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1.
J Clin Apher ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31705563

RESUMO

IMPORTANCE: Neuromyelitis optica/neuromyelitis optica spectrum disorder patients' response to therapeutic plasma exchange (TPE) is currently incompletely characterized. OBJECTIVE: Our study aims to understand the clinical status improvement of neuromyelitis optica/neuromyelitis optica spectrum disorder patients treated with TPE. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective study conducted between 1 January 2003 and 31 July 2017 at 13 US hospitals performing apheresis procedures. Subjects studied were diagnosed with neuromyelitis optica/neuromyelitis optica spectrum disorder who received TPE during presentation with acute disease. MAIN OUTCOMES AND MEASURES: The primary outcome was clinical status improvement in patients treated with TPE. Secondary measures were procedural and patient characteristics associated with response to treatment. RESULTS: We evaluated 114 patients from 13 institutions. There was a female predilection. The largest ethnic group affected was non-Hispanic Caucasian. The average age of diagnosis was 43.1 years. The average time to diagnosis was 3.1 years. On average, five procedures were performed during each treatment series. The most commonly performed plasma volume exchange was 1.0 to 1.25 using 5% albumin as replacement fluid. Most patients (52%) did not require an additional course of TPE and noted "mild" to "moderate" clinical status improvement. Maximal symptom improvement appeared by the fourth or fifth TPE treatment. CONCLUSION AND RELEVANCE: TPE improved the clinical status of patients. Adults responded more favorably than children. Procedural characteristics, including number of TPEs, plasma volume exchanged, and replacement fluid used, were similar between institutions. TPE was well-tolerated and had a low severe adverse event profile.

2.
Am J Hum Genet ; 105(4): 706-718, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564435

RESUMO

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

3.
Nat Genet ; 51(11): 1580-1587, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31659325

RESUMO

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

4.
Nat Commun ; 10(1): 4267, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537805

RESUMO

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

5.
PLoS One ; 14(5): e0216222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075152

RESUMO

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

6.
Sci Rep ; 9(1): 6992, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061447

RESUMO

Prostate cancer (PCa) is a major cause of cancer death among men. The histopathological examination of post-surgical prostate specimens and manual annotation of PCa not only allow for detailed assessment of disease characteristics and extent, but also supply the ground truth for developing of computer-aided diagnosis (CAD) systems for PCa detection before definitive treatment. As manual cancer annotation is tedious and subjective, there have been a number of publications describing methods for automating the procedure via the analysis of digitized whole-slide images (WSIs). However, these studies have focused only on the analysis of WSIs stained with hematoxylin and eosin (H&E), even though there is additional information that could be obtained from immunohistochemical (IHC) staining. In this work, we propose a framework for automating the annotation of PCa that is based on automated colorimetric analysis of both H&E and IHC WSIs stained with a triple-antibody cocktail against high-molecular weight cytokeratin (HMWCK), p63, and α-methylacyl CoA racemase (AMACR). The analysis outputs were then used to train a regression model to estimate the distribution of cancerous epithelium within slides. The approach yielded an AUC of 0.951, sensitivity of 87.1%, and specificity of 90.7% as compared to slide-level annotations, and generalized well to cancers of all grades.

7.
Nat Rev Cardiol ; 16(11): 687-698, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31065045

RESUMO

The Framingham Heart Study (FHS) was established in 1948 to improve understanding of the epidemiology of coronary heart disease (CHD) in the USA. In 1961, seminal work identified major risk factors for CHD (high blood pressure, high cholesterol levels and evidence on the electrocardiogram of left ventricular hypertrophy), which later formed the basis for multivariable 10-year and 30-year risk-prediction algorithms. The FHS cohorts now comprise three generations of participants (n ≈ 15,000) and two minority cohorts. The FHS cohorts are densely phenotyped, with recurring follow-up examinations and surveillance for cardiovascular and non-cardiovascular end points. Assessment of subclinical disease and physiological profiling of these cohorts (with the use of echocardiography, ambulatory electrocardiographic monitoring, exercise stress testing, cardiac CT, heart and brain MRI, serial vascular tonometry and accelerometry) have been performed repeatedly. Over the past decade, the FHS cohorts have undergone deep 'omics' profiling (including whole-genome sequencing, DNA methylation analysis, transcriptomics, high-throughput proteomics and metabolomics, and microbiome studies). The FHS is a rich, longitudinal, transgenerational and deeply phenotyped cohort study with a sustained focus on state-of-the-art epidemiological methods and technological advances to facilitate scientific discoveries.

