How Safe are Outpatient Electronic Health Records? An Evaluation of Medication-Related Decision Support using the Ambulatory Electronic Health Record Evaluation Tool.

BACKGROUND: The purpose of the Ambulatory Electronic Health Record (EHR) Evaluation Tool is to provide outpatient clinics with an assessment that they can use to measure the ability of the EHR system to detect and prevent common prescriber errors. The tool consists of a medication safety test and a medication reconciliation module. OBJECTIVES: The goal of this study was to perform a broad evaluation of outpatient medication-related decision support using the Ambulatory EHR Evaluation Tool. METHODS: We performed a cross-sectional study with 10 outpatient clinics using the Ambulatory EHR Evaluation Tool. For the medication safety test, clinics were provided test patients and associated medication test orders to enter in their EHR, where they recorded any advice or information they received. Once finished, clinics received an overall percentage score of unsafe orders detected and individual order category scores. For the medication reconciliation module, clinics were asked to electronically reconcile two medication lists, where modifications were made by adding and removing medications and changing the dosage of select medications. RESULTS: For the medication safety test, the mean overall score was 57%, with the highest score being 70%, and the lowest score being 40%. Clinics performed well in the drug allergy (100%), drug dose daily (85%), and inappropriate medication combinations (74%) order categories. Order categories with the lowest performance were drug laboratory (10%) and drug monitoring (3%). Most clinics (90%) scored a 0% in at least one order category. For the medication reconciliation module, only one clinic (10%) could reconcile medication lists electronically; however, there was no clinical decision support available that checked for drug interactions. CONCLUSION: We evaluated a sample of ambulatory practices around their medication-related decision support and found that advanced capabilities within these systems have yet to be widely implemented. The tool was practical to use and identified substantial opportunities for improvement in outpatient medication safety.

Mutations in AcrR and RNA Polymerase Confer High-Level Resistance to Psoralen-UVA Irradiation.

DNA interstrand cross-links, such as those formed by psoralen-UVA irradiation, are highly toxic lesions in both humans and bacteria, with a single lesion being lethal in Escherichia coli. Despite the lack of effective repair, human cancers and bacteria can develop resistance to cross-linking treatments, although the mechanisms of resistance remain poorly defined. Here, we subjected E. coli to repeated psoralen-UVA exposure to isolate three independently derived strains that were >10,000-fold more resistant to this treatment than the parental strain. Analysis of these strains identified gain-of-function mutations in the transcriptional regulator AcrR and the alpha subunit of RNA polymerase that together could account for the resistance of these strains. Resistance conferred by the AcrR mutation is mediated at least in part through the regulation of the AcrAB-TolC efflux pump. Resistance via mutations in the alpha subunit of RNA polymerase occurs through a still-uncharacterized mechanism that has an additive effect with mutations in AcrR. Both acrR and rpoA mutations reduced cross-link formation in vivo. We discuss potential mechanisms in relation to the ability to repair and survive interstrand DNA cross-links. IMPORTANCE Psoralen DNA interstrand cross-links are highly toxic lesions with antimicrobial and anticancer properties. Despite the lack of effective mechanisms for repair, cells can become resistant to cross-linking agents through mechanisms that remain poorly defined. We derived resistant mutants and identified that two gain-of-function mutations in AcrR and the alpha subunit of RNA polymerase confer high levels of resistance to E. coli treated with psoralen-UVA. Resistance conferred by AcrR mutations occurs through regulation of the AcrAB-TolC efflux pump, has an additive effect with RNA polymerase mutations, acts by reducing the formation of cross-links in vivo, and reveals a novel mechanism by which these environmentally and clinically important agents are processed by the cell.

The Development and Piloting of the Ambulatory Electronic Health Record Evaluation Tool: Lessons Learned.

