The Value of Monitoring Clinical Decision Support Interventions.

BACKGROUND: Well-functioning clinical decision support (CDS) can facilitate provider workflow, improve patient care, promote better outcomes, and reduce costs. However, poorly functioning CDS may lead to alert fatigue, cause providers to ignore important CDS interventions, and increase provider dissatisfaction. OBJECTIVE: The purpose of this article is to describe one institution's experience in implementing a program to create and maintain properly functioning CDS by systematically monitoring CDS firing rates and patterns. METHODS: Four types of CDS monitoring activities were implemented as part of the CDS lifecycle. One type of monitoring occurs prior to releasing active CDS, while the other types occur at different points after CDS activation. RESULTS: Two hundred and forty-eight CDS interventions were monitored over a 2-year period. The rate of detecting a malfunction or significant opportunity for improvement was 37% during preactivation and 18% during immediate postactivation monitoring. Monitoring also informed the process of responding to user feedback about alerts. Finally, an automated alert detection tool identified 128 instances of alert pattern change over the same period. A subset of cases was evaluated by knowledge engineers to identify true and false positives, the results of which were used to optimize the tool's pattern detection algorithms. CONCLUSION: CDS monitoring can identify malfunctions and/or significant improvement opportunities even after careful design and robust testing. CDS monitoring provides information when responding to user feedback. Ongoing, continuous, and automated monitoring can detect malfunctions in real time, before users report problems. Therefore, CDS monitoring should be part of any systematic program of implementing and maintaining CDS.

Criteria for assessing high-priority drug-drug interactions for clinical decision support in electronic health records.

BACKGROUND: High override rates for drug-drug interaction (DDI) alerts in electronic health records (EHRs) result in the potentially dangerous consequence of providers ignoring clinically significant alerts. Lack of uniformity of criteria for determining the severity or validity of these interactions often results in discrepancies in how these are evaluated. The purpose of this study was to identify a set of criteria for assessing DDIs that should be used for the generation of clinical decision support (CDS) alerts in EHRs. METHODS: We conducted a 20-year systematic literature review of MEDLINE and EMBASE to identify characteristics of high-priority DDIs. These criteria were validated by an expert panel consisting of medication knowledge base vendors, EHR vendors, in-house knowledge base developers from academic medical centers, and both federal and private agencies involved in the regulation of medication use. RESULTS: Forty-four articles met the inclusion criteria for assessing characteristics of high-priority DDIs. The panel considered five criteria to be most important when assessing an interaction- Severity, Probability, Clinical Implications of the interaction, Patient characteristics, and the Evidence supporting the interaction. In addition, the panel identified barriers and considerations for being able to utilize these criteria in medication knowledge bases used by EHRs. CONCLUSIONS: A multi-dimensional approach is needed to understanding the importance of an interaction for inclusion in medication knowledge bases for the purpose of CDS alerting. The criteria identified in this study can serve as a first step towards a uniform approach in assessing which interactions are critical and warrant interruption of a provider's workflow.

High-priority drug-drug interactions for use in electronic health records.

OBJECTIVE: To develop a set of high-severity, clinically significant drug-drug interactions (DDIs) for use in electronic health records (EHRs). METHODS: A panel of experts was convened with the goal of identifying critical DDIs that should be used for generating medication-related decision support alerts in all EHRs. Panelists included medication knowledge base vendors, EHR vendors, in-house knowledge base developers from academic medical centers, and both federal and private agencies involved in the regulation of medication use. Candidate DDIs were assessed by the panel based on the consequence of the interaction, severity levels assigned to them across various medication knowledge bases, availability of therapeutic alternatives, monitoring/management options, predisposing factors, and the probability of the interaction based on the strength of evidence available in the literature. RESULTS: Of 31 DDIs considered to be high risk, the panel approved a final list of 15 interactions. Panelists agreed that this list represented drugs that are contraindicated for concurrent use, though it does not necessarily represent a complete list of all such interacting drug pairs. For other drug interactions, severity may depend on additional factors, such as patient conditions or timing of co-administration. DISCUSSION: The panel provided recommendations on the creation, maintenance, and implementation of a central repository of high severity interactions. CONCLUSIONS: A set of highly clinically significant drug-drug interactions was identified, for which warnings should be generated in all EHRs. The panel highlighted the complexity of issues surrounding development and implementation of such a list.