8.
Blood ; 133(9): 967-977, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30642921

RESUMO

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.


Assuntos
Isquemia Encefálica/etiologia , Fator VII/genética , Estudo de Associação Genômica Ampla , Proteínas de Membrana Transportadoras/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Estudos de Coortes , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Fator VII/metabolismo , Feminino , Seguimentos , Loci Gênicos , Predisposição Genética para Doença , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Fenótipo , Prognóstico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/metabolismo , Tromboembolia Venosa/patologia
9.
Am J Hum Genet ; 104(2): 260-274, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639324

RESUMO

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.


Assuntos
Estudos de Associação Genética , Modelos Genéticos , Sequenciamento Completo do Genoma , Cromossomos Humanos Par 4/genética , Computação em Nuvem , Feminino , Fibrinogênio/análise , Fibrinogênio/genética , Genética Populacional , Humanos , Masculino , National Heart, Lung, and Blood Institute (U.S.) , Medicina de Precisão , Projetos de Pesquisa , Fatores de Tempo , Estados Unidos
10.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30659681

RESUMO

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise em Microsséries/métodos , Tromboembolia Venosa/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra , Tromboembolia Venosa/etnologia
11.
Nat Commun ; 9(1): 3853, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228274

RESUMO

In the originally published version of this Article, financial support was not fully acknowledged. The sentence "KS was supported by the 'Biomedical Research Program' funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation" has been added to the acknowledgement section in both the PDF and HTML versions of the Article.

12.
Nat Commun ; 9(1): 3268, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111768

RESUMO

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.

13.
Blood ; 132(17): 1842-1850, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30042098

RESUMO

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

14.
Oncotarget ; 9(22): 16008-16027, 2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29662623

RESUMO

Inducing stable control of tumour growth by tumour reversion is an alternative approach to cancer treatment when eradication of the disease cannot be achieved. The process requires re-establishment of normal control mechanisms that are lost in cancer cells so that abnormal proliferation can be halted. Embryonic environments can reset cellular programmes and we previously showed that axolotl oocyte extracts can reprogram breast cancer cells and reverse their tumorigenicity. In this study, we analysed the gene expression profiles of oocyte extract-treated tumour xenografts to show that tumour reprogramming involves cell cycle arrest and acquisition of a quiescent state. Tumour dormancy is associated with increased P27 expression, restoration of RB function and downregulation of mitogen-activated signalling pathways. We also show that the quiescent state is associated with increased levels of H4K20me3 and decreased H4K20me1, an epigenetic profile leading to chromatin compaction. The epigenetic reprogramming induced by oocyte extracts is required for RB hypophosphorylation and induction of P27 expression, both occurring during exposure to the extracts and stably maintained in reprogrammed tumour xenografts. Therefore, this study demonstrates the value of oocyte molecules for inducing tumour reversion and for the development of new chemoquiescence-based therapies.

