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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G, Faraway R, Finan C, Valentine D, Fairhurst-Hunter Z, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh K, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Lill CM, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott RA, Luan J, Bobak M, Malyutina S, Pająk A, Kubinova R, Tamosiunas A, Pikhart H, Grarup N, Pedersen O, Hansen T, Linneberg A, Jess T, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Lester KH, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, Scott R, Schofield P, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Lifelines Cohort authors, Christen T, Mook-Kanamori DO, ICBP Consortium, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dörr M, Lerch MM, Völker U, Völzke H, Ward J, Pell JP, Meade T, Christophersen IE, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Roussel R, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Hopewell JC, Seshadri S, METASTROKE Consortium of the ISGC, Dale C, Costa RPE, Ridker PM, Chasman DI, Reiner AP, Ritchie MD, Lange LA, Cornish AJ, Dobbins SE, Hemminki K, Kinnersley B, Sanson M, Labreche K, Simon M, Bondy M, Law P, Speedy H, Allan J, Li N, Went M, Weinhold N, Morgan G, Sonneveld P, Nilsson B, Goldschmidt H, Sud A, Engert A, Hansson M, Hemingway H, Asselbergs FW, Patel RS, Keating BJ, Sattar N, Houlston R, Casas JP, Hingorani AD
(2019) BMC Cardiovasc Disord 19: 240
MeSH Terms: Anticholesteremic Agents, Biomarkers, Brain Ischemia, Cholesterol, LDL, Down-Regulation, Dyslipidemias, Genome-Wide Association Study, Humans, Myocardial Infarction, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Serine Proteinase Inhibitors, Stroke, Treatment Outcome
Show Abstract · Added March 24, 2020
BACKGROUND - We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.
METHODS - Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.
RESULTS - The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.
CONCLUSIONS - Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.
Assassi S, Wang X, Chen G, Goldmuntz E, Keyes-Elstein L, Ying J, Wallace PK, Turner J, Zheng WJ, Pascual V, Varga J, Hinchcliff ME, Bellocchi C, McSweeney P, Furst DE, Nash RA, Crofford LJ, Welch B, Pinckney A, Mayes MD, Sullivan KM
(2019) Ann Rheum Dis 78: 1371-1378
MeSH Terms: Adult, Cyclophosphamide, Down-Regulation, Female, Hematopoietic Stem Cell Transplantation, Humans, Interferons, Male, Middle Aged, Multilevel Analysis, Myeloablative Agonists, Neutrophils, Randomized Controlled Trials as Topic, Scleroderma, Systemic, Transcriptome, Transplantation Conditioning, Transplantation, Autologous, Treatment Outcome, Up-Regulation
Show Abstract · Added March 25, 2020
OBJECTIVE - In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study.
METHODS - Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples.
RESULTS - At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score.
CONCLUSION - HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
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Early medical therapy for acute laryngeal injury (ALgI) following endotracheal intubation: a protocol for a prospective single-centre randomised controlled trial.
Lowery AS, Kimura K, Shinn J, Shannon C, Gelbard A
(2019) BMJ Open 9: e027963
MeSH Terms: Acute Disease, Azithromycin, Budesonide, Double-Blind Method, Early Medical Intervention, Humans, Intensive Care Units, Intubation, Intratracheal, Larynx, Noninvasive Ventilation, Prospective Studies, Randomized Controlled Trials as Topic, Tennessee, Time Factors, Wounds and Injuries
Show Abstract · Added July 30, 2020
INTRODUCTION - Respiratory failure requiring endotracheal intubation accounts for a significant proportion of intensive care unit (ICU) admissions. Little attention has been paid to the laryngeal consequences of endotracheal intubation. Acute laryngeal injury (ALgI) after intubation occurs at the mucosal interface of the endotracheal tube and posterior larynx and although not immediately manifest at extubation, can progress to mature fibrosis, restricted glottic mobility and clinically significant ventilatory impairment. A recent prospective observational study has shown that >50% of patients intubated >24 hours in an ICU develop ALgI. Strikingly, patients with AlgI manifest significantly worse subjective breathing at 12 weeks. Current ALgI treatments are largely surgical yet offer a marginal improvement in symptoms. METHODS AND ANALYSIS: A prospective, single-centre, double-blinded, randomised, control trial will be conducted at Vanderbilt Medical Center. Participants will be recruited from adult patients in ICUs. Participants will undergo a bedside flexible nasolaryngoscopy for the identification of ALgI within 72 hours postextubation. In addition, participants will be asked to complete peak expiratory flow measurements immediately postintubation. Patients found to have ALgI will be randomised to the placebo control or medical therapy group (azithromycin 250 mg and budesonide 0.5 mg for 14 days). Repeat peak expiratory flow, examination of the larynx and patient-reported Clinical COPD (chronic obstructive pulmonary disease) Questionnaire, Voice Handicap Index and 12-Item Short Form Health Survey questionnaires will be conducted at 12 weeks postextubation. Consented patients will also have patient-specific, disease-specific and procedure-specific covariates abstracted from their medical record.
