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Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

BackgroundMulti-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.ObjectivesTo discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.MethodsSummary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27).ResultsAcross the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes.ConclusionsThe discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Although the majority of U.S. medical students predominantly apply to only one specialty, some apply to more than one. When it comes to emergency medicine (EM), applicants may apply to additional specialties due to several reasons: being international medical graduates as well as their inability to make a decision regarding the choice of specialty, fear from the growing competitiveness of EM, or the desire to stay in a specific geographic area. Accordingly, in this article we aim to guide medical students through the process of applying to more than one specialty, including using the Electronic Residency Application Service application, writing a personal statement, getting letters of recommendation, and an Early Match. Moreover, we elaborate on the effect of applying to more than one specialty on a student's application to a residency in EM.

Although the majority of U.S. medical students predominantly apply to only one specialty, some apply to more than one. When it comes to emergency medicine (EM), applicants may apply to additional specialties due to several reasons: being international medical graduates as well as their inability to make a decision regarding the choice of specialty, fear from the growing competitiveness of EM, or the desire to stay in a specific geographic area. Accordingly, in this article we aim to guide medical students through the process of applying to more than one specialty, including using the Electronic Residency Application Service application, writing a personal statement, getting letters of recommendation, and an Early Match. Moreover, we elaborate on the effect of applying to more than one specialty on a student's application to a residency in EM.

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.

Introduction: The emergency medicine clerkship curriculum at Los Angeles County + University of Southern California Medical Center includes monthly lectures on pediatric fever and shortness of breath (SOB). This educational innovation evaluated if learning could be enhanced by “priming” the students with educational online videos prior to an in-class session. Factors that impacted completion rates were also evaluated (planned specialty and time given for video viewing).Methods: Twenty minute videos were to be viewed prior to the didactic session. Students were assigned to either the fever or SOB group and received links to those respective videos. All participating students took a pre-test prior to viewing the online lectures. For analysis, test scores were placed into concordant groups (test results on fever questions in the group assigned the fever video and test results on SOB questions in the group assigned the SOB video) and discordant groups (crossover between video assigned and topic tested). Each subject contributed one set of concordant results and one set of discordant results. Descriptive statistics were performed with the Mann-Whitney U test. Lecture links were distributed to students two weeks prior to the in-class session for 7 months and three days prior to the in-class session for 8 months (in which both groups included both EM-bound and non-EM bound students).Results: In the 15 months study period, 64% of students rotating through the EM elective prepared for the in class session by watching the videos. During 10 months where exclusively EM-bound students were rotating (n=144), 71.5% of students viewed the lectures. In 4 months where students were not EM-bound (n=54), 55.6% of students viewed the lectures (p=0.033). Participation was 60.2% when lecture links were given three days in advance and 68.7% when links were given two weeks in advance (p=0.197). In the analysis of concordant scores, the pre-test averaged 56.7% correct, the immediate post-test averaged 78.1% correct, and the delayed post-test was 67.2%. In the discordant groups, the pretest averaged 51.9%, the immediate posttest was 67.1% and the delayed by 68.8%. In the concordant groups, the immediate post-test scores improved by 21.4%, compared with 15.2% in the discordant groups (p = 0.655). In the delayed post-test the concordant scores improved by 10.5% and discordant scores by 16.9 percent (p=0.609). Sixty-two percent of students surveyed preferred the format of online videos with in-class case discussion to a traditional lecture format.Conclusion: Immediate post-tests and delayed post-tests improved but priming was not demonstrated to be a statistically superior educational method in this study. Medical student completion of the preparatory materials for the emergency medicine rotation session increased when the students were emergency medicine-bound. Participation rates were not significantly different when given at 2 weeks versus 3 days.

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p  30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p  30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

BackgroundThe flipped classroom model for didactic education has recently gained popularity in medical education; however, there is a paucity of performance data showing its effectiveness for knowledge gain in graduate medical education.ObjectiveWe assessed whether a flipped classroom module improves knowledge gain compared with a standard lecture.MethodsWe conducted a randomized crossover study in 3 emergency medicine residency programs. Participants were randomized to receive a 50-minute lecture from an expert educator on one subject and a flipped classroom module on the other. The flipped classroom included a 20-minute at-home video and 30 minutes of in-class case discussion. The 2 subjects addressed were headache and acute low back pain. A pretest, immediate posttest, and 90-day retention test were given for each subject.ResultsOf 82 eligible residents, 73 completed both modules. For the low back pain module, mean test scores were not significantly different between the lecture and flipped classroom formats. For the headache module, there were significant differences in performance for a given test date between the flipped classroom and the lecture format. However, differences between groups were less than 1 of 10 examination items, making it difficult to assign educational importance to the differences.ConclusionsIn this crossover study comparing a single flipped classroom module with a standard lecture, we found mixed statistical results for performance measured by multiple-choice questions. As the differences were small, the flipped classroom and lecture were essentially equivalent.

