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 , 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.
This pilot study sought to evaluate the impact of pharmacist involvement in the preexisting telehealth transitional care management (TCM) program at Atrium Health on the quality and safety of the medication discharge process for high medication risk patients. Eligible participants were those 18 years of age or older with moderate-to-high risk for hospital readmission who were contacted by a TCM Nurse, identified as high medication risk patients, and referred to the TCM Pharmacist from September 2018 through February 2019. The TCM Pharmacist contacted patients by phone, completed a comprehensive medication review, identified medication list discrepancies (MLDs) and medication-related problems (MRPs), and made interventions or recommendations to primary care providers. Primary endpoints included the number and types of MLDs identified, number and types of MRPs identified, and the rate of unplanned 30-day hospital readmissions. Seventy-six patients were enrolled, and 78 MLDs and 108 MRPs were identified. Of the identified MRPs, 74.1% were resolved. A relative risk reduction of 36.8% was achieved for 30-day hospital readmissions for those with high medication risk contacted by the TCM Pharmacist compared to those only contacted by the TCM Nurse. Overall, TCM Pharmacists identified and resolved 80 medication-related problems, improved access to medication therapy, provided comprehensive medication counseling, and bridged gaps in care following hospital discharge.
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.
DNA interstrand cross-links are complex lesions that covalently bind complementary strands of DNA and whose mechanism of repair remains poorly understood. In , 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 may lack an efficient repair mechanism for this form of damage.
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