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BackgroundAntibiotics are among the most frequently administered drugs globally, yet they are often prescribed inappropriately. Guidelines for prescribing are developed by expert committees at international and national levels to form regional standards and by local experts to form hospital guidance documents. Our aim was to assess variability in antibiotic prescription guidelines for both regional standards and individual hospitals.MethodsA search through 3 publicly accessible databases from February to June 2018 led to a corpus of English language guidance documents from 70 hospitals in 12 countries and regional standards from 7 academic societies.ResultsGuidelines varied markedly in content and structure, reflecting a paucity of rules governing their format. We compared recommendations for 3 common bacterial infections: community-acquired pneumonia, urinary tract infection, and cellulitis. Hospital guidance documents and regional standards frequently disagreed on preferable antibiotic classes for common infections. Where agreement was observed, guidance documents appeared to inherit recommendations from their respective regional standards. Several regional prescribing patterns were identified, including a greater reliance on penicillins over cephalosporins in the United Kingdom and fluoroquinolones in the United States. Regional prescribing patterns could not be explained by antibiotic resistance or costs. Additionally, literature that cited underlying recommendations did not support the magnitude of recommendation differences observed.ConclusionsThe observed discordance among prescription recommendations highlights a lack of evidence for superior treatments, likely resulting from a preponderance of noninferiority trials comparing antibiotics. In response, we make several suggestions for developing guidelines that support best practices of antibiotic stewardship.

ObjectiveTo elucidate the genetic architecture of gene expression in pancreatic tissues.DesignWe performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison.ResultsWe identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate cis-eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8×10−8) and tumour-derived (p=8.3×10−5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the ‘O’ mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO ‘O’ mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL.ConclusionsWe have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.

Background The accrediting institution for hospitals in the United States made antimicrobial stewardship programs (ASPs) mandatory in 2017. In part due to the relatively new status of ASPs, standards surrounding the content produced by these programs are still in their infancy. One product of ASPs are antibiotic prescription guidelines, which vary greatly across hospitals in terms of their structure and content. Methods In this study, we reviewed 70 publicly available antibiotic prescription guidelines published from 2006 to 2017, originating from 12 countries on four continents to evaluate their coverage and variability. Results Guidelines varied greatly in terms of their length, word count, page layout, revision frequency, and number of contributing authors. In terms of content, guidelines were discordant in their inclusion of cost information, restricted antibiotics, disclaimers, and pediatric recommendations. Guidelines also varied in their approach, in that some were focused on how to approach specific diagnoses, while others were focused on the usage of particular antibiotics. Many guidelines made use of decision trees to convey information, especially for the diagnosis and treatment of Clostridium difficile-associated diarrhea, cellulitis, and community-acquired pneumonia; however, the number of decision trees included in a hospital’s guideline varied greatly. A small minority of guidelines included identification trees for classifying bacterial isolates. Guidelines also notably differed in the extent to which they incorporated local antibiotic susceptibility data. Some guidelines did not report antibiogram summaries, while others displayed information for 5 to 34 organisms. Furthermore, we assessed guidelines’ prescription recommendations for 12 common bacterial infections and found large variation in suggested prescribing practices across hospitals. Conclusion To our knowledge, this study provides the first large-scale analysis of antibiotic prescription guidelines and highlights the extreme variation in approaches to stewardship across hospitals. Furthermore, our analysis provides a baseline of current practices for future comparison, and initiates a discussion into what comprises a model antibiotic prescription guideline. Disclosures All authors: No reported disclosures.

Objective: To elucidate the genetic architecture of gene expression in pancreatic tissues. Design: We performed expression quantitative trait locus (eQTL) and allele specific expression (ASE) analyses using RNA-sequence data and 1000 Genomes (1000G) imputed GWAS genotypes from 95 fresh frozen histologically normal pancreatic tissue samples. Data from 115 pancreatic tumor-derived tissue samples from The Cancer Genome Atlas (TCGA) was included for comparison. Results: We identified 38,615 cis-eQTLs (corresponding to 484 Genes) in histologically normal tissues and 39,713 cis-eQTL (corresponding to 237 Genes) in tumor tissues (FDR Conclusions: We have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich dataset for further studies on gene expression and regulation in pancreatic tissues. Citation Format: Laufey T. Amundadottir, Soren Lykke Andresen, Wenming Xiao, Jason Hoskins, Ashley Jermusyk, Lauren Rost, Irene Collins, Jinping Jia, Michael Mobaraki, Bin Zhu, Robert Kurtz, Hemang Parikh, Lei Song, Meredith Yeager, Torben Jensen, William Bamlet, Nilanjan Chatterjee, Brian Wolpin, Jill Smith, Sara Olson, Gloria Petersen, Jianxin Shi, Mingfeng Zhang. Analysis of cis-eQTLs in normal and tumor-derived pancreatic tissues reveals functional insights, including for the 9q34.1 ABO pancreatic cancer risk locus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1442. doi:10.1158/1538-7445.AM2017-1442

Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P = 2.30 × 10−11, OR = 1.22, 95% CI 1.15–1.28) and highly correlated to rs9543325 (r2 = 0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (β = 0.26, P = 0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ∼6 kb upstream of DIS3. Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.