ETHICS AND DISSEMINATION - The Institutional Review Board (IRB) Committee of the Vanderbilt University Medical Center has approved this protocol (IRB #171066). The findings of the trial will be disseminated through peer-reviewed journals, national and international conferences.
TRIAL REGISTRATION NUMBER - NCT03250975.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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15 MeSH Terms
Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis.
Brown JR, Moslehi J, Ewer MS, O'Brien SM, Ghia P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Coutre SE, Dilhuydy MS, Cramer P, Jaeger U, Dreyling M, Byrd JC, Treon S, Liu EY, Chang S, Bista A, Vempati R, Boornazian L, Valentino R, Reddy V, Mahler M, Yang H, Graef T, Burger JA
(2019) Br J Haematol 184: 558-569
MeSH Terms: Aged, Female, Hematologic Neoplasms, Hemorrhage, Humans, Incidence, Male, Middle Aged, Pyrazoles, Pyrimidines, Randomized Controlled Trials as Topic, Risk Factors, Time Factors
Show Abstract · Added December 13, 2018
Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.
© 2018 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
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13 MeSH Terms
Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation.
Sullivan KM, Majhail NS, Bredeson C, Carpenter PA, Chatterjee S, Crofford LJ, Georges GE, Nash RA, Pasquini MC, Sarantopoulos S, Storek J, Savani B, St Clair EW
(2018) Biol Blood Marrow Transplant 24: 1961-1964
MeSH Terms: Autografts, Bone Marrow Transplantation, Cyclophosphamide, Hematopoietic Stem Cell Transplantation, Humans, Randomized Controlled Trials as Topic, Scleroderma, Systemic, Societies, Medical, United States
Show Abstract · Added March 25, 2020
Systemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options. High-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) has been evaluated as treatment for this disease in observational studies, multicenter randomized controlled clinical trials, and meta-analyses. On behalf of the American Society for Blood and Marrow Transplantation (ASBMT), a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis. Three randomized trials have compared the efficacy of AHCT with cyclophosphamide only, and all demonstrated benefit for the AHCT arm for their primary endpoint (improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial, event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial, and change in global rank composite score in Scleroderma: Cyclophosphamide or Transplantation trial). AHCT recipients also had better overall survival and a lower rate of disease progression. These findings have been confirmed in subsequent meta-analyses. Based on this high-quality evidence, the ASBMT recommends systemic sclerosis should be considered as a "standard of care" indication for AHCT. Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes. Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication.
Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Course of Disinhibited Social Engagement Disorder From Early Childhood to Early Adolescence.
Guyon-Harris KL, Humphreys KL, Fox NA, Nelson CA, Zeanah CH
(2018) J Am Acad Child Adolesc Psychiatry 57: 329-335.e2
MeSH Terms: Caregivers, Child, Child, Institutionalized, Child, Preschool, Female, Foster Home Care, Humans, Infant, Longitudinal Studies, Male, Randomized Controlled Trials as Topic, Reactive Attachment Disorder, Social Behavior Disorders, Surveys and Questionnaires
Show Abstract · Added March 3, 2020
OBJECTIVE - Disinhibited social engagement disorder (DSED) is poorly understood beyond early childhood. The course of DSED signs in a sample of children who experienced severe, early deprivation from early childhood to early adolescence was examined using variable-centered (linear mixed modeling) and person-centered (growth mixture modeling) approaches.
METHOD - The study included 124 children with a history of institutional care from a randomized controlled trial of foster care as an alternative to institutional care and 69 community comparison children matched by age and sex. DSED signs were assessed at baseline (mean age 22 months), 30, 42, and 54 months of age, and 8 and 12 years of age using a validated caregiver report of disturbed attachment behavior.
RESULTS - Variable-centered analyses based on intent-to-treat groups indicated that signs of DSED decreased sharply for children randomized to foster care and decreased slightly but remained high for children randomized to care as usual. Person-centered analyses showed 4 profiles (i.e., elevated, persistent modest, early decreasing, and minimal). Elevated and persistent modest courses were associated with greater placement disruptions (F = 4.29, p = .007, partial eta-squared [η] = 0.12), older age at placement into foster care (F = 3.41, p < .05, partial η = 0.16), and more time in institutional care (F = 11.91, p < .001, partial η = 0.24) compared with decreasing and minimal courses.