15.
Sci Rep ; 8(1): 6148, 2018 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-29654245

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

16.
J Am Heart Assoc ; 7(5)2018 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-29502103

RESUMO

BACKGROUND: Platelet function is associated with adverse events in patients with cardiovascular disease (CVD). METHODS AND RESULTS: We examined associations of baseline platelet function with incident CVD events in the community-based FHS (Framingham Heart Study). Participants free of prevalent CVD and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991-1995) and Omni cohort (1994-1998) were included. Platelet function was measured with light transmission aggregometry using collagen (1.9 µg/mL), ADP (0.05-15 µmol/L), and epinephrine (0.01-15 µmol/L). We used proportional hazards models to analyze incident outcomes (myocardial infarction/stroke, CVD, and CVD mortality) with respect to platelet measures. The study sample included 2831 participants (average age, 54.3 years; 57% women). During follow-up (median, 20.4 years), we observed 191 composite incident myocardial infarction or stroke events, 432 incident CVD cases, and 117 CVD deaths. Hyperreactivity to ADP and platelet aggregation at ADP concentration of 1.0 µmol/L were significantly associated with incident myocardial infarction/stroke in a multivariable model (hazard ratio, 1.68 [95% confidence interval, 1.13-2.50] [P=0.011] for hyperreactivity across ADP doses; and hazard ratio, 1.16 [95% confidence interval, 1.02-1.33] [P=0.029] for highest quartile of ADP response at 1.0 µmol/L versus others). No association was observed for collagen lag time or any epinephrine measures with incident myocardial infarction or stroke. CONCLUSIONS: Intrinsic hyperreactivity to low-dose ADP in our community-based sample, who were free of CVD and any antiplatelet therapy, is associated with future arterial thrombosis during a 20-year follow-up. These findings reinforce ADP activation inhibition as a critical treatment paradigm and encourage further study of ADP inhibitor-refractive populations.

17.
Transfus Med Rev ; 32(2): 117-122, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29395602

RESUMO

Knowledge deficits of transfusion medicine are prevalent among learners and practicing physicians. In the past, the transfusion medicine community has thoughtfully defined the content of transfusion medicine curriculums through Transfusion Medicine Academic Award Group and The Academy of Clinical Laboratory Physicians and Scientists. The manner in which the curriculum should be delivered has been less carefully examined and defined. We completed an observational study in which we analyzed 3 different teaching techniques: in-person faculty-led simulation curriculum consisting of didactic session and simulation ("Simulation group"); hybrid education with a combination of online materials and short in-person simulation ("Hybrid group"); and online-only education module, which delivered the whole curricular content through a variety of online materials and videos ("Online-only group"). Knowledge acquisition was assessed with a 10-question multiple-choice questionnaire, and satisfaction was assessed by a 9-question online student satisfaction survey. A total of 276second-year medical students participated in the study. There was statistically significant difference between pre- and posttest results and in knowledge gain favoring the Simulation group as compared with the Online-only group (P=.03, P<.0001) and favoring the Simulation group as compared with the Hybrid group (P=.004, P<.0001). The Simulation group and Hybrid group medical students were also more satisfied with the education activity as compared with the Online-only group (P<.0001, P<.001). Our study demonstrated that a faculty-run transfusion medicine simulation curriculum consisting of an in-person didactic session and simulation session for the second-year medical students produced greater immediate knowledge acquisition compared with an online only or a hybrid curriculum. Furthermore, any curriculum that contained in-person teaching by faculty was preferred over the online only education.

18.
Sci Rep ; 8(1): 618, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330416

RESUMO

Large repeat rich genomes present challenges for assembly using short read technologies. The 32 Gb axolotl genome is estimated to contain ~19 Gb of repetitive DNA making an assembly from short reads alone effectively impossible. Indeed, this model species has been sequenced to 20× coverage but the reads could not be conventionally assembled. Using an alternative strategy, we have assembled subsets of these reads into scaffolds describing over 19,000 gene models. We call this method Virtual Genome Walking as it locally assembles whole genome reads based on a reference transcriptome, identifying exons and iteratively extending them into surrounding genomic sequence. These assemblies are then linked and refined to generate gene models including upstream and downstream genomic, and intronic, sequence. Our assemblies are validated by comparison with previously published axolotl bacterial artificial chromosome (BAC) sequences. Our analyses of axolotl intron length, intron-exon structure, repeat content and synteny provide novel insights into the genic structure of this model species. This resource will enable new experimental approaches in axolotl, such as ChIP-Seq and CRISPR and aid in future whole genome sequencing efforts. The assembled sequences and annotations presented here are freely available for download from https://tinyurl.com/y8gydc6n . The software pipeline is available from https://github.com/LooseLab/iterassemble .


