole Richter, Tobias Frank, Katharina Hein, Frank Hanisch, Dagmar Hanke, Torsten Kraya, Andreas Posa, Martina Romanakova, Susanne Schilling, Susanne Abdulla, Sebastian Böselt, Claas Janssen, Imken Lange, Xenia Kobeleva, Sonja Körner, Katja Kollewe, Alma Osmanovic, Nicole Scharn, Klaus J Rath, Christiane Dahms, Anne Gunkel, Bianka Heiling, Thomas Ringer, Uta Smesny, Sarah Baumeister, Achim Berthele, Sarah Bublitz, Esra Akova-Öztürk, Bianca Stubbe-Dräger, Alexandra Rahmann, Charlotte Young, Peter Young, Dobri Baldaranov, Ulrich Bogdahn, Andrei Khomenko, Wilhelm Schulte-Mattler, Christina Stadler, Susanne Husung, Simone Tesar, Nigar Dargah-Zaden, Christina Last, Eva Langer, Ann-Sophie Lauenstein, Eckard Lensch, Carolyn Mc Farlane, Heike Fischer-Brasse, Klara Orbán, Bertold Schrank, Sonja Schürger, Stephan Klebe, Peter Kraft, Thomas Musacchio, Carola Seiler, University of Ulm (UUlm), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hannover Medical School [Hannover] (MHH), Humboldt-Universität zu Berlin, Jena University Hospital [Jena], DKD Helios Klinik Wiesbaden [Wiesbaden, Germany] (DKD HELIOS Medical Center), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Martin-Luther-University Halle-Wittenberg, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), University of Würzburg = Universität Würzburg, University of Rostock, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Ruhr-Universität Bochum [Bochum], University of Bonn, University of Regensburg, University Medical Center Göttingen (UMG), RAS-ALS Study Group: Andreas Funke, Dagmar Kettemann, Robert Meyer, Thomas Meyer, Torsten Grehl, Kai Gruhn, Peter Schwenkreis, Philipp Stude, Michael T Heneka, Delia Kurzwelly, Andreas Hermann, Alexander Storch, Nicole Richter, Tobias Frank, Bettina Göricke, Katharina Hein, Alexander Emmer, Frank Hanisch, Dagmar Hanke, Torsten Kraya, Andreas Posa, Martina Romanakova, Susanne Schilling, Susanne Abdulla, Sebastian Böselt, Dagmar Hanke, Claas Janssen, Imken Lange, Xenia Kobeleva, Sonja Körner, Katja Kollewe, Alma Osmanovic, Susanne Petri, Nicole Scharn, Klaus J Rath, Christiane Dahms, Julian Grosskreutz, Anne Gunkel, Bianka Heiling, Thomas Ringer, Uta Smesny, Sarah Baumeister, Achim Berthele, Sarah Bublitz, Andrea S Winkler, Esra Akova-Öztürk, Matthias Boentert, Bianca Stubbe-Dräger, Alexandra Rahmann, Charlotte Young, Peter Young, Dobri Baldaranov, Ulrich Bogdahn, Siw Wollebæk Johannesen, Andrei Khomenko, Wilhelm Schulte-Mattler, Christina Stadler, Susanne Husung, Johannes Prudlo, Simone Tesar, Nigar Dargah-Zaden, Christina Last, Eva Langer, Albert C Ludolph, Jochen H Weishaupt, Ulrike Weiland, Ann-Sophie Lauenstein, Eckard Lensch, Carolyn Mc Farlane, Heike Fischer-Brasse, Klara Orbán, Bertold Schrank, Sonja Schürger, Stephan Klebe, Peter Kraft, Thomas Musacchio, Carola Seiler, Daniel Zeller., Technical University of Munich (TUM), Dieterle, Stéphane, Humboldt University Of Berlin, and Klebe, Stephan (Beitragende*r)
Subjects: Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Vital Capacity, Medizin, Body Mass Index, chemistry.chemical_compound, MESH: Riluzole, 0302 clinical medicine, Clinical endpoint, Medicine, MESH: Double-Blind Method, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, MESH: Treatment Outcome, MESH: Aged, education.field_of_study, Riluzole, MESH: Middle Aged, Hazard ratio, MESH: Neuroprotective Agents, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Neuroprotective Agents, Treatment Outcome, Indans, Disease Progression, Female, MESH: Disease Progression, medicine.drug, medicine.medical_specialty, Population, Placebo, MESH: Body Mass Index, 03 medical and health sciences, Double-Blind Method, Internal medicine, Humans, education, Aged, Retrospective Studies, Rasagiline, MESH: Humans, business.industry, Amyotrophic Lateral Sclerosis, MESH: Retrospective Studies, MESH: Vital Capacity, medicine.disease, MESH: Indans, MESH: Male, Clinical trial, 030104 developmental biology, chemistry, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Background: Rasagiline, a monoamine oxidase B inhibitor with neuroprotective potential in Parkinson's disease, has shown a disease-modifying effect in the SOD1-Gly93Ala low-expressing mouse model of amyotrophic lateral sclerosis, both alone and in combination with riluzole. We sought to test whether or not rasagiline 1 mg/day can prolong survival in patients with amyotrophic lateral sclerosis also receiving riluzole.Methods: Patients with possible, probable, or definite amyotrophic lateral sclerosis were enrolled to our randomised, placebo-controlled, parallel-group, double-blind, phase 2 trial from 15 German network for motor neuron diseases (MND-NET) centres (university hospitals or clinics). Eligible patients were aged at least 18 years, had onset of progressive weakness within the 36 months before the study, had disease duration of more than 6 months and less than 3 years, and had a best-sitting slow vital capacity of at least 50%. After a 4-week screening period, eligible patients were randomly assigned (1:1) to receive either rasagiline (1 mg/day) or placebo in addition to riluzole (100 mg/day), after stratification for site of onset (bulbar or spinal) and study centre. Patients and all personnel assessing outcome parameters were masked to treatment allocation. Patients were followed up 2, 6, 12, and 18 months after randomisation. The primary endpoint was survival time, defined as the time to death or time to study cutoff date (ie, the last patient's last visit plus 14 days). Analyses of primary outcome and safety measures were done in all patients who received at least one dose of trial treatment (intention-to-treat population). The trial is registered with ClinicalTrials.gov, number NCT01879241.Findings: Between July 2, 2013, and Nov 11, 2014, 273 patients were screened for eligibility, and 252 patients were randomly assigned to receive rasagiline (n=127) or placebo (n=125). 126 patients taking rasagiline and 125 taking placebo were included in the intention-to-treat analysis. For the primary outcome, the survival probability at the end of the study was 0·43 (95% CI 0·25-0·59) in the rasagiline group (n=126) and 0·53 (0·43-0·62) in the placebo group (n=125). The estimated effect size (hazard ratio) was 0·91 (one-sided 97·5% CI -infinity to 1·34; p=0·31). Rasagiline was well tolerated, and most adverse events were due to amyotrophic lateral sclerosis disease progression rather than treatment; the most frequent of these were dysphagia (32 [25%] taking rasagiline vs 24 [19%] taking placebo) and respiratory failure (25 [20%] vs 31 [25%]). Frequency of adverse events were comparable between both groups.Interpretation: Rasagiline was safe in patients with amyotrophic lateral sclerosis. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised greater than 0·5 points per month at baseline. This should be confirmed in another clinical trial.Funding: Teva Pharmaceutical Industries.
Published: 2018

32. Clinical validation, implementation, and reporting of polygenic risk scores for common diseases

Author: Marcie A. Steeves, Prathik K. Vijay Kumar, Shruti Parpattedar, Ashley Antwi, Robert C. Green, Charles A. Brunette, Limin Hao, Manish Gala, Matthew S. Lebo, Elizabeth Hynes, Peter Kraft, Steven Lubitz, Christopher Koch, Morgan Danowski, Wanfeng Yu, Jason L. Vassy, Gabriel Berriz, Pradeep Natajaran, Anna C. F. Lewis, and Natalie Jones
Subjects: business.industry, Medicine, Polygenic risk score, business, Clinical psychology
Abstract: Implementation of polygenic risk scores (PRS) may improve disease prevention and management but requires the construction and validation of clinical assays, interpretation, and reporting pipelines. We developed a clinical genotype array-based assay for published PRS for 6 common diseases. First, we calculated PRS for 36,423 Mass General Brigham Biobank (MGBB) participants. Finding significant variation in the PRS distributions by race, we implemented adjustment for population structure with ancestry-informative principal components. We replicated published thresholds for odds ratio (OR)>2 in MGBB overall [ranging from 1.75 (1.57, 1.95) for Type 2 diabetes to 2.38 (2.07, 2.73) for breast cancer]. After confirming the high performance and robustness of the pipeline for use as a clinical assay, we analyzed the first 141 prospective samples from the Genomic Medicine at VA Study; frequency of PRS corresponding to published OR>2 ranged from 5/141 (3.6%) for colorectal cancer to 8/48 (16.7%) for breast cancer. Our development of a clinical PRS assay for multiple conditions illustrates the generalizability of this process and necessary technical and reporting decisions for meaningful clinical PRS implementation.
Published: 2021

33. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021

34. Obesity, adiposity, and risk of symptomatic gallstone disease according to genetic susceptibility

Author: Kana Wu, Edward Giovannucci, Junghyun Lim, Mingyang Song, Amit Joshi, Constance Turman, Andrew T. Chan, Peter Kraft, Janine Wirth, and Manol Jovani
Subjects: Male, medicine.medical_specialty, Waist, Gallstones, Article, Body Mass Index, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Obesity, Prospective Studies, Adiposity, Hepatology, business.industry, Weight change, Gastroenterology, Absolute risk reduction, Odds ratio, Anthropometry, medicine.disease, Nurses' Health Study, Female, business, Body mass index, Follow-Up Studies
Abstract: BACKGROUND & AIMS: Adiposity has been consistently associated with gallstone disease risk. We aimed to characterize associations of anthropometric measures (body mass index [BMI], recent weight change, long-term weight change, waist circumference, and waist-to-hip ratio) with symptomatic gallstone disease according to strata of gallstone disease polygenic risk score (PRS). METHODS: We conducted analysis among 34,626 participants with available genome-wide genetic data within three large, prospective, US cohorts – Nurses’ Health Study (NHS), Health Professionals Follow-up Study, and NHS II. We characterized joint associations of PRS and anthropometric measures and tested for interactions on the relative and absolute risk scales. RESULTS: Women in the highest BMI and PRS categories (BMI ≥ 30 kg/m(2) and PRS ≥ 1 SD above mean) had odds ratio (OR) for gallstone disease of 5.55 (95% CI, 5.29–5.81) compared with those in the lowest BMI and PRS categories (BMI < 25 kg/m(2) and PRS < 1 SD below mean). The corresponding OR among men was 1.65 (95% CI, 1.02–2.29). Associations for BMI did not vary within strata of PRS on the relative risk scale. On the absolute risk scale, the incidence rate difference between obese and normal-weight individuals was 1086/100,000 PYs within the highest PRS category, compared to 666/100,000 PYs in the lowest PRS category, with strong evidence for interaction with the ABCG8 locus. CONCLUSIONS: While maintenance of a healthy body weight reduces gallstone disease risk among all individuals, risk reduction is higher among the subset with greater genetic susceptibility to gallstone disease.
Published: 2021

35. Prediagnostic Leukocyte Telomere Length and Pancreatic Cancer Survival

Author: Brian M. Wolpin, Vicente Morales-Oyarvide, Jonathan A. Nowak, Peter Kraft, Thomas E. Rohan, Meir J. Stampfer, Kimmie Ng, Howard D. Sesso, Immaculata De Vivo, J. Michael Gaziano, Tsuyoshi Hamada, Chen Yuan, Ana Babic, Mingfeng Zhang, Ying Bao, JoAnn E. Manson, Barbara B. Cochrane, Shuji Ogino, Edward Giovannucci, Laufey T. Amundadottir, Charles S. Fuchs, and Natalia Khalaf
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Single-nucleotide polymorphism, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Pancreatic cancer, Internal medicine, Leukocytes, medicine, Humans, Telomerase reverse transcriptase, Prospective Studies, Prospective cohort study, Aged, business.industry, Proportional hazards model, Hazard ratio, Middle Aged, Telomere, medicine.disease, Survival Analysis, Pancreatic Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, business
Abstract: Background: Leukocyte telomere length has been associated with risk of subsequent pancreatic cancer. Few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival. Methods: We prospectively examined the association of prediagnostic leukocyte telomere length with overall survival (OS) time among 423 participants diagnosed with pancreatic adenocarcinoma between 1984 and 2008 within the Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, and Women's Health Initiative. We measured prediagnostic leukocyte telomere length in banked blood samples using quantitative PCR. Cox proportional hazards models were used to estimate HRs for OS with adjustment for potential confounders. We also evaluated 10 SNPs at the telomerase reverse transcriptase locus. Results: Shorter prediagnostic leukocyte telomere length was associated with reduced OS among patients with pancreatic cancer (Ptrend = 0.04). The multivariable-adjusted HR for OS comparing the lowest with highest quintiles of leukocyte telomere length was 1.39 (95% confidence interval, 1.01–1.93), corresponding to a 3-month difference in median OS time. In an analysis excluding cases with blood collected within 2 years of cancer diagnosis, the association was moderately stronger (HR, 1.55; 95% confidence interval, 1.09–2.21; comparing the lowest with highest quintiles; Ptrend = 0.01). No prognostic association or effect modification for the prognostic association of prediagnostic leukocyte telomere length was noted in relation to the studied SNPs. Conclusions: Prediagnostic leukocyte telomere length was associated with pancreatic cancer survival. Impact: Prediagnostic leukocyte telomere length can be a prognostic biomarker in pancreatic cancer.
Published: 2019

36. Loss of Orai2-Mediated Capacitative Ca2+ Entry Is Neuroprotective in Acute Ischemic Stroke

Author: Michael K. Schuhmann, Antonia Post, Christoph Kleinschnitz, Vanessa Klaus, Marlen Höhn, Sandy Popp, Guido Stoll, Bernhard Nieswandt, Sven G. Meuth, David Stegner, Klaus-Peter Lesch, Sebastian Hofmann, Peter Kraft, Robert Kraft, Attila Braun, Michael Popp, Alexander M. Herrmann, Psychiatrie & Neuropsychologie, and RS: MHeNs - R3 - Neuroscience
Subjects: medicine.medical_specialty, STIM2, Ischemia, chemistry.chemical_element, neurons, Calcium, Neuroprotection, Calcium in biology, 03 medical and health sciences, RETICULUM CALCIUM SENSORS, 0302 clinical medicine, Internal medicine, medicine, Stroke, 030304 developmental biology, Advanced and Specialized Nursing, RELEASE, 0303 health sciences, calcium, CHANNELS, business.industry, ORAI1, MOLECULAR-MECHANISMS, Calcium channel, medicine.disease, reperfusion, ENDOVASCULAR THROMBECTOMY, cell death, GLUCOSE DEPRIVATION, chemistry, Cardiology, neuroprotection, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, MAST-CELL ACTIVATION, STORE
Abstract: Background and Purpose— Ischemic stroke is one of the leading causes of disability and death. The principal goal of acute stroke treatment is the recanalization of the occluded cerebral arteries, which is, however, only effective in a very narrow time window. Therefore, neuroprotective treatments that can be combined with recanalization strategies are needed. Calcium overload is one of the major triggers of neuronal cell death. We have previously shown that capacitative Ca 2+ entry, which is triggered by the depletion of intracellular calcium stores, contributes to ischemia-induced calcium influx in neurons, but the responsible Ca 2+ channel is not known. Methods— Here, we have generated mice lacking the calcium channel subunit Orai2 and analyzed them in experimental stroke. Results— Orai2-deficient mice were protected from ischemic neuronal death both during acute ischemia under vessel occlusion and during ischemia/reperfusion upon successful recanalization. Calcium signals induced by calcium store depletion or oxygen/glucose deprivation were significantly diminished in Orai2-deficient neurons demonstrating that Orai2 is a central mediator of neuronal capacitative Ca 2+ entry and is involved in calcium overload during ischemia. Conclusions— Our experimental data identify Orai2 as an attractive target for pharmaceutical intervention in acute stroke.
Published: 2019

37. Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies

Author: Mingyang Song, Dong Hang, Xiaosheng He, Kana Wu, Zhibin Hu, Ulrike Peters, Amit Joshi, Edward Giovannucci, Manish Gala, Manol Jovani, Stephanie A. Bien, Shuji Ogino, Peter Kraft, Hongbing Shen, Andrew T. Chan, Constance Turman, and Yi Lin
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, business.industry, Colorectal cancer, fungi, Single-nucleotide polymorphism, Genome-wide association study, General Medicine, Odds ratio, medicine.disease, Confidence interval, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, business, Prospective cohort study, Genetic association, Cohort study
Abstract: Background Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. Methods Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. Results During 18–20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). Conclusions Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.
Published: 2019

38. Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage

Author: Miriam Bauer, Gereon R. Fink, Sebastian Stösser, Gerhard F. Hamann, Albrecht Guenther, Georg Hagemann, Armin J. Grau, Hansjörg Bäzner, Florian Rakers, Frederick Palm, Anna Lena Fisse, Joji B. Kuramatsu, Joachim Röther, Timolaos Rizos, Martin Nueckel, Markus Horn, Manuel Hagen, Arnd Dörfler, Maximilian I. Sprügel, Hauke Schneider, Matthias Endres, Johannes C. Wöhrle, Peter Michels, Hagen B. Huttner, Christian Urbanek, Peter D. Schellinger, Fahid Alshammari, Frank Erbguth, Dirk Bahner, Jan C. Purrucker, Stefan T. Gerner, Michael P. Schwarz, Otto W. Witte, Jochen A. Sembill, Jörg Glahn, Hermann Neugebauer, Karl Georg Haeusler, Stefan Schwab, Johannes Schurig, Joseph Classen, Sebastian S. Roeder, Henning Schwert, Hannes Lücking, Peter A. Ringleb, Dominik Michalski, Albert C. Ludolph, Sigrid Wöpking, Jens Volkmann, Sarah Zweynert, Jan Sobesky, Wolfgang Muellges, Heinz Reichmann, Ulrich J. Knappe, Gernot Reimann, Peter Kraft, Peter Vajkoczy, Christian Dohmen, Jens Minnerup, Anna-Lena Schubert, and Henning Stetefeld
Subjects: Male, medicine.medical_specialty, medicine.drug_class, 030204 cardiovascular system & hematology, Rate ratio, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, Internal medicine, medicine, Humans, Prospective Studies, cardiovascular diseases, Stroke, Aged, Cerebral Hemorrhage, Retrospective Studies, Aged, 80 and over, Heparin, business.industry, Retrospective cohort study, Venous Thromboembolism, Vitamin K antagonist, medicine.disease, nervous system diseases, Psychiatry and Mental health, Immunohistochemistry, Female, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study, medicine.drug
Abstract: ObjectiveTo determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH.MethodsRetrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC.ResultsIHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04–1.93) vs non-LDSH: 1.32 (0.33–3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38–4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4–6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume ConclusionsHeparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.
Published: 2019

