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Background Following the implementation of the HeartRescue project, with interventions in the community, emergency medical services, and hospitals to improve care and outcomes for out‐of‐hospital cardiac arrests (OHCA) in North Carolina, improved bystander and first responder treatments as well as survival were observed. This study aimed to determine whether these improvements were consistent across Black versus White individuals. Methods and Results Using the Cardiac Arrest Registry to Enhance Survival (CARES), we identified OHCA from 16 counties in North Carolina (population 3 million) from 2010 to 2014. Temporal changes in interventions and outcomes were assessed using multilevel multivariable logistic regression, adjusted for patient and socioeconomic neighborhood‐level factors. Of 7091 patients with OHCA, 36.5% were Black and 63.5% were White. Black patients were younger, more females, had more unwitnessed arrests and non‐shockable rhythm (Black: 81.0%; White: 75.4%). From 2010 to 2014, the adjusted probabilities of bystander cardiopulmonary resuscitation (CPR) went from 38.5% to 51.2% in White, P

Background Firefighter first responders dispatched in parallel with emergency medical services (EMS) personnel for out‐of‐hospital cardiac arrests (OHCA) can provide early defibrillation to improve survival. We examined whether survival following first responder defibrillation differed according to driving distance from nearest fire station to OHCA site. Methods and Results From the CARES (Cardiac Arrest Registry to Enhance Survival) registry, we identified non‐EMS witnessed OHCAs of presumed cardiac cause from 2010 to 2014 in Durham, Mecklenburg, and Wake counties, North Carolina. We used logistic regression to estimate the association between calculated driving distances (≤1, 1–1.5, 1.5–2, and >2 miles) and survival to hospital discharge following first responder defibrillation compared with defibrillation by EMS personnel. In total, 5020 OHCAs were included in the study. First responders more often applied the first automated external defibrillators at the shortest distances (≤1 mile) versus longest distances (>2 miles) (53.4% versus 46.6%, respectively, P2.0 miles), survival following first responder defibrillation did not differ from EMS defibrillation (odds ratio 0.77 [95% confidence interval 0.48–1.21] and odds ratio 0.97 [95% confidence interval 0.67–1.41], respectively). Conclusions Shorter driving distance from nearest fire station to OHCA location was associated with improved survival following defibrillation by first responders. These results suggest that the location of first responder units should be considered when organizing prehospital systems of OHCA care.

Background The Institute of Medicine has called for actions to understand and target sex‐related differences in care and outcomes for out‐of‐hospital cardiac arrest patients. We assessed changes in bystander and first‐responder interventions and outcomes for males versus females after statewide efforts to improve cardiac arrest care. Methods and Results We identified out‐of‐hospital cardiac arrests from North Carolina (2010–2014) through the CARES (Cardiac Arrest Registry to Enhance Survival) registry. Outcomes for men versus women were examined through multivariable logistic regression analyses adjusted for (1) nonmodifiable factors (age, witnessed status, and initial heart rhythm) and (2) nonmodifiable plus modifiable factors (bystander cardiopulmonary resuscitation and defibrillation before emergency medical services), including interactions between sex and time (ie, year and year2). Of 8100 patients, 38.1% were women. From 2010 to 2014, there was an increase in bystander cardiopulmonary resuscitation (men, 40.5%–50.6%; women, 35.3%–51.8%; P for each

Abstract Background Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST) that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression. Results We analyzed 20 paired tumor-normal colon cancer samples using a microarray designed to detect over one million putative exons that can be virtually assembled into potential gene-level transcripts according to various levels of prior supporting evidence. Analysis of high confidence (empirically supported) transcripts identified 160 differentially expressed genes, with 42 genes occupying a network impacting cell proliferation and another twenty nine genes with unknown functions. A more speculative analysis, including transcripts based solely on computational prediction, produced another 160 differentially expressed genes, three-fourths of which have no previous annotation. We also present a comparison of gene signal estimations from the Exon 1.0 ST and the U133 Plus 2.0 arrays. Novel splicing events were predicted by experimental algorithms that compare the relative contribution of each exon to the cognate transcript intensity in each tissue. The resulting candidate splice variants were validated with RT-PCR. We found nine genes that were differentially spliced between colon tumors and normal colon tissues, several of which have not been previously implicated in cancer. Top scoring candidates from our analysis were also found to substantially overlap with EST-based bioinformatic predictions of alternative splicing in cancer. Conclusion Differential expression of high confidence transcripts correlated extremely well with known cancer genes and pathways, suggesting that the more speculative transcripts, largely based solely on computational prediction and mostly with no previous annotation, might be novel targets in colon cancer. Five of the identified splicing events affect mediators of cytoskeletal organization (ACTN1, VCL, CALD1, CTTN, TPM1), two affect extracellular matrix proteins (FN1, COL6A3) and another participates in integrin signaling (SLC3A2). Altogether they form a pattern of colon-cancer specific alterations that may particularly impact cell motility.