Assuntos
Ambystoma mexicanum/genética , Passeio de Cromossomo/métodos , Biologia Computacional/métodos , Animais , Perfilação da Expressão Gênica/métodos , Íntrons , Anotação de Sequência Molecular , Software
19.
J Clin Apher ; 33(1): 108-112, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28543448

RESUMO

BACKGROUND: Pure red cell aplasia (PRCA) is a well-documented potential side effect of ABO major mismatched allogeneic hematopoietic stem cell transplants. This side effect may be self-limiting, but is sometimes treated using modalities such as steroids, antithymocyte globulin, donor lymphocyte infusions, rituximab, or plasma exchanges. Another well-documented cause of pure red cell aplasia is a chronic parvovirus B19 infection, which may be seen in immunocompromised hosts. The treatment of this cause of PRCA includes removal of immunosuppression, intravenous immunoglobulin (IVIg), or rituximab; however, this condition may also be self-limiting. CASE REPORT: We show a case of a patient with PRCA who had previously received an ABO major mismatched allogeneic hematopoietic stem cell transplant, but also had an identified source of parvovirus B19 in his marrow post-transplant. RESULTS: He underwent several various treatments for his PRCA, including rituximab, bortezomib, and then plasma exchange. Anti-A IgM and IgG titers were drawn throughout his treatment course, and fell from 512 (anti-A IgM) and 1024 (anti-A IgG) to 2 (anti-A IgM) and 8 (anti-A IgG). After his last plasma exchange procedure, the patient's hemoglobin and reticulocyte count rose from 6.6 g/dL and 12.5 × 109 /L (respectively) at the onset of the PRCA diagnosis to 9.6 g/dL and 138.1 × 109 /L after a series of 14 plasma exchanges. CONCLUSION: This demonstrates a case of PRCA caused by an ABO major mismatched allogeneic hematopoietic stem cell transplant that was potentially complicated by a parvovirus infection, which was treated with multiple therapeutic interventions including a series of therapeutic plasma exchanges, rituximab, and bortezomib. Successful resolution of the patient's PRCA was achieved.


Assuntos
Sistema do Grupo Sanguíneo ABO/imunologia , Incompatibilidade de Grupos Sanguíneos , Aplasia Pura de Série Vermelha/etiologia , Aplasia Pura de Série Vermelha/terapia , Bortezomib/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Infecções por Parvoviridae , Troca Plasmática , Aplasia Pura de Série Vermelha/complicações , Rituximab/uso terapêutico , Resultado do Tratamento
20.
Platelets ; 29(2): 125-130, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28649937

RESUMO

The last decade has witnessed an explosion in the depth, variety, and amount of human genetic data that can be generated. This revolution in technical and analytical capacities has enabled the genetic investigation of human traits and disease in thousands to now millions of participants. Investigators have taken advantage of these advancements to gain insight into platelet biology and the platelet's role in human disease. To do so, large human genetics studies have examined the association of genetic variation with two quantitative traits measured in many population and patient based cohorts: platelet count (PLT) and mean platelet volume (MPV). This article will review the many human genetic strategies-ranging from genome-wide association study (GWAS), Exomechip, whole exome sequencing (WES), to whole genome sequencing (WGS)-employed to identify genes and variants that contribute to platelet traits. Additionally, we will discuss how these investigations have examined and interpreted the functional implications of these newly identified genetic factors and whether they also impart risk to human disease. The depth and size of genetic, phenotypic, and other -omic data are primed to continue their growth in the coming years and provide unprecedented opportunities to gain critical insights into platelet biology and how platelets contribute to disease.


Assuntos
Plaquetas/metabolismo , Volume Plaquetário Médio/métodos , Contagem de Plaquetas/métodos , Feminino , Humanos , Masculino
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