BACKGROUND: Substantial research has been performed about the impact of computerized physician order entry on medication safety in the inpatient setting; however, relatively little has been done in ambulatory care, where most medications are prescribed. OBJECTIVE: To outline the development and piloting process of the Ambulatory Electronic Health Record (EHR) Evaluation Tool and to report the quantitative and qualitative results from the pilot. METHODS: The Ambulatory EHR Evaluation Tool closely mirrors the inpatient version of the tool, which is administered by The Leapfrog Group. The tool was piloted with seven clinics in the United States, each using a different EHR. The tool consists of a medication safety test and a medication reconciliation module. For the medication test, clinics entered test patients and associated test orders into their EHR and recorded any decision support they received. An overall percentage score of unsafe orders detected, and order category scores were provided to clinics. For the medication reconciliation module, clinics demonstrated how their EHR electronically detected discrepancies between two medication lists. RESULTS: For the medication safety test, the clinics correctly alerted on 54.6% of unsafe medication orders. Clinics scored highest in the drug allergy (100%) and drug-drug interaction (89.3%) categories. Lower scoring categories included drug age (39.3%) and therapeutic duplication (39.3%). None of the clinics alerted for the drug laboratory or drug monitoring orders. In the medication reconciliation module, three (42.8%) clinics had an EHR-based medication reconciliation function; however, only one of those clinics could demonstrate it during the pilot. CONCLUSION: Clinics struggled in areas of advanced decision support such as drug age, drug laboratory, and drub monitoring. Most clinics did not have an EHR-based medication reconciliation function and this process was dependent on accessing patients' medication lists. Wider use of this tool could improve outpatient medication safety and can inform vendors about areas of improvement.

Limited Capacity or Involvement of Excision Repair, Double-Strand Breaks, or Translesion Synthesis for Psoralen Cross-Link Repair in Escherichia coli.

DNA interstrand cross-links are complex lesions that covalently bind complementary strands of DNA and whose mechanism of repair remains poorly understood. In Escherichia coli, several gene products have been proposed to be involved in cross-link repair based on the hypersensitivity of mutants to cross-linking agents. However, cross-linking agents induce several forms of DNA damage, making it challenging to attribute mutant hypersensitivity specifically to interstrand cross-links. To address this, we compared the survival of UVA-irradiated repair mutants in the presence of 8-methoxypsoralen-which forms interstrand cross-links and monoadducts-to that of angelicin-a congener forming only monoadducts. We show that incision by nucleotide excision repair is not required for resistance to interstrand cross-links. In addition, neither RecN nor DNA polymerases II, IV, or V is required for interstrand cross-link survival, arguing against models that involve critical roles for double-strand break repair or translesion synthesis in the repair process. Finally, estimates based on Southern analysis of DNA fragments in alkali agarose gels indicate that lethality occurs in wild-type cells at doses producing as few as one to two interstrand cross-links per genome. These observations suggest that E. coli may lack an efficient repair mechanism for this form of damage.

SbcC-SbcD and ExoI process convergent forks to complete chromosome replication.

SbcC-SbcD are the bacterial orthologs of Mre11-Rad50, a nuclease complex essential for genome stability, normal development, and viability in mammals. In vitro, these enzymes degrade long DNA palindromic structures. When inactivated along with ExoI in Escherichia coli, or Sae2 in eukaryotes, palindromic amplifications arise and propagate in cells. However, long DNA palindromes are not normally found in bacterial or human genomes, leaving the cellular substrates and function of these enzymes unknown. Here, we show that during the completion of DNA replication, convergent replication forks form a palindrome-like structural intermediate that requires nucleolytic processing by SbcC-SbcD and ExoI before chromosome replication can be completed. Inactivation of these nucleases prevents completion from occurring, and under these conditions, cells maintain viability by shunting the reaction through an aberrant recombinational pathway that leads to amplifications and instability in this region. The results identify replication completion as an event critical to maintain genome integrity and cell viability, demonstrate SbcC-SbcD-ExoI acts before RecBCD and is required to initiate the completion reaction, and reveal how defects in completion result in genomic instability.