Abstract
Background
CancelRx allows prescribers to send electronic cancellation messages to pharmacies when medications are discontinued. Little is known about its functionality and impact on ...clinical workflows.
Objectives
To understand CancelRx functionality, its potential impact on workflows and medication safety risks, and to develop mitigating strategies for risks introduced by implementation.
Methods
We conducted direct observations and semi-structured interviews to develop CancelRx use cases and assessed CancelRx in an end-to-end test environment, proactive risk assessment, and pilot implementation from April 16 to July 15, 2018.
Results
E-cancellations were sent upon discontinuation of e-prescriptions written within the electronic health record (EHR), but not other medications (e.g., printed prescriptions) and could be initiated by nonprescribers. In our proactive risk assessment, CancelRx implementation eliminated five of seven failure modes in outpatient prescribing to Johns Hopkins pharmacies, but introduced new risks, including (1) failure to act if an e-cancellation was not sent or was unsuccessful; (2) failure to cancel all prescriptions for a medication; (3) errors in manual matching; and (4) erroneous medication cancellations. We identified potential mitigation strategies for these risks. During pilot implementation, 92.4% (428/463) of e-cancellations had confirmed approval by the receiving pharmacy, while 4.5% (21/463) were denied, and 3.0% (14/463) had no e-cancellation response. Among e-cancellations received by the pilot pharmacy, 1.7% (7/408) required manual matching by pharmacy staff. Based on performance in testing, 73.4% (340/463) of completed e-cancellations would be expected to generate an in-basket message, including 21 (6.2%) denials and 319/340 (93.8%) approvals with a note from the pharmacy.
Conclusion
CancelRx is an important functionality with the potential to decrease adverse events due to medication errors. However, changes in implementation in our EHR and pharmacy software and enhancements in the CancelRx standard are needed to maximize safety and usability. Further studies are needed to evaluate the impact of e-cancellation on medication safety.
Abstract
Electronic communication of prescription discontinuation, or CancelRx, has the potential to improve medication safety. We aimed to describe the proportion of discontinued outpatient ...medications that would result in a CancelRx message to understand its impact on medication safety. We used a data report to identify all outpatient medications discontinued in the electronic health record (EHR) of an academic health system in 1 month (October 2018). Among all 63 485 medications discontinued, 23 118 (36.4%) were e-prescribed, 25 982 (40.9%) were patient-reported or reconciled, and the remainder prescribed nonelectronically. Discontinued high-risk medications were more likely to be e-prescribed (2768 of 5896, 47.0%). A discontinuation reason was specified in 37 353 (58.9%) of all discontinued medications. Approximately one-third to one-half of discontinued medications were e-prescribed within the same EHR and would result in a CancelRx message to the pharmacy. Extension of this functionality to medications reconciled in the EHR could significantly expand the impact of CancelRx on medication safety. In addition, complete and accurate discontinuation reasons are needed to optimize CancelRx implementation.
Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system ...(CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.
The atypical chemokine receptor ACKR2 promotes resolution of acute inflammation by operating as a scavenger receptor for inflammatory CC chemokines in several experimental models of inflammatory ...disorders, however its role in the brain remains unclear. Based on our previous reports of increased expression of inflammatory chemokines and their corresponding receptors following traumatic brain injury (TBI), we hypothesised that ACKR2 modulates neuroinflammation following brain trauma and that its deletion exacerbates cellular inflammation and chemokine production. We demonstrate increased CCL2 and ACKR2 mRNA expression in post-mortem human brain, whereby ACKR2 mRNA levels correlated with later times post-TBI. This data is consistent with the transient upregulation of ACKR2 observed in mouse brain after closed head injury (CHI). As compared to WT animals, ACKR2-/- mice showed a higher mortality rate after CHI, while the neurological outcome in surviving mice was similar. At day 1 post-injury, ACKR2-/- mice displayed aggravated lesion volume and no differences in CCL2 expression and macrophage recruitment relative to WT mice. Reciprocal regulation of ACKR2 and CCL2 expression was explored in cultured astrocytes, which are recognized as the major source of CCL2 and also express ACKR2. ACKR2 mRNA increased as early as 2 hours after an inflammatory challenge in WT astrocytes. As expected, CCL2 expression also dramatically increased at 4 hours in WT astrocytes but was significantly lower in ACKR2-/- astrocytes, possibly indicating a co-regulation of CCL2 and ACKR2 in these cells. Conversely, in vivo, CCL2 mRNA/protein levels were increased similarly in ACKR2-/- and WT brains at 4 and 12 hours after CHI, in line with the lack of differences in cerebral macrophage recruitment and neurological recovery. In conclusion, ACKR2 is induced after TBI and has a significant impact on mortality and lesion development acutely following CHI, while its role in chemokine expression, macrophage activation, brain pathology, and neurological recovery at later time-points is minor. Concordant to evidence in multiple sclerosis experimental models, our data corroborate a distinct role for ACKR2 in cerebral inflammatory processes compared to its reported functions in peripheral tissues.
