Faculty Bibliography

The USA300 North American epidemic (USA300-NAE) clone of methicillin-resistantStaphylococcus aureushas caused a wave of severe skin and soft tissue infections in the United States since it emerged in the early 2000s, but its geographic origin is obscure. Here we use the population genomic signatures expected from the serial founder effects of a geographic range expansion to infer the origin of USA300-NAE and identify polymorphisms associated with its spread. Genome sequences from 357 isolates from 22 U.S. states and territories and seven other countries are compared. We observe two significant signatures of range expansion, including decreases in genetic diversity and increases in derived allele frequency with geographic distance from the Pennsylvania region. These signatures account for approximately half of the core nucleotide variation of this clone, occur genome wide, and are robust to heterogeneity in temporal sampling of isolates, human population density, and recombination detection methods. The potential for positive selection of agyrAfluoroquinolone resistance allele and several intergenic regions, along with a 2.4 times higher recombination rate in a resistant subclade, is noted. These results are the first to show a pattern of genetic variation that is consistent with a range expansion of an epidemic bacterial clone, and they highlight a rarely considered but potentially common mechanism by which genetic drift may profoundly influence bacterial genetic variation.IMPORTANCEThe process of geographic spread of an origin population by a series of smaller populations can result in distinctive patterns of genetic variation. We detect these patterns for the first time with an epidemic bacterial clone and use them to uncover the clone's geographic origin and variants associated with its spread. We study the USA300 clone of methicillin-resistantStaphylococcus aureus, which was first noticed in the early 2000s and subsequently became the leading cause of skin and soft tissue infections in the United States. The eastern United States is the most likely origin of epidemic USA300. Relatively few variants, which include an antibiotic resistance mutation, have persisted during this clone's spread. Our study suggests that an early chapter in the genetic history of this epidemic bacterial clone was greatly influenced by random subsampling of isolates during the clone's geographic spread.

Context:Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, usually benign, tumors. Currently, the only reliable criterion of malignancy is the presence of metastases. Objective:The aim of this study was to identify genes associated with malignancy in PPGLs. Design:Transcriptomic profiling was performed on 40 benign and 11 malignant PPGLs. Genes showing a significantly different expression between benign and malignant PPGLs with a ratio ≥4 were confirmed and tested in an independent series by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed for the validated genes on 109 benign and 32 malignant PPGLs. Functional assays were performed with hPheo1 cells. Setting:This study was conducted at the Department of Pathology of the Erasmus MC University Medical Center Rotterdam Human Molecular Genetics laboratory of the de Duve Institute, University of Louvain. Patients:PPGL samples from 179 patients, diagnosed between 1972 and 2015, were included. Main outcome measures:Associations between gene expression and malignancy were tested using supervised clustering approaches. Results:Ten differentially expressed genes were selected based on messenger RNA (mRNA) expression array data. Contactin 4 (CNTN4) was overexpressed in malignant vs benign tumors [4.62-fold; false discovery rate (FDR), 0.001]. Overexpression at the mRNA level was confirmed using qRT-PCR (2.90-fold, P = 0.02; validation set: 4.26-fold, P = 0.005). Consistent findings were obtained in The Cancer Genome Atlas cohort (2.7-fold; FDR, 0.02). CNTN4 protein was more frequently expressed in malignant than in benign PPGLs by immunohistochemistry (58% vs 17%; P = 0.002). Survival after 7 days of culture under starvation conditions was significantly enhanced in hPheo1 cells transfected with CNTN4 complementary DNA. Conclusion:CNTN4 expression is consistently associated with malignant behavior in PPGLs.

Although blood transfusion is a lifesaving therapy for some patients, transfusion has been named 1 of the top 5 overused procedures in US hospitals. As unnecessary transfusions only increase risk and cost without providing benefit, improving transfusion practice is an effective way of promoting high-value care. Most high-quality clinical trials supporting a restrictive transfusion strategy have been published in the past 5 to 10 years, so the value of a successful patient blood management program has only recently been recognized. We review the most recent transfusion practice guidelines and the evidence supporting these guidelines. We also discuss several medical societies' Choosing Wisely campaigns to reduce or eliminate overuse of transfusions. A blueprint is presented for developing a patient blood management program, which includes discussion of specific methods for optimizing transfusion practice.