CONCLUSION - Early and sustained placement into families after deprivation is associated with minimal or decreasing signs of DSED across development. Shortening the amount of time children spend in institutions and preserving placements could help decrease signs of DSED into early adolescence in previously institutionalized children.
Copyright © 2018 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
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Opportunities and Challenges in Cardiovascular Pharmacogenomics: From Discovery to Implementation.
Roden DM, Van Driest SL, Wells QS, Mosley JD, Denny JC, Peterson JF
(2018) Circ Res 122: 1176-1190
MeSH Terms: Biological Variation, Individual, Biotransformation, Cardiovascular Agents, Drug Development, Drug-Related Side Effects and Adverse Reactions, Forecasting, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genomics, Genotyping Techniques, Human Genome Project, Humans, Pharmacogenetics, Precision Medicine, Randomized Controlled Trials as Topic, Risk Assessment, Sample Size
Show Abstract · Added March 24, 2020
This review will provide an overview of the principles of pharmacogenomics from basic discovery to implementation, encompassing application of tools of contemporary genome science to the field (including areas of apparent divergence from disease-based genomics), a summary of lessons learned from the extensively studied drugs clopidogrel and warfarin, the current status of implementing pharmacogenetic testing in practice, the role of genomics and related tools in the drug development process, and a summary of future opportunities and challenges.
© 2018 American Heart Association, Inc.
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Adjuvant therapy is associated with improved survival after curative resection for hilar cholangiocarcinoma: A multi-institution analysis from the U.S. extrahepatic biliary malignancy consortium.
Krasnick BA, Jin LX, Davidson JT, Sanford DE, Ethun CG, Pawlik TM, Poultsides GA, Tran T, Idrees K, Hawkins WG, Chapman WC, Doyle MBM, Weber SM, Strasberg SM, Salem A, Martin RCG, Isom CA, Scoggins C, Schmidt CR, Shen P, Beal E, Hatzaras I, Shenoy R, Maithel SK, Fields RC
(2018) J Surg Oncol 117: 363-371
MeSH Terms: Aged, Bile Duct Neoplasms, Chemoradiotherapy, Adjuvant, Chemotherapy, Adjuvant, Cholangiocarcinoma, Disease-Free Survival, Female, Humans, Male, Middle Aged, Randomized Controlled Trials as Topic, Retrospective Studies, Survival Rate
Show Abstract · Added April 10, 2018
BACKGROUND - Curative-intent treatment for localized hilar cholangiocarcinoma (HC) requires surgical resection. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall (OS) and recurrence free survival (RFS) in patients undergoing curative resection.
METHODS - We reviewed patients with resected HC between 2000 and 2015 from the ten institutions participating in the U.S. Extrahepatic Biliary Malignancy Consortium. We analyzed the impact of AT on RFS and OS. The probability of RFS and OS were calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis.
RESULTS - A total of 249 patients underwent curative resection for HC. Patients who received AT and those who did not had similar demographic and preoperative features. In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.58, P = 0.013), and this was maintained in a propensity matched analysis (HR 0.66, P = 0.033). The protective effect of AT remained significant when node negative patients were excluded (HR 0.28, P = 0.001), while it disappeared (HR 0.76, P = 0.260) when node positive patients were excluded.
CONCLUSIONS - AT should be strongly considered after curative-intent resection for HC, particularly in patients with node positive disease.
© 2017 Wiley Periodicals, Inc.
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The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.
Denny JC, Van Driest SL, Wei WQ, Roden DM
(2018) Clin Pharmacol Ther 103: 409-418
MeSH Terms: Big Data, Drug Repositioning, Electronic Health Records, Humans, Pharmacogenetics, Pharmacology, Clinical, Precision Medicine, Randomized Controlled Trials as Topic
Show Abstract · Added March 14, 2018
Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine.
© 2017 American Society for Clinical Pharmacology and Therapeutics.
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8 MeSH Terms
Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials.
Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA
(2017) Haematologica 102: 1796-1805
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Atrial Fibrillation, Disease Management, Female, Follow-Up Studies, Hemorrhage, Humans, Incidence, Male, Middle Aged, Protein Kinase Inhibitors, Pyrazoles, Pyrimidines, Randomized Controlled Trials as Topic, Risk Factors, Time Factors
Show Abstract · Added December 2, 2017
The first-in-class Bruton's tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6-16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation ().
Copyright© 2017 Ferrata Storti Foundation.
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19 MeSH Terms