Triple‐negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen‐activated ...protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial‐to‐mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)‐approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan‐MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.
Dual inhibition of the MEK1/2 and MEK5 signaling pathways suppressed triple‐negative breast cancer cell migration, mesenchymal features, and metastasis. Mechanistically, MEK1/2 and MEK5 function through FRA‐1 activity to exert the observed pro‐migratory and mesenchymal phenotypes.
microRNAs (miRNAs) are small noncoding RNA molecules involved in the regulation of gene expression and play critical roles in human malignancies. Next‐generation sequencing analysis of the MCF‐7 ...breast cancer cell line overexpressing miR‐335‐5p and miR‐335‐3p demonstrated that the miRNA duplex repressed genes involved in the ERα signaling pathway, and enhanced resistance of MCF‐7 cells to the growth inhibitory effects of tamoxifen. These data suggest that despite its conventional role in tumor suppression, the miR‐335 transcript can also play an oncogenic role in promoting agonistic estrogen signaling in a cancerous setting.
Microbial monitoring in marine recreational waterways often overlooks environmental variables associated with pathogen occurrence. This study employs a predictive boosted regression trees (BRT) model ...to predict Staphylococcus aureus abundance in the Tampa Bay estuary and identify related environmental variables associated with the microbial pathogen’s occurrence. We provide evidence that the BRT model’s adaptability and ability to capture complex interactions among predictors make it invaluable for research on microbial indicator research. Over 18 months, water samples from 7 recreational sites underwent microbial quantitation and S. aureus isolation, followed by genetic validation. BRT analysis of S. aureus occurrence and environmental variables revealed month, precipitation, salinity, site, temperature, and year as relevant predictors. In addition, the BRT model accurately predicted S. aureus occurrence, setting a precedent for pathogen–environment research. The approach described here is novel and informs proactive management strategies and community health initiatives in marine recreational waterways.
Tamoxifen is used to prevent and treat estrogen receptor-positive (ER+) breast cancer (BC); however, its chronic use can increase uterine cancer risk and induce tamoxifen resistance. Novel ...melatonin-tamoxifen drug conjugates may be promising to treat BC and may help offset the adverse effects of tamoxifen usage alone due to the presence of melatonin. We synthesized and screened five drug conjugates (C2, C4, C5, C9, and C15 linked) for their effects on BC cell (MCF-7, tamoxifen-resistant MCF-7, mouse mammary carcinoma, MDA-MB-231, and BT-549) viability, migration, and binding affinity to melatonin receptor 1 (MT1R) and estrogen receptor 1 (ESR1). C4 and C5 demonstrated the most favorable pharmacological characteristics with respect to binding profiles (affinity for ESR1 and MT1R) and their potency/efficacy to inhibit BC cell viability and migration in four phenotypically diverse invasive ductal BC cell lines. C4 and C5 were further assessed for their actions against tamoxifen-resistant MCF-7 cells and a patient-derived xenograft triple-negative BC cell line (TU-BcX-4IC) and for their mechanisms of action using selective mitogen-activated protein kinase kinase MEK1/2, MEK5, and phosphoinositide 3-kinase (PI3K) inhibitors. C4 and C5 inhibited tamoxifen-resistant MCF-7 cells with equal potency (IC
= 4-8
M) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC
= 80-211
M) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC
= 181-304 mM; efficacy ∼80% inhibition) in TU-BcX-4IC cells. Unique pharmacokinetic profiles were observed, with C4 having greater bioavailability than C5. Further assessment of C4 and C5 demonstrates that they create novel pharmacophores within each BC cell that is context specific and involves MEK1/2/pERK1/2, MEK5/pERK5, PI3K, and nuclear factor
B. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.
PDF