39. Family history of cancer, Ashkenazi Jewish ancestry, and pancreatic cancer risk

Author: Brian M. Wolpin, Douglas A. Rubinson, Kimberly Perez, Edward Giovannucci, Jonathan A. Nowak, Vicente Morales-Oyarvide, Meir J. Stampfer, Tsuyoshi Hamada, Natalia Khalaf, Charles S. Fuchs, Matthew B. Yurgelun, Peter Kraft, Ana Babic, Chen Yuan, Kimmie Ng, Marios Giannakis, and Shuji Ogino
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Breast Neoplasms, Malignancy, Article, 03 medical and health sciences, Cancer epidemiology, 0302 clinical medicine, Breast cancer, Internal medicine, Pancreatic cancer, medicine, Humans, Family history, Medical History Taking, Aged, Proportional hazards model, business.industry, Hazard ratio, Cancer, Middle Aged, medicine.disease, 3. Good health, Pancreatic Neoplasms, Risk factors, Jews, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, business
Abstract: Background Individuals with a family history of cancer may be at increased risk of pancreatic cancer. Ashkenazi Jewish (AJ) individuals carry increased risk for pancreatic cancer and other cancer types. Methods We examined the association between family history of cancer, AJ heritage, and incident pancreatic cancer in 49 410 male participants of the prospective Health Professionals Follow-up Study. Hazard ratios (HRs) were estimated using multivariable-adjusted Cox proportional hazards models. Results During 1.1 million person-years (1986–2016), 452 participants developed pancreatic cancer. Increased risk of pancreatic cancer was observed in individuals with a family history of pancreatic (HR, 2.79; 95% confidence interval [CI], 1.28–6.07) or breast cancer (HR, 1.40; 95% CI, 1.01–1.94). There was a trend towards higher risk of pancreatic cancer in relation to a family history of colorectal cancer (HR, 1.21; 95% CI, 0.95–1.55) or AJ heritage (HR, 1.29; 95% CI, 0.94–1.77). The risk was highly elevated among AJ men with a family history of breast or colorectal cancer (HR, 2.61 [95% CI, 1.41–4.82] and 1.92 [95% CI, 1.05–3.49], respectively). Conclusion Family history of pancreatic cancer was associated with increased risk of this malignancy. Family history of breast or colorectal cancer was associated with the increased risk among AJ men.
Published: 2019

40. Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Author: Sara Benlloch, Roger L. Milne, Azad Hassan Abdul Razack, José Manuel Ruiz-Dominguez, Steven Joniau, Maria P. Silva, Martin Andreas Røder, Constance Turman, Anne-Maree Haynes, Jin Ling, Robert N. Hoover, Jong Y. Park, Johanna Schleutker, Brian E. Henderson, Amy Hutchinson, Stephanie J. Weinstein, Manolis Kogevinas, Melissa Papargiris, Monique J. Roobol, Gill Barnett, Wayne D. Tilley, Elio Riboli, Samantha E.T. Larkin, Melissa C. Southey, Michelle Guy, Jeanette T. Bensen, Henrik Grönberg, Fredrick R. Schumacher, Karina Dalsgaard Sørensen, Davor Lessel, Carin Cavalli-Bjoerkman, Tomislav Kuliš, Barry S. Rosenstein, Paula Kujala, Michael Davis, Andrzej M. Kierzek, Antonio Finelli, Gerald L. Andriole, Leire Moya, Antonio Gómez-Caamaño, Demetrius Albanes, Jianming Guo, Lisa F. Newcomb, Koveela Govindasami, Ji Lin, Gert De Meerleer, Manuel Luedeke, Richard M. Martin, Zeljko Kastelan, Kay-Tee Khaw, Ruth C. Travis, Rebecca Elliott, Alexandre R. Zlotta, Xin Guo, Kirsi Talala, Yangling Zhang, Lorelei A. Mucci, Marie Sanchez, Paul D.P. Pharoah, Mariona Bustamante, Peter Klarskov, Aleksandrina Vlahova, Srilakshmi Srinivasan, Aik T. Ong, David E. Neal, Sylvie Cénée, Esther M. John, Sonja I. Berndt, Kan Wang, Peter Iversen, Harry Ostrer, Michael Borre, Freddie C. Hamdy, Christopher A. Haiman, Ji Wu, Florence Menegaux, Jacek Marzec, Sara S. Strom, David P. Dearnaley, Jyotsna Batra, Piet Ost, Mariana C. Stern, Kim De Ruyck, Hyun Soo Park, Trina Yeadon, Elenko Popov, Yudong Wu, Svetlana Christova, Thomas Van den Broeck, Loic Le Marchand, Daniel J. Schaid, Babu Zachariah, Sune F. Nielsen, Mary-Anne Kedda, Judith A. Clements, Olivier Cussenot, Robert Szulkin, Shiro Saito, Andrew Evans, Douglas F. Easton, Gemma Castaño-Vinyals, Steve Hazel, Thérèse Truong, Guomin Wang, Katarina Cuk, Ants Toi, Rosalind A. Eeles, Darina Kachakova, Lourdes Mengual, Lisa G. Horvath, Yuan Chun Ding, Catharine M L West, Ana Carballo, Suzanne K. Chambers, Aurelie Vogt, Angela Cox, Daniel W. Lin, Dominika Wokołorczyk, Manuela Gago-Dominguez, Stephen J. Chanock, Federico Canzian, Aleksandra Klim, Tokhir Dadaev, Kathleen Herkommer, Tihomir Dikov, Lovise Maehle, Jasmine Lim, Janet L. Stanford, Martin Eklund, Guido Jenster, Soo-Hwang Teo, Teemu J. Murtola, Torben F. Ørntoft, Stella Koutros, Christa Stegmaier, Sofia Maia, Mitchell J. Machiela, Lisa A. Cannon-Albright, Clare Berry, Pamela Saunders, Lluís Cecchini, Jeri Kim, Radka Kaneva, Brigitte Trétarre, Anne George, Meir J. Stampfer, Marija Gamulin, Meng H. Tan, Angela Morgan, Jenny L Donovan, Graham G. Giles, Geraldine Cancel-Tassin, Neil Fleshner, Shannon K. McDonnell, Hardeep Ranu, Naomi Livni, Kimmo Taari, Sarah L. Kerns, Csilla Sipeky, Alicja Wolk, Edward Giovannucci, Ninghan Feng, Marta Cardoso, Jan-Erik Johansson, Catherine M. Tangen, Guangwen Cao, Adam S. Kibel, Robert J. MacInnis, Bernd Holleczek, Sarah J Lewis, Bo Zhou, Michael Broms, Maria Elena Martinez, Renea A. Taylor, Børge G. Nordestgaard, Fritz H. Schröder, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jie Li, Lori S. Tillmans, Ana Vega, Patricia Calvo, Christopher J. Logothetis, David V. Conti, Miguel Aguado, Inés Gómez-Acebo, Tobias Nordström, Meiling Li, Elaine A. Ostrander, C.H. Bangma, Cyril Fisher, Joanne F. Aitken, Matthew Parliament, Gail P. Risbridger, John L. Hopper, Takashi Imai, Belynda Hicks, Victoria L. Stevens, Cezary Cybulski, G Marsden, Brian D. Carter, Vanessa M. Hayes, Nawaid Usmani, Vanio Mitev, Shan-Chao Zhao, Margaret Cook, Milan S. Geybels, Phyllis J. Goodman, Mark N. Brook, Nora Pashayan, Timothy J. Key, Yongwei Yu, Xavier Rebillard, David J. Hunter, Laura Fachal, Javier Llorca, Afshan Siddiq, Claire Aukim-Hastie, Trinidad Dierssen-Sotos, Walther Vogel, Angel Carracedo, Laura E. Beane Freeman, Julio M. Pow-Sang, Hardev Pandha, Robert A. Gardiner, Shaun M. Riska, Yong-Jie Lu, Zan Sun, Ramón Lobato-Busto, Ami Karlsson, Hongwei Zhang, Guoping Ren, Jing Ma, Huihai Wu, Søren M. Bentzen, John Pedersen, Claire Mulot, Girish S. Kulkarni, Jan Lubinski, Antonio Alcaraz, Jose E. Castelao, Athene Lane, Rasmus Bisbjerg, Thomas A. Sellers, Robert J. Hamilton, Jianfeng Xu, Sofie De Langhe, Artitaya Lophatananon, Maren Weisher, Agnieszka Michael, Yves Akoli Koudou, Niclas Håkansson, Alison M. Dunning, Hubert Thierens, Matthew L. Freedman, Kenneth Muir, Ian M. Thompson, Ian Whitmore, Susan L. Neuhausen, Chavdar Slavov, Wojciech Kluzniak, Laurence N. Kolonel, Lisa M. Butler, Teuvo L.J. Tammela, Alison Thwaites, Theodorus van der Kwast, Liesel M. FitzGerald, Thomas J. Schnoeller, Hermann Brenner, Christiane Maier, Amanda B. Spurdle, Jan Adolfsson, Atanaska Mitkova, Peter Kraft, Paula Peleteiro, Pär Stattin, Xin Sheng, Paul D. Brown, Ron H.N. van Schaik, Zsofia Kote-Jarai, Susan M. Gapstur, Paul A. Townsend, Edward J. Saunders, Bettina F. Drake, Stephen N. Thibodeau, Fredrik Wiklund, Paula Paulo, Esther Gracia-Lavedan, Xueying Mao, Marco Matejcic, Neil G. Burnet, A. L. Eckert, Manuel R. Teixeira, Sara Lindström, Weiyang He, Hui-Yi Lin, Suzanne Kolb, Linda Steele, Philipp Bohnert, Anssi Auvinen, Eli Marie Grindedal, Frank Claessens, and Kathryn L. Penney
Subjects: Urologic Diseases, 0301 basic medicine, Oncology, medicine.medical_specialty, Science, MEDLINE, General Physics and Astronomy, 02 engineering and technology, General Biochemistry, Genetics and Molecular Biology, Germline, 03 medical and health sciences, Internal medicine, medicine, PRACTICAL Consortium, lcsh:Science, Cancer, Prostate cancer risk, Multidisciplinary, business.industry, Prostate Cancer, Published Erratum, General Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, Spelling, 3. Good health, 030104 developmental biology, Variation (linguistics), lcsh:Q, 0210 nano-technology, business
Abstract: The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019

41. Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study

Author: Graham G. Giles, Xia Jiang, Konstantinos K. Tsilidis, Deborah J. Thompson, Meir J. Stampfer, Wei Zheng, Edward Giovannucci, Peter Kraft, Richard M. Martin, Joellen M. Schildkraut, Marc J. Gunter, Kawthar Al-Dabhani, Timothy J. Key, Philip C Haycock, Shaneda N. Warren Andersen, Niki Dimou, Sarah J Lewis, Rosalind A. Eeles, Kenneth Muir, Brandon L. Pierce, and David E. Neal
Subjects: Male, 0301 basic medicine, Oncology, Epidemiology, Prostatic Neoplasms/epidemiology, Receptors, Estrogen/biosynthesis, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Prostate, Medicine, 030212 general & internal medicine, prostate, Breast Neoplasms/epidemiology, 0104 Statistics, Mendelian Randomization Analysis, General Medicine, Middle Aged, Causality, serum vitamin D concentrations, medicine.anatomical_structure, Vitamin D/blood, Female, ICEP, Vitamin, medicine.medical_specialty, PRACTICAL, CRUK, BPC3, CAPS and PEGASUS consortia, Polymorphism, Single Nucleotide, 1117 Public Health and Health Services, 03 medical and health sciences, Breast cancer, Internal medicine, Mendelian randomization, Vitamin D and neurology, Humans, breast, Aged, business.industry, Cancer, medicine.disease, 030104 developmental biology, chemistry, business, malignancy, Genome-Wide Association Study
Abstract: BackgroundObservational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power.MethodsWe aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods.ResultsWe found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97–1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94–1.07), P = 0.99] or ER− [1.02 (0.90–1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93–1.07), P = 0.99] or the advanced subtype [1.02 (0.90–1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy.ConclusionsDespite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.
Published: 2018

42. Description of a Novel Phosphodiesterase (PDE)-3 Inhibitor Protecting Mice From Ischemic Stroke Independent From Platelet Function

Author: Mirko Pham, Christoph Kleinschnitz, Jayathirtha Rao Vaidya, Michael Bieber, Peter Kraft, Julia Volz, Guido Stoll, Bernhard Nieswandt, Michael K. Schuhmann, and Gangasani Jagadeesh Kumar
Subjects: Blood Platelets, Male, Original Contributions, Ischemia, Medizin, Pharmacology, Blood–brain barrier, Phosphodiesterase 3 Inhibitors, Neuroprotection, Brain ischemia, 03 medical and health sciences, Mice, 0302 clinical medicine, Antithrombotic, medicine, magnetic resonance imaging, Animals, 030304 developmental biology, Advanced and Specialized Nursing, brain edema, 0303 health sciences, business.industry, Basic Sciences, Phosphodiesterase, blood-brain barrier, medicine.disease, Clopidogrel, brain ischemia, Cilostazol, Stroke, Disease Models, Animal, medicine.anatomical_structure, cell death, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, neuroprotection, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Supplemental Digital Content is available in the text., Background and Purpose— Acetylsalicylic acid and clopidogrel are the 2 main antithrombotic drugs for secondary prevention in patients with ischemic stroke (IS) without indication for anticoagulation. Because of their limited efficacy and potential side effects, novel antiplatelet agents are urgently needed. Cilostazol, a specific phosphodiesterase (PDE)-3 inhibitor, protected from IS in clinical studies comprising mainly Asian populations. Nevertheless, the detailed mechanistic role of PDE-3 inhibitors in IS pathophysiology is hardly understood. In this project, we analyzed the efficacy and pathophysiologic mechanisms of a novel and only recently described PDE-3 inhibitor (substance V) in a mouse model of focal cerebral ischemia. Methods— Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in 6- to 8-week-old male C57Bl/6 wild-type mice receiving substance V or vehicle 1 hour after ischemia induction. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, as well as the extent of local inflammatory response and cell death, was determined. Results— Inhibition of PDE-3 by pharmacological blockade with substance V significantly reduced infarct volumes and improved neurological outcome on day 1 and 7 after experimental cerebral ischemia. Reduced blood-brain barrier damage, attenuated brain tissue inflammation, and decreased local cell death could be identified as potential mechanisms. PDE-3 inhibitor treatment did neither increase the number of intracerebral hemorrhages nor affect platelet function. Conclusions— The novel PDE-3 inhibitor substance V protected mice from IS independent from platelet function. Pharmaceutical inactivation of PDE-3 might become a promising therapeutic approach to combat IS via inhibition of thromboinflammatory mechanisms and stabilization of the blood-brain barrier.
Published: 2018

43. 76. IMPACT OF ASCERTAINMENT BIAS ON POLYGENIC RISK SCORE ESTIMATES IN HEALTHCARE SETTINGS

Author: Peter Kraft, Tian Ge, Yen-Chen Anne Feng, Yi-Han Sheu, Jordan W. Smoller, Younga H Lee, and Tanayott Thaweethai
Subjects: Pharmacology, Psychiatry and Mental health, Neurology, business.industry, Healthcare settings, Medicine, Pharmacology (medical), Polygenic risk score, Neurology (clinical), business, Biological Psychiatry, Sampling bias, Demography
Published: 2021

44. Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy: Beyond the First-Pass Effect

Author: Fabian Flottmann, Caspar Brekenfeld, Gabriel Broocks, Hannes Leischner, Rosalie McDonough, Tobias D. Faizy, Milani Deb-Chatterji, Anna Alegiani, Götz Thomalla, Anastasios Mpotsaris, Christian H. Nolte, Jens Fiehler, Máté E. Maros, Tobias Boeckh-Behrens, Silke Wunderlich, Martin Wiesmann, Ulrike Ernemann, Till-Karsten Hauser, Eberhard Siebert, Sarah Zweynert, Georg Bohner, Alexander Ludolph, Karl-Heinz Henn, Waltraud Pfeilschifter, Marlis Wagner, Joachim Röther, Bernd Eckert, Jörg Berrouschot, Albrecht Bormann, Christian Gerloff, Elke Hattingen, Gabor Petzold, Sven Thonke, Christopher Bangard, Christoffer Kraemer, Martin Dichgans, Frank Wollenwebe, Lars Kellert, Franziska Dorn, Moriz Herzberg, Marios Psychogios, Jan Liman, Martina Petersen, Florian Stögbauer, Peter Kraft, Mirko Pham, Michael Braun, Gerhard F. Hamann, Andreas Kastrup, Christian Roth, Klaus Gröschel, Timo Uphaus, and Volker Limmroth
Subjects: Male, medicine.medical_specialty, Standard of care, Outcome (game theory), Endovascular therapy, 030218 nuclear medicine & medical imaging, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Occlusion, medicine, Humans, Stroke, Acute ischemic stroke, Aged, Thrombectomy, Advanced and Specialized Nursing, Aged, 80 and over, Cerebral infarction, business.industry, Endovascular Procedures, Recovery of Function, Middle Aged, medicine.disease, Ischemic stroke, Cardiology, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: Background and Purpose: Endovascular therapy is the standard of care in the treatment of acute ischemic stroke due to large-vessel occlusion. Often, more than one retrieval attempt is needed to achieve reperfusion. We aimed to quantify the influence of endovascular therapy on clinical outcome depending on the number of retrievals needed for successful reperfusion in a large multi-center cohort. Methods: For this observational cohort study, 2611 patients from the prospective German Stroke Registry included between June 2015 and April 2018 were analyzed. Patients who received endovascular therapy for acute anterior circulation stroke with known admission National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT Score, final Thrombolysis in Cerebral Infarction score, and number of retrievals were included. Successful reperfusion was defined as a Thrombolysis in Cerebral Infarction score of 2b or 3. The primary outcome was defined as functional independence (modified Rankin Scale score of 0–2) at day 90. Multivariate mixed-effects models were used to adjust for cluster effects of the participating centers and confounders. Results: The inclusion criteria were met by 1225 patients. The odds of good clinical outcome decreased with every retrieval attempt required for successful reperfusion: the first retrieval had the highest odds of good clinical outcome (adjusted odds ratio, 6.45 [95% CI, 4.0–10.4]), followed by the second attempt (adjusted odds ratio, 4.56 [95% CI, 2.7–7.7]), and finally the third (adjusted odds ratio, 3.16 [95% CI, 1.8–5.6]). Conclusions: Successful reperfusion within the first 3 retrieval attempts is associated with improved clinical outcome compared with patients without reperfusion. We conclude that at least 3 retrieval attempts should be performed in endovascular therapy of anterior circulation strokes. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03356392.
Published: 2021

45. Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author: Brian D. Carter, Gert De Meerleer, Michael B. Cook, Paul A. Townsend, Kim De Ruyck, Edward J. Saunders, Christopher A. Haiman, Atushi Takahashi, Sonja I. Berndt, Florence Menegaux, Cezary Cybulski, Barbara Nemesure, Loic Le Marchand, Sune F. Nielsen, Demetrius Albanes, Robert J. Hamilton, Ninghan Feng, Stella Koutros, Stephen J. Chanock, Wei Zheng, Thomas A. Sellers, Rick A. Kittles, Craig C. Teerlink, Stephen N. Thibodeau, Marija Gamulin, Artitaya Lophatananon, Niclas Håkansson, Fredrik Wiklund, Roberta McKean-Cowdin, Yuan Chun Ding, Nora Pashayan, Timothy J. Key, Børge G. Nordestgaard, Shannon K. McDonnell, Jong Y. Park, Laura Fachal, Martin Andreas Røder, Johanna Schleutker, Edward Giovannucci, Anssi Auvinen, Hardev Pandha, Maria Elena Martinez, Mitchell J. Machiela, Gill Barnett, Melissa C. Southey, Graham G. Giles, Barry S. Rosenstein, Stephen Watya, Bernd Holleczek, Pascal Blanchet, Agnieszka Michael, William J. Blot, James L. Mohler, Jack A. Taylor, Sarah L. Kerns, Adam S. Kibel, Piet Ost, Ana Vega, Richard M. Martin, Jennifer J. Hu, Nicholas Mancuso, Yukihide Momozawa, Robert J. MacInnis, Sue A. Ingles, Maureen Sanderson, Kai Uwe Saum, Markus Aly, Robert Szulkin, Davor Lessel, Hermann Brenner, Yves Akoli Koudou, Jan Lubinski, Mina Torres, Anselm Hennis, Eli Marie Grindedal, Csilla Sipeky, Susan L. Neuhausen, Alison M. Dunning, Alicja Wolk, Adam B. Murphy, Brandi Weaver, Mariana C. Stern, Paula Paulo, Stephanie J. Weinstein, Xueying Mao, Tobias Nordström, Neil Fleshner, Tokhir Dadaev, Teuvo L.J. Tammela, Jay H. Fowke, Tomislav Kuliš, Steven Joniau, Yudong Wu, Rosalind A. Eeles, Shan Chao Zhao, Kenneth Muir, Mark N. Brook, Hidewaki Nakagawa, Freddie C. Hamdy, Karina Dalsgaard Sørensen, Linda Steele, Alisha Chou, Dominika Wokołorczyk, Peggy Wan, Martin Eklund, Laurent Brureau, Lisa A. Cannon-Albright, Lilit C. Moss, Daniel J. Schaid, Luc Multigner, Benjamin A. Rybicki, Xin Sheng, Constance Turman, Ron H.N. van Schaik, Radka Kaneva, Zsofia Kote-Jarai, Frank Claessens, Katarina Cuk, Kay-Tee Khaw, Chad D. Huff, Henrik Grönberg, Kathryn L. Penney, Geraldine Cancel-Tassin, Eric A. Klein, Masashi Fujita, Jennifer Cullen, Michael Borre, Jenny L Donovan, Dana C. Crawford, Antonio Gómez-Caamaño, David V. Conti, Manuel Luedeke, Maya Ghoussaini, Janet L. Stanford, Peter Kraft, Ian M. Thompson, Koichi Matsuda, Soo-Hwang Teo, Christopher J. Logothetis, Robin J. Leach, Monique J. Roobol, Manuel R. Teixeira, Jose Esteban Castelao, Sara S. Strom, Vanio Mitev, Stig E. Bojesen, David J. Hunter, Wayne D. Tilley, Jyotsna Batra, Gerald L. Andriole, Christine Neslund-Dudas, Sara Lindström, Guido Jenster, Catherine M. Tangen, William S. Bush, Maren Weischer, Chavdar Slavov, Thomas J. Schnoeller, Javier Llorca, Claire Aukim-Hastie, Nawaid Usmani, Lisa G. Horvath, Daniel W. Lin, Esther M. John, Burcu F. Darst, Milan S. Geybels, Phyllis J. Goodman, Lynne R. Wilkens, Ali Amin Al Olama, Lorelei A. Mucci, Peter Iversen, Christiane Maier, Victoria L. Stevens, Andreia Brandão, Graham Casey, Neil G. Burnet, Ann W. Hsing, Hongwei Zhang, Laura E. Beane Freeman, Susan M. Gapstur, Sara Benlloch, James E. Mensah, Marie-Élise Parent, Jianfeng Xu, Bettina F. Drake, Jeannette T. Bensen, Azad Hassan Abdul Razack, Edward D. Yeboah, David E. Neal, John D. Carpten, Ruth C. Travis, Thomas J. Hoffmann, Thomas Van den Broeck, Jeri Kim, Ali Sahimi, Gemma Castaño-Vinyals, Alexander Lubwama, Leire Moya, Elio Riboli, Douglas F. Easton, Suzanne K. Chambers, Yong-Jie Lu, Melinda C. Aldrich, Manuela Gago-Dominguez, John S. Witte, Matthew Parliament, Gail P. Risbridger, Samantha E.T. Larkin, Lisa F. Newcomb, Fredrick R. Schumacher, Shiv Srivastava, Jasmine Lim, Meir J. Stampfer, Harry Ostrer, Judith A. Clements, Thérèse Truong, Catharine M L West, Zan Sun, Olivier Cussenot, Gyorgy Petrovics, Lovise Maehle, Elizabeth T. H. Fontham, William B. Isaacs, Hui Yi Lin, Rohit Varma, Elaine A. Ostrander, Manolis Kogevinas, Robert N. Hoover, Sandeep Singhal, Antonio Finelli, and Stephen K. Van Den Eeden
Subjects: 0303 health sciences, business.industry, Published Erratum, MEDLINE, Genome-wide association study, Computational biology, Biology, medicine.disease, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Meta-analysis, Genetics, medicine, Susceptibility locus, 06 Biological Sciences, 11 Medical and Health Sciences, Personalized medicine, Genetic risk, business, 030217 neurology & neurosurgery, 030304 developmental biology, Developmental Biology
Abstract: In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.
Published: 2021

46. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author: Timothy H.T. Cheng, V. Wendy Setiawan, Jolanta Lissowska, Kamila Czene, Zhaoming Wang, Linda S. Cook, Shirley Hodgson, Mitul Shah, Matthias W. Beckmann, Douglas F. Easton, Annika Lindblom, Daniel D. Buchanan, Wei Zheng, Constance Turman, Gloria E. Sarto, Susan E. Hankinson, Chu Chen, Joe Dennis, Christine M. Friedenreich, Dylan M. Glubb, Peter Hillemanns, Tracy A. O'Mara, Camilla Krakstad, Yong-Bing Xiang, Arif B. Ekici, Maxine M. Chen, Marta Crous-Bous, Montserrat Garcia-Closas, David Van Den Berg, Amanda Black, Immaculata De Vivo, Roger L. Milne, Geoffrey Otton, Frédéric Amant, Timothy R. Rebbeck, Carlotta Sacerdote, Erling A. Hoivik, Xiao-Ou Shu, Melissa C. Southey, Paul L. Auer, Brooke L. Fridley, Thilo Dörk, Elizabeth G. Holliday, Fredrick R. Schumacher, Loreall Pooler, Daniela Annibali, Mia M. Gaudet, Maggie Gorman, Peter A. Fasching, Matthias Rübner, Hannah P. Yang, Graham G. Giles, Stefan P. Renner, Jirong Long, Ellen L. Goode, Katie A. Ashton, Claire Palles, Emma Tham, Diether Lambrechts, Xin Sheng, Rodney J. Scott, Angela M. Jones, Alexander Hein, Amanda B. Spurdle, Nicolas Wentzensen, David J. Hunter, Rami Nassir, Peter Kraft, Lynn Martin, Christopher A. Haiman, Alison M. Dunning, Stephen J. Chanock, Jone Trovik, Loic Le Marchand, Harvey A. Risch, Tony Proietto, Matthias Dürst, Sean C. Dowdy, Lucy Xia, Miriam Mints, Anthony M. Magliocco, Pik Fang Kho, Herbert Yu, Lingeng Lu, Mark McEvoy, Xiaolin Liang, Louise A. Brinton, Per Hall, Jonathan Tyrer, Ingo B. Runnebaum, Penelope M. Webb, John Attia, Ian Tomlinson, Deborah J. Thompson, Buchanan, Daniel D [0000-0003-2225-6675], Chen, Chu [0000-0003-2267-8050], De Vivo, Immaculata [0000-0002-7185-7402], Dörk, Thilo [0000-0002-9458-0282], Fasching, Peter A [0000-0003-4885-8471], Friedenreich, Christine M [0000-0002-4783-1966], Gaudet, Mia M [0000-0002-6429-4007], Goode, Ellen L [0000-0002-9094-8326], Lu, Lingeng [0000-0001-9871-0809], Sacerdote, Carlotta [0000-0002-8008-5096], Shu, Xiao-Ou [0000-0002-0711-8314], Wang, Zhaoming [0000-0001-7556-3869], Wentzensen, Nicolas [0000-0003-1251-0836], Xiang, Yong-Bing [0000-0002-3840-9915], Yu, Herbert [0000-0003-3950-4815], Spurdle, Amanda B [0000-0003-1337-7897], O'Mara, Tracy A [0000-0002-5436-3232], Apollo - University of Cambridge Repository, ARD - Amsterdam Reproduction and Development, Obstetrics and Gynaecology, and CCA - Imaging and biomarkers
Subjects: Oncology, Cancer Research, Colorectal cancer, Blood lipids, chemistry.chemical_compound, 0302 clinical medicine, HDL cholesterol, Medicine, triglycerides, METABOLIC SYNDROME, 2. Zero hunger, Mendelian Randomization Analysis, ASSOCIATION, 3. Good health, 030220 oncology & carcinogenesis, LDL cholesterol, SERUM-LIPIDS, Female, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Risk, medicine.medical_specialty, endometrial cancer risk, Article, 03 medical and health sciences, INFLAMMATION, Internal medicine, Mendelian randomization, CAUSAL, Humans, Science & Technology, Cholesterol, business.industry, Endometrial cancer, Cholesterol, HDL, Case-control study, Cholesterol, LDL, medicine.disease, Endometrial Neoplasms, BODY-MASS INDEX, LIPOPROTEIN, chemistry, Case-Control Studies, RISK-FACTORS, Metabolic syndrome, business, Genome-Wide Association Study
Abstract: Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P
Published: 2021

47. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Agnes Jager, Christopher A. Haiman, William G. Newman, Georgia Chenevix-Trench, Loic Le Marchand, Tjoung-Won Park-Simon, Eric Hahnen, Peter Kraft, Montserrat Garcia-Closas, Alison M. Dunning, Roger L. Milne, Christine L. Clarke, Wei He, Thomas Brüning, David J. Hunter, Alicja Wolk, Arto Mannermaa, William J. Tapper, Dimitrios Mavroudis, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Annelie Augustinsson, Rob A. E. M. Tollenaar, Stella Koutros, Heiko Becher, Machteld Keupers, Abctb Investigators, Esther M. John, Heli Nevanlinna, Simon S. Cross, Rita K. Schmutzler, Melanie Gündert, Elinor J. Sawyer, Anna Morra, Melissa C. Southey, Robert Luben, Daniele Campa, Hoda Anton-Culver, Hiltrud Brauch, Børge G. Nordestgaard, Wolfgang Janni, Douglas F. Easton, Diether Lambrechts, Marjanka K. Schmidt, Jonathan Beesley, Thilo Dörk, Miriam Dwek, Robert Winqvist, Irene L. Andrulis, Paolo Peterlongo, Manjeet K. Bolla, Manuela Gago-Dominguez, Matthias Ruebner, Nick Orr, Stephen J. Chanock, Paul L. Auer, Michael Lush, Sune F. Nielsen, Amber N Hurson, Alpa V. Patel, Sander Canisius, Vessela N. Kristensen, José A. García-Sáenz, Joe Dennis, Mervi Grip, Sarah Colonna, Tongguang Cheng, Martha S. Linet, Cari M. Kitahara, Annika Lindblom, Anna Jakubowska, Paul D.P. Pharoah, Bernard Peissel, Christopher G. Scott, Maria Elena Martinez, Laure Dossus, Saundra S. Buys, Graham G. Giles, Pascal Guénel, Anthony J. Swerdlow, Allison W. Kurian, Jan Lubinski, Andrew F. Olshan, A. Heather Eliassen, Valerie Rhenius, Jose E. Castelao, Renske Keeman, Diana Eccles, John W.M. Martens, Melissa A. Troester, Sara Margolin, Thomas U. Ahearn, Hedy S. Rennert, Nadege Presneau, Mehdi Manoochehri, Laura E. Beane Freeman, Lauren R. Teras, Jaana M. Hartikainen, Hermann Brenner, Reiner Hoppe, Atocha Romero, Mitul Shah, Peter A. Fasching, Argyrios Ziogas, Matthias W. Beckmann, Ross L. Prentice, James V. Lacey, Harald Surowy, Rulla M. Tamimi, D. Gareth Evans, Celine M. Vachon, Snezhana Smichkoska, Mary B. Daly, Karolina Prajzendanc, Arif B. Ekici, Stig E. Bojesen, Niclas Håkansson, Steven N. Hart, Mikael Eriksson, Maria Escala-Garcia, Taru A. Muranen, Arndt Hartmann, Henrik Flyger, Håkan Olsson, Federico Canzian, Rebecca Roylance, Mary Beth Terry, Jenny Chang-Claude, Andreas Schneeweiss, Angela Cox, Maartje J. Hooning, Anthony Howell, Volker Arndt, Lin Fritschi, Bette J. Caan, Kyriaki Michailidou, Per Hall, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Fergus J. Couch, Gad Rennert, Ute Hamann, Brigitte Rack, Sabine Behrens, Jennifer Stone, Qin Wang, kConFab Investigators, Kamila Czene, John L. Hopper, Audrey Y. Jung, Rudolf Kaaks, Schmidt, Marjanka K. [0000-0002-2228-429X], Apollo - University of Cambridge Repository, Dörk, Thilo [0000-0002-9458-0282], Newman, William G [0000-0002-6382-4678], Romero, Atocha [0000-0002-1634-7397], Stone, Jennifer [0000-0001-5077-0124], Schmidt, Marjanka K [0000-0002-2228-429X], HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and Medical Oncology
Subjects: Oncology, medicine.medical_treatment, LOCI, PROGRESSION, Systemic treatment, SUSCEPTIBILITY, BETA-CATENIN, Germline, SUBTYPES, 0302 clinical medicine, Surgical oncology, TOOL, Medicine, RC254-282, 0303 health sciences, Tumor biology, ROLES, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Single Nucleotide, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Female, Research Article, EXPRESSION, medicine.medical_specialty, 3122 Cancers, Breast Neoplasms, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Humans, ddc:610, Polymorphism, Allele, Breast cancer-specific survival, Common germline genetic variants, Patient subgroups, Genome-Wide Association Study, Survival Analysis, Germ-Line Mutation, Pathological, 030304 developmental biology, Cancer och onkologi, Chemotherapy, IDENTIFICATION, business.industry, Proportional hazards model, medicine.disease, Confidence interval, Cancer and Oncology, Breast Cancer-specific Survival, Common Germline Genetic Variants, Patient Subgroups, Systemic Treatment, Tumor Biology, business
Abstract: Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
Published: 2021

48. Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Author: George Ntaios, Menno V. Huisman, Hans-Christoph Diener, Jonathan L. Halperin, Christine Teutsch, Sabrina Marler, Venkatesh K. Gurusamy, Milla Thompson, Gregory Y.H. Lip, Brian Olshansky, Dzifa Wosornu Abban, Nasser Abdul, Atilio Marcelo Abud, Fran Adams, Srinivas Addala, Pedro Adragão, Walter Ageno, Rajesh Aggarwal, Sergio Agosti, Piergiuseppe Agostoni, Francisco Aguilar, Julio Aguilar Linares, Luis Aguinaga, Jameel Ahmed, Allessandro Aiello, Paul Ainsworth, Jorge Roberto Aiub, Raed Al-Dallow, Lisa Alderson, Jorge Antonio Aldrete Velasco, Dimitrios Alexopoulos, Fernando Alfonso Manterola, Pareed Aliyar, David Alonso, Fernando Augusto Alves da Costa, José Amado, Walid Amara, Mathieu Amelot, Nima Amjadi, Fabrizio Ammirati, Marianna Andrade, Nabil Andrawis, Giorgio Annoni, Gerardo Ansalone, M.Kevin Ariani, Juan Carlos Arias, Sébastien Armero, Chander Arora, Muhammad Shakil Aslam, M. Asselman, Philippe Audouin, Charles Augenbraun, S. Aydin, Ivaneta Ayryanova, Emad Aziz, Luciano Marcelo Backes, E. Badings, Ermentina Bagni, Seth H. Baker, Richard Bala, Antonio Baldi, Shigenobu Bando, Subhash Banerjee, Alan Bank, Gonzalo Barón Esquivias, Craig Barr, Maria Bartlett, Vanja Basic Kes, Giovanni Baula, Steffen Behrens, Alan Bell, Raffaella Benedetti, Juan Benezet Mazuecos, Bouziane Benhalima, Jutta Bergler-Klein, Jean-Baptiste Berneau, Richard A. Bernstein, Percy Berrospi, Sergio Berti, Andrea Berz, Elizabeth Best, Paulo Bettencourt, Robert Betzu, Ravi Bhagwat, Luna Bhatta, Francesco Biscione, Giovanni BISIGNANI, Toby Black, Michael J. Bloch, Stephen Bloom, Edwin Blumberg, Mario Bo, Ellen Bøhmer, Andreas Bollmann, Maria Grazia Bongiorni, Giuseppe Boriani, D.J. Boswijk, Jochen Bott, Edo Bottacchi, Marica Bracic Kalan, Drew Bradman, Donald Brautigam, Nicolas Breton, P.J.A.M. Brouwers, Kevin Browne, Jordi Bruguera Cortada, A. Bruni, Claude Brunschwig, Hervé Buathier, Aurélie Buhl, John Bullinga, Jose Walter Cabrera, Alberto Caccavo, Shanglang Cai, Sarah Caine, Leonardo Calò, Valeria Calvi, Mauricio Camarillo Sánchez, Rui Candeias, Vincenzo Capuano, Alessandro Capucci, Ronald Caputo, Tatiana Cárdenas Rizo, Francisco Cardona, Francisco Carlos da Costa Darrieux, Yan Carlos Duarte Vera, Antonio Carolei, Susana Carreño, Paula Carvalho, Susanna Cary, Gavino Casu, Claudio Cavallini, Guillaume Cayla, Aldo Celentano, Tae-Joon Cha, Kwang Soo Cha, Jei Keon Chae, Kathrine Chalamidas, Krishnan Challappa, Sunil Prakash Chand, Harinath Chandrashekar, Ludovic Chartier, Kausik Chatterjee, Carlos Antero Chavez Ayala, Aamir Cheema, Amjad Cheema, Lin Chen, Shih-Ann Chen, Jyh Hong Chen, Fu-Tien Chiang, Francesco Chiarella, Lin Chih-Chan, Yong Keun Cho, Jong-Il Choi, Dong Ju Choi, Guy Chouinard, Danny Hoi-Fan Chow, Dimitrios Chrysos, Galina Chumakova, Eduardo Julián José Roberto Chuquiure Valenzuela, Nicoleta Cindea Nica, David J. Cislowski, Anthony Clay, Piers Clifford, Andrew Cohen, Michael Cohen, Serge Cohen, Furio Colivicchi, Ronan Collins, Paolo Colonna, Steve Compton, Derek Connolly, Alberto Conti, Gabriel Contreras Buenostro, Gregg Coodley, Martin Cooper, Julian Coronel, Giovanni Corso, Juan Cosín Sales, Yves Cottin, John Covalesky, Aurel Cracan, Filippo Crea, Peter Crean, James Crenshaw, Tina Cullen, Harald Darius, Patrick Dary, Olivier Dascotte, Ira Dauber, Vicente Davalos, Ruth Davies, Gershan Davis, Jean-Marc Davy, Mark Dayer, Marzia De Biasio, Silvana De Bonis, Raffaele De Caterina, Teresiano De Franceschi, J.R. de Groot, José De Horta, Axel De La Briolle, Gilberto de la Pena Topete, Angelo Amato Vicenzo de Paola, Weimar de Souza, A. de Veer, Luc De Wolf, Eric Decoulx, Sasalu Deepak, Pascal Defaye, Freddy Del-Carpio Munoz, Diana Delic Brkljacic, N. Joseph Deumite, Silvia Di Legge, Igor Diemberger, Denise Dietz, Pedro Dionísio, Qiang Dong, Fabio Rossi dos Santos, Elena Dotcheva, Rami Doukky, Anthony D'Souza, Simon Dubrey, Xavier Ducrocq, Dmitry Dupljakov, Mauricio Duque, Dipankar Dutta, Nathalie Duvilla, A. Duygun, Rainer Dziewas, Charles B. Eaton, William Eaves, L.A. Ebels-Tuinbeek, Clifford Ehrlich, Sabine Eichinger-Hasenauer, Steven J. Eisenberg, Adnan El Jabali, Mahfouz El Shahawy, Mauro Esteves Hernandes, Ana Etxeberria Izal, Rudolph Evonich, Oksana Evseeva, Andrey Ezhov, Raed Fahmy, Quan Fang, Ramin Farsad, Laurent Fauchier, Stefano Favale, Maxime Fayard, Jose Luis Fedele, Francesco Fedele, Olga Fedorishina, Steven R. Fera, Luis Gustavo Gomes Ferreira, Jorge Ferreira, Claudio Ferri, Anna Ferrier, Hugo Ferro, Alexandra Finsen, Brian First, Stuart Fischer, Catarina Fonseca, Luísa Fonseca Almeida, Steven Forman, Brad Frandsen, William French, Keith Friedman, Athena Friese, Ana Gabriela Fruntelata, Shigeru Fujii, Stefano Fumagalli, Marta Fundamenski, Yutaka Furukawa, Matthias Gabelmann, Nashwa Gabra, Niels Gadsbøll, Michel Galinier, Anders Gammelgaard, Priya Ganeshkumar, Christopher Gans, Antonio Garcia Quintana, Olivier Gartenlaub, Achille Gaspardone, Conrad Genz, Frédéric Georger, Jean-Louis Georges, Steven Georgeson, Evaldas Giedrimas, Mariusz Gierba, Ignacio Gil Ortega, Eve Gillespie, Alberto Giniger, Michael C. Giudici, Alexandros Gkotsis, Taya V. Glotzer, Joachim Gmehling, Jacek Gniot, Peter Goethals, Seth Goldbarg, Ronald Goldberg, Britta Goldmann, Sergey Golitsyn, Silvia Gómez, Juan Gomez Mesa, Vicente Bertomeu Gonzalez, Jesus Antonio Gonzalez Hermosillo, Víctor Manuel González López, Hervé Gorka, Charles Gornick, Diana Gorog, Venkat Gottipaty, Pascal Goube, Ioannis Goudevenos, Brett Graham, G. Stephen Greer, Uwe Gremmler, Paul G. Grena, Martin Grond, Edoardo Gronda, Gerian Grönefeld, Xiang Gu, Ivett Guadalupe Torres Torres, Gabriele Guardigli, Carolina Guevara, Alexandre Guignier, Michele Gulizia, Michael Gumbley, Albrecht Günther, Andrew Ha, Georgios Hahalis, Joseph Hakas, Christian Hall, Bing Han, Seongwook Han, Joe Hargrove, David Hargroves, Kenneth B. Harris, Tetsuya Haruna, Emil Hayek, Jeff Healey, Steven Hearne, Michael Heffernan, Geir Heggelund, J.A. Heijmeriks, Maarten Hemels, I. Hendriks, Sam Henein, Sung-Ho Her, Paul Hermany, Jorge Eduardo Hernández Del Río, Yorihiko Higashino, Michael Hill, Tetsuo Hisadome, Eiji Hishida, Etienne Hoffer, Matthew Hoghton, Kui Hong, Suk keun Hong, Stevie Horbach, Masataka Horiuchi, Yinglong Hou, Jeff Hsing, Chi-Hung Huang, David Huckins, null kathy Hughes, A. Huizinga, E.L. Hulsman, Kuo-Chun Hung, Gyo-Seung Hwang, Margaret Ikpoh, Davide Imberti, Hüseyin Ince, Ciro Indolfi, Shujiro Inoue, Didier Irles, Harukazu Iseki, C. Noah Israel, Bruce Iteld, Venkat Iyer, Ewart Jackson-Voyzey, Naseem Jaffrani, Frank Jäger, Martin James, Sung-Won Jang, Nicolas Jaramillo, Nabil Jarmukli, Robert J. Jeanfreau, Ronald D. Jenkins, Carlos Jerjes Sánchez, Javier Jimenez, Robert Jobe, Tomas Joen-Jakobsen, Nicholas Jones, Jose Carlos Moura Jorge, Bernard Jouve, Byung Chun Jung, Kyung Tae Jung, Werner Jung, Mikhail Kachkovskiy, Krystallenia Kafkala, Larisa Kalinina, Bernd Kallmünzer, Farzan Kamali, Takehiro Kamo, Priit Kampus, Hisham Kashou, Andreas Kastrup, Apostolos Katsivas, Elizabeth Kaufman, Kazuya Kawai, Kenji Kawajiri, John F. Kazmierski, P. Keeling, José Francisco Kerr Saraiva, Galina Ketova, AJIT Singh Khaira, Aleksey Khripun, Doo-Il Kim, Young Hoon Kim, Nam Ho Kim, Dae Kyeong Kim, Jeong Su Kim, June Soo Kim, Ki Seok Kim, Jin bae Kim, Elena Kinova, Alexander Klein, James J. Kmetzo, G. Larsen Kneller, Aleksandar Knezevic, Su Mei Angela Koh, Shunichi Koide, Anastasios Kollias, J.A. Kooistra, Jay Koons, Martin Koschutnik, William J. Kostis, Dragan Kovacic, Jacek Kowalczyk, Natalya Koziolova, Peter Kraft, Johannes A. Kragten, Mori Krantz, Lars Krause, B.J. Krenning, F. Krikke, Z. Kromhout, Waldemar Krysiak, Priya Kumar, Thomas Kümler, Malte Kuniss, Jen-Yuan Kuo, Achim Küppers, Karla Kurrelmeyer, Choong Hwan Kwak, Bénédicte Laboulle, Arthur Labovitz, Wen Ter Lai, Andy Lam, Yat Yin Lam, Fernando Lanas Zanetti, Charles Landau, Giancarlo Landini, Estêvão Lanna Figueiredo, Torben Larsen, Karine Lavandier, Jessica LeBlanc, Moon Hyoung Lee, Chang-Hoon Lee, John Lehman, Ana Leitão, Nicolas Lellouche, Malgorzata Lelonek, Radoslaw Lenarczyk, T. Lenderink, Salvador León González, Peter Leong-Sit, Matthias Leschke, Nicolas Ley, Zhanquan Li, Xiaodong Li, Weihua Li, Xiaoming Li, Christhoh Lichy, Ira Lieber, Ramon Horacio Limon Rodriguez, Hailong Lin, Feng Liu, Hengliang Liu, Guillermo Llamas Esperon, Nassip Llerena Navarro, Eric Lo, Sergiy Lokshyn, Amador López, José Luís López-Sendón, Adalberto Menezes Lorga Filho, Richard S. Lorraine, Carlos Alberto Luengas, Robert Luke, Ming Luo, Steven Lupovitch, Philippe Lyrer, Changsheng Ma, Genshan Ma, Irene Madariaga, Koji Maeno, Dominique Magnin, Gustavo Maid, Sumeet K. Mainigi, Konstantinos Makaritsis, Rohit Malhotra, Rickey Manning, Athanasios Manolis, Helard Andres Manrique Hurtado, Ioannis Mantas, Fernando Manzur Jattin, Vicky Maqueda, Niccolo Marchionni, Francisco Marin Ortuno, Antonio Martín Santana, Jorge Martinez, Petra Maskova, Norberto Matadamas Hernandez, Katsuhiro Matsuda, Tillmann Maurer, Ciro Mauro, Erik May, Nolan Mayer, John McClure, Terry McCormack, William McGarity, Hugh McIntyre, Brent McLaurin, Feliz Alvaro Medina Palomino, Francesco Melandri, Hiroshi Meno, Dhananjai Menzies, Marco Mercader, Christian Meyer, Beat j. Meyer, Jacek Miarka, Frank Mibach, Dominik Michalski, Patrik Michel, Rami Mihail Chreih, Ghiath Mikdadi, Milan Mikus, Davor Milicic, Constantin Militaru, Sedi Minaie, Bogdan Minescu, Iveta Mintale, Tristan Mirault, Michael J. 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Subjects: Oral, medicine.medical_specialty, anticoagulants, Vitamin K, medicine.drug_class, Medizin, Administration, Oral, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, Antithrombotic treatment, 0302 clinical medicine, Randomized controlled trial, law, Risk Factors, Internal medicine, Antithrombotic, medicine, non-vitamin-K antagonist oral anticoagulant, Diseases of the circulatory (Cardiovascular) system, Humans, SAMe-TT2R2, In patient, atrial fibrillation, 030212 general & internal medicine, Prospective Studies, Registries, Medical prescription, business.industry, Anticoagulant, non-vitamin-K antagonist oral, Atrial fibrillation, medicine.disease, non-vitamin-K antagonist oral anticoagulants, Clinical trial, Stroke, Treatment Outcome, SAMe-TT, RC666-701, 2, R, vitamin-K-antagonist oral anticoagulants, Administration, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, SAMe-TT R, Cardiology and Cardiovascular Medicine, business
Abstract: CA extern - Weitere Nicht-UDE-Autoren sind nicht genannt. Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiology
Published: 2021

49. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Georgia Chenevix-Trench, Tjoung-Won Park-Simon, David J. Hunter, Lauren R. Teras, Harald Surowy, Rulla M. Tamimi, Jaana M. Hartikainen, Fergus J. Couch, Heli Nevanlinna, Celine M. Vachon, Per Hall, Arif B. Ekici, Vessela N. Kristensen, Ute Hamann, Alpa V. Patel, Christopher A. Haiman, Sander Canisius, Jonathan Beesley, Sara Margolin, Hedy S. Rennert, Thilo Dörk, Paolo Peterlongo, Hoda Anton-Culver, Matthias W. Beckmann, Renske Keeman, Christopher G. Scott, Rudolf Kaaks, Melissa C. Southey, Atocha Romero, Stig E. Bojesen, Graham G. Giles, Federico Canzian, Rebecca Roylance, Stephen J. Chanock, Loic Le Marchand, Eric Hahnen, Robert Winqvist, Mervi Grip, Taru A. Muranen, A. Heather Eliassen, Ian Tomlinson, Anna Jakubowska, Emilie Thomas, Douglas F. Easton, William Jacot, Paul D.P. Pharoah, Elinor J. Sawyer, Linetta B. Koppert, Manuela Gago-Dominguez, Anthony J. Swerdlow, Matthias Ruebner, Joe Dennis, Alison M. Dunning, Esther M. John, Elza Khusnutdinova, Melanie Gündert, Kamila Czene, Dimitrios Mavroudis, Henrik Flyger, Minouk J. Schoemaker, Manjeet K. Bolla, Rita K. Schmutzler, Jenny Chang-Claude, Kyriaki Michailidou, Håkan Olsson, John L. Hopper, Marjanka K. Schmidt, Melissa A. Troester, Audrey Y. Jung, Maria Escala-Garcia, Bernadette A M Heemskerk-Gerritsen, Argyrios Ziogas, Thomas Rüdiger, Antoinette Hollestelle, José A. García-Sáenz, Marina Bermisheva, Alicja Wolk, Volker Arndt, Robert N. Luben, Mary B. Daly, Niclas Håkansson, Jan Lubinski, Jose E. Castelao, Emmanouil Saloustros, Jürgen Geisler, Qin Wang, Paolo Radice, Gad Rennert, Thomas Bachelot, Sabine Behrens, Peter Kraft, Arto Mannermaa, Heiko Becher, Annika Lindblom, Annelie Augustinsson, Andrew F. Olshan, Mehdi Manoochehri, Peter A. Fasching, Allison W. Kurian, Hermann Brenner, Reiner Hoppe, Montserrat Garcia-Closas, Diether Lambrechts, Kevin Punie, Peter Devilee, Dörk, Thilo [0000-0002-9458-0282], Romero, Atocha [0000-0002-1634-7397], Apollo - University of Cambridge Repository, Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Medical Oncology, Surgery, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology
Subjects: Oncology, Kaplan-Meier Estimate, SUSCEPTIBILITY, Germline, Metastasis, Breast cancer, 0302 clinical medicine, Cancer Survivors, 3123 Gynaecology and paediatrics, NETWORK, skin and connective tissue diseases, Cancer genetics, 0303 health sciences, Multidisciplinary, article, WOMEN, Metastatic breast cancer, 3. Good health, Multidisciplinary Sciences, 631/67/322, 030220 oncology & carcinogenesis, Medicine, Science & Technology - Other Topics, Female, Primary breast cancer, medicine.medical_specialty, Science, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 631/67/68, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, In patient, Germ-Line Mutation, 030304 developmental biology, Cancer och onkologi, Science & Technology, business.industry, Genetic Variation, Breast cancer metastasis, 631/67/1347, medicine.disease, Germ Cells, Cancer and Oncology, business
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021

50. Systematic monitoring for detection of atrial fibrillation in patients with acute ischaemic stroke (MonDAFIS): a randomised, open-label, multicentre study

Author: Georg Gahn, Annette Evens, Stefan Merkelbach, Georg Royl, T Büttner, Robert Stingele, Peter Kraft, Rainer Dziewas, D. G. Nabavi, Jens Diekmann, Sven Ehrlich, Roland Veltkamp, Manuel C. Olma, Peter U. Heuschmann, F Hoffmann, Matthias Maschke, Christian Tanislav, Michael Rosenkranz, Renate B Schnabel, Waltraud Pfeilschifter, Serdar Tütüncü, Claudia Kunze, Götz Thomalla, Joachim Röther, A Steinbrecher, Andreas Hartmann, Johannes Schurig, Marie Prince, Muhammad Jawad-Ul-Qamar, Ludwig Niehaus, Olaf Hoffmann, Joanna Dietzel, Gesa Nören, Rolf Wachter, Paulus Kirchhof, Cornelia Fiessler, Gerhard F. Hamann, Peter A. Ringleb, Timolaos Rizos, Eva-Maria Kampschulte, Karl Georg Haeusler, Andrea Kraft, Frederick Palm, Carolin Malsch, Christos Krogias, Ulrich Laufs, Gerhard J Jungehulsing, Petra Dem, Christian Urbanek, Gabor C. Petzold, T Helberg, Matthias Endres, P Oschmann, Fedor Heidenreich, Johannes Muehler, Elke Leinisch, Michael Besselmann, Albrecht Günther, Karen Louise Harvey, Michael Krämer, Dominik Michalski, Carsten Hobohm, Michael Bauerle, Klaus Gröschel, Louise Tyler, and Larissa Pfeiler
Subjects: Male, medicine.medical_specialty, epidemiology [Atrial Fibrillation], methods [Electrocardiography], Population, diagnosis [Ischemic Stroke], 030204 cardiovascular system & hematology, Brain Ischemia, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, Risk Factors, Internal medicine, Ischaemic stroke, Atrial Fibrillation, diagnosis [Brain Ischemia], medicine, epidemiology [Brain Ischemia], Humans, In patient, Myocardial infarction, ddc:610, education, epidemiology [Ischemic Stroke], Ischemic Stroke, Monitoring, Physiologic, Aged, Aged, 80 and over, education.field_of_study, business.industry, physiopathology [Ischemic Stroke], Hazard ratio, diagnosis [Atrial Fibrillation], Atrial fibrillation, Odds ratio, Middle Aged, methods [Monitoring, Physiologic], medicine.disease, physiopathology [Atrial Fibrillation], physiopathology [Brain Ischemia], 3. Good health, Female, Neurology (clinical), Open label, business, 030217 neurology & neurosurgery
Abstract: Summary Background Systematic electrocardiogram (ECG) monitoring improves detection of covert atrial fibrillation in stroke survivors but the effect on secondary prevention is unknown. We aimed to assess the effect of systematic ECG monitoring of patients in hospital on the rate of oral anticoagulant use after 12 months. Methods In this investigator-initiated, randomised, open-label, parallel-group multicentre study with masked endpoint adjudication, we recruited patients aged at least 18 years with acute ischaemic stroke or transient ischaemic attack without known atrial fibrillation in 38 certified stroke units in Germany. Patients were randomly assigned (1:1) to usual diagnostic procedures for atrial fibrillation detection (control group) or additional Holter-ECG recording for up to 7 days in hospital (intervention group). Patients were stratified by centre using a random permuted block design. The primary outcome was the proportion of patients on oral anticoagulants at 12 months after the index event in the intention-to-treat population. Secondary outcomes included the number of patients with newly diagnosed atrial fibrillation in hospital and the composite of recurrent stroke, major bleeding, myocardial infarction, or death after 6 months, 12 months, and 24 months. This trial was registered with ClinicalTrials.gov , NCT02204267 , and is completed and closed for participants. Findings Between Dec 9, 2014, and Sept 11, 2017, 3465 patients were randomly assigned, 1735 (50·1%) to the intervention group and 1730 (49·9%) to the control group. Oral anticoagulation status was available in 2920 (84·3%) patients at 12 months (1484 [50·8%] in the intervention group and 1436 [49·2%] in the control group). For the primary outcome, at 12 months, 203 (13·7%) of 1484 patients in the intervention group versus 169 (11·8%) of 1436 in the control group were on oral anticoagulants (odds ratio [OR] 1·2 [95% CI 0·9–1·5]; p=0·13). Atrial fibrillation was newly detected in patients in hospital in 97 (5·8%) of 1714 in the intervention group versus 68 (4·0%) of 1717 in the control group (hazard ratio [HR] 1·4 [95% CI 1·0–2·0]; p=0·024). The composite of cardiovascular outcomes and death did not differ between patients randomly assigned to the intervention group versus the control group at 24 months (232 [13·5%] of 1714 vs 249 [14·5%] of 1717; HR 0·9 [0·8–1·1]; p=0·43). Skin reactions due to study ECG electrodes were reported in 56 (3·3%) patients in the intervention group. All-cause death occured in 73 (4·3%) patients in the intervention group and in 103 (6·0%) patients in the control group (OR 0·7 [0·5–0·9]). Interpretation Systematic core centrally reviewed ECG monitoring is feasible and increases the detection rate of atrial fibrillation in unselected patients hospitalised with acute ischaemic stroke or transient ischaemic attack, if added to usual diagnostic care in certified German stroke units. However, we found no effect of systematic ECG monitoring on the rate of oral anticoagulant use after 12 months and further efforts are needed to improve secondary stroke prevention. Funding Bayer Vital. Translation For the German translation of the abstract see Supplementary Materials section.
Published: 2021

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