Listeria monocytogenes is a bacterial pathogen that is found in a wide variety of anthropogenic and natural environments. Genome sequencing technologies are rapidly becoming a powerful tool in facilitating our understanding of how genotype, classification phenotypes, and virulence phenotypes interact to predict the health risks of individual bacterial isolates. Currently, 57 closed L. monocytogenes genomes are publicly available, representing three of the four phylogenetic lineages, and they suggest that L. monocytogenes has high genomic synteny. This study contributes an additional 15 closed L. monocytogenes genomes that were used to determine the associations between the genome and methylome with host invasion magnitude. In contrast to previous findings, large chromosomal inversions and rearrangements were detected in five isolates at the chromosome terminus and within rRNA genes, including a previously undescribed inversion within rRNA-encoding regions. Each isolate's epigenome contained highly diverse methyltransferase recognition sites, even within the same serotype and methylation pattern. Eleven strains contained a single chromosomally encoded methyltransferase, one strain contained two methylation systems (one system on a plasmid), and three strains exhibited no methylation, despite the occurrence of methyltransferase genes. In three isolates a new, unknown DNA modification was observed in addition to diverse methylation patterns, accompanied by a novel methylation system. Neither chromosome rearrangement nor strain-specific patterns of epigenome modification observed within virulence genes were correlated with serotype designation, clonal complex, or in vitro infectivity. These data suggest that genome diversity is larger than previously considered in L. monocytogenes and that as more genomes are sequenced, additional structure and methylation novelty will be observed in this organism.ImportanceListeria monocytogenes is the causative agent of listeriosis, a disease which manifests as gastroenteritis, meningoencephalitis, and abortion. Among Salmonella, Escherichia coli, Campylobacter, and Listeria-causing the most prevalent foodborne illnesses-infection by L. monocytogenes carries the highest mortality rate. The ability of L. monocytogenes to regulate its response to various harsh environments enables its persistence and transmission. Small-scale comparisons of L. monocytogenes focusing solely on genome contents reveal a highly syntenic genome yet fail to address the observed diversity in phenotypic regulation. This study provides a large-scale comparison of 302 L. monocytogenes isolates, revealing the importance of the epigenome and restriction-modification systems as major determinants of L. monocytogenes phylogenetic grouping and subsequent phenotypic expression. Further examination of virulence genes of select outbreak strains reveals an unprecedented diversity in methylation statuses despite high degrees of genome conservation.

DNA methylation acts in concert with restriction enzymes to protect the integrity of prokaryotic genomes. Studies in a limited number of organisms suggest that methylation also contributes to prokaryotic genome regulation, but the prevalence and properties of such non-restriction-associated methylation systems remain poorly understood. Here, we used single molecule, real-time sequencing to map DNA modifications including m6A, m4C, and m5C across the genomes of 230 diverse bacterial and archaeal species. We observed DNA methylation in nearly all (93%) organisms examined, and identified a total of 834 distinct reproducibly methylated motifs. This data enabled annotation of the DNA binding specificities of 620 DNA Methyltransferases (MTases), doubling known specificities for previously hard to study Type I, IIG and III MTases, and revealing their extraordinary diversity. Strikingly, 48% of organisms harbor active Type II MTases with no apparent cognate restriction enzyme. These active 'orphan' MTases are present in diverse bacterial and archaeal phyla and show motif specificities and methylation patterns consistent with functions in gene regulation and DNA replication. Our results reveal the pervasive presence of DNA methylation throughout the prokaryotic kingdoms, as well as the diversity of sequence specificities and potential functions of DNA methylation systems.

Protein-RNA interactions have critical roles in all aspects of gene expression. However, applying biochemical methods to understand such interactions in living tissues has been challenging. Here we develop a genome-wide [...]

The pair wise association of several transcriptional gene-expression values with a large number of single-nucleotide polymorphisms (SNPs) in different population samples is studied. The genetic architecture and the gene expressions are shown to be highly affected by several different biological pathways.

The impact of the genetic variations and the nongenetic factors on the differences found in the gene expression between different populations is investigated. The observed population differences in the gene expression are found to highly affect the susceptibility of the people to several common diseases as well.

Genetic variants contributing to cisplatin-induced cytotoxicity is studied by use of a genomewide approach and concluded that the whole genome approach can be applied to uncover the genetic signatures contributing to a wide range of cellular phenotypes.