ResultsThe oral administration of rebamipide decreased plaque formation in atherosclerotic lesions as well as the markers of metabolic disorder in ApoE-deficient mice with atherosclerosis. Pro-inflammatory cytokines were also suppressed by rebamapide. In addition, the population of Th17 was decreased, whereas Treg was increased in the spleen of rebamipide-treated ApoE deficient mice. Rebamipide also ameliorated the severity of obese arthritis and has the capability to reduce the development of atherosclerosis by controlling the balance between Th17 and Treg cells. Thus, rebamipide could be a therapeutic agent to improve the progression of inflammation in metabolic diseases.

BackgroundThe burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.Methods and resultsWe studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10-10). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10-12) and 1.4% reduced carotid intima-media thickness (P=4×10-14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10-11).ConclusionsExome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

IntroductionCurrent residency didactic schedules that are built upon hour-long, lecture-based presentations are incongruous with adult learning theory and the needs of millennial generation residents. An alternative to the traditional lecture, the flipped classroom involves viewing a short video lecture at home, followed by an active discussion during class time. This module was developed for emergency medicine residents and rotating medical students without previous training on the subject.MethodsThe at-home portion of the module was designed to be delivered at home, while the in-class discussion was designed to be carried out over 30-45 minutes during a regularly scheduled didactic time. Small-group size may be determined by faculty availability, though groups of five are optimal. There is no requirement for faculty preparation prior to the in-class session. Associated materials include objectives, the at-home video, a discussion guide for faculty facilitators, a case-based handout for students and residents, and assessment questions. We assessed our module with a pretest, immediate posttest, and the posttest again after 90 days.ResultsThe mean pretest score was 66%, mean posttest score 76%, and mean retention test score 66%. There was an immediate increase of 10%, which did not remain at 90 days.DiscussionWe developed a flipped classroom module that can be implemented in any emergency medicine residency or clerkship. It addresses the theoretical challenges posed to traditional conference didactics by increasing the focus on problem solving and self-directed learning.

IntroductionCurrent residency didactic schedules that are built upon hour-long, lecture-based presentations are incongruous with adult learning theory and the needs of millennial generation residents. An alternative to the traditional lecture, the flipped classroom involves viewing a short video lecture at home, followed by an active discussion during class time. This module was developed for emergency medicine residents and rotating medical students without previous training on the subject.MethodsThe at-home portion of the module was designed to be delivered at home, while the in-class discussion was designed to be carried out over 30-45 minutes during a regularly scheduled didactic time. Small-group size may be determined by faculty availability, though groups of five are optimal. There is no requirement for faculty preparation prior to the in-class session. Associated materials include objectives, the at-home video, a discussion guide for faculty facilitators, a case-based handout for students and residents, and assessment questions. We assessed our module with a pretest, immediate posttest, and the posttest again after 90 days.ResultsThe mean pretest score was 66%, mean posttest score 76%, and mean retention test score 66%. There was an immediate increase of 10%, which did not remain at 90 days.DiscussionWe developed a flipped classroom module that can be implemented in any emergency medicine residency or clerkship. It addresses the theoretical challenges posed to traditional conference didactics by increasing the focus on problem solving and self-directed learning.

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Audience: This module is designed for emergency medicine trainees. Though it focuses on those early in their career (medical students and junior residents), it is applicable to all emergency medicine learners. Introduction: In the United States, headache is the fifth most-common primary complaint of patients presenting to the emergency department and can be the primary symptomatic manifestation of many life-threatening illnesses. The emergency physician plays a unique role in diagnosing and managing these patients. The emergency physician’s two major responsibilities are to relieve headache pain and to ensure that life-threatening causes are diagnosed and treated. Objectives: At the end of this module, the learner will be able to: 1) list the diagnoses critical to the emergency physician that may present with headache; 2) identify key historical and examination findings that help differentiate primary (benign) from secondary (serious) causes of headache; 3) discuss the indications for diagnostic imaging, lumbar puncture and laboratory testing in patients with headache; 4) recognize life-threatening diagnoses on CT imaging and CSF examination; 5) describe treatment strategies to relieve headache symptoms.  Methods: This module includes a complete flipped classroom module. Learners are responsible for viewing a 20-minute video prior to the 30-minute small-group, case-based didactic discussion portion. The learners are assessed with multiple-choice question assessments, for low stakes retrieval practice or spaced practice. This could alternatively be run as a team-based learning session, with the pre- and post-tests used as an individual or group readiness assessment test, and the small group exercises converted to a group application exercise. Topics: Headache, subarachnoid hemorrhage, migraine, occult trauma, meningitis, temporal arteritis, carbon monoxide toxicity, acute glaucoma, cervical artery dissection, space occupying lesion, idiopathic intracranial hypertension.

We discuss a case of a 64-year-old male with a history of liver failure presenting with altered mental status, initially diagnosed with hepatic encephalopathy but ultimately diagnosed with nonconvulsive status epilepticus (NCSE) by electroencephalogram (EEG). NCSE is a difficult diagnosis to make, given no clear consensus on diagnostic criteria. Especially in the intensive care unit setting of persistent altered mental status with no clear etiology, NCSE must be considered in the differential diagnosis, as the consequences of delayed diagnosis and treatment can be substantial. EEG can be useful in the evaluation of patients with hepatic encephalopathy who have persistently altered levels of consciousness despite optimal medical management. [West J Emerg Med. 2011;12(4):372–374.]