Progranulin deficiency decreases gross neural connectivity but enhances transmission at individual synapses.

Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that knocking down PGRN levels in rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization and length as well as synapse density. Despite this, the number of synaptic vesicles per synapse and the frequency of mEPSCs are increased in PGRN knockdown cells, suggesting an increase in the probability of release at remaining synapses. Interestingly, we demonstrate that the number of vesicles per synapse is also increased in postmortem brain sections from FTD patients with PGRN haploinsufficiency, relative to controls. Our observations show that PGRN knockdown severely alters neuronal connectivity in vitro and that the synaptic vesicle phenotype observed in culture is consistent with that observed in the hippocampus of FTD patients.

Scribble interacts with beta-catenin to localize synaptic vesicles to synapses.

An understanding of how synaptic vesicles are recruited to and maintained at presynaptic compartments is required to discern the molecular mechanisms underlying presynaptic assembly and plasticity. We have previously demonstrated that cadherin-beta-catenin complexes cluster synaptic vesicles at presynaptic sites. Here we show that scribble interacts with the cadherin-beta-catenin complex to coordinate vesicle localization. Scribble and beta-catenin are colocalized at synapses and can be coimmunoprecipitated from neuronal lysates, indicating an interaction between scribble and beta-catenin at the synapse. Using an RNA interference approach, we demonstrate that scribble is important for the clustering of synaptic vesicles at synapses. Indeed, in scribble knockdown cells, there is a diffuse distribution of synaptic vesicles along the axon, and a deficit in vesicle recycling. Despite this, synapse number and the distribution of the presynaptic active zone protein, bassoon, remain unchanged. These effects largely phenocopy those observed after ablation of beta-catenin. In addition, we show that loss of beta-catenin disrupts scribble localization in primary neurons but that the localization of beta-catenin is not dependent on scribble. Our data supports a model by which scribble functions downstream of beta-catenin to cluster synaptic vesicles at developing synapses.

Tiering drug-drug interaction alerts by severity increases compliance rates.

OBJECTIVE: Few data exist measuring the effect of differentiating drug-drug interaction (DDI) alerts in computerized provider order entry systems (CPOE) by level of severity ("tiering"). We sought to determine if rates of provider compliance with DDI alerts in the inpatient setting differed when a tiered presentation was implemented. DESIGN: We performed a retrospective analysis of alert log data on hospitalized patients at two academic medical centers during the period from 2/1/2004 through 2/1/2005. Both inpatient CPOE systems used the same DDI checking service, but one displayed alerts differentially by severity level (tiered presentation, including hard stops for the most severe alerts) while the other did not. Participants were adult inpatients who generated a DDI alert, and providers who wrote the orders. Alerts were presented during the order entry process, providing the clinician with the opportunity to change the patient's medication orders to avoid the interaction. MEASUREMENTS: Rate of compliance to alerts at a tiered site compared to a non-tiered site. RESULTS: We reviewed 71,350 alerts, of which 39,474 occurred at the non-tiered site and 31,876 at the tiered site. Compliance with DDI alerts was significantly higher at the site with tiered DDI alerts compared to the non-tiered site (29% vs. 10%, p < 0.001). At the tiered site, 100% of the most severe alerts were accepted, vs. only 34% at the non-tiered site; moderately severe alerts were also more likely to be accepted at the tiered site (29% vs. 10%). CONCLUSION: Tiered alerting by severity was associated with higher compliance rates of DDI alerts in the inpatient setting, and lack of tiering was associated with a high override rate of more severe alerts.

Induction of SM-20 in PC12 cells leads to increased cytochrome c levels, accumulation of cytochrome c in the cytosol, and caspase-dependent cell death.

Sympathetic neurons deprived of nerve growth factor (NGF) release cytochrome c into the cytosol and undergo caspase-dependent cell death through a process that requires de novo gene expression. Expression of the SM-20 gene increases after NGF withdrawal, and ectopic SM-20 expression induces cell death in NGF-maintained neurons. To further evaluate the mechanism by which SM-20 promotes cell death, we developed a PC12-derived cell line in which SM-20 expression can be induced by addition of doxycycline to the culture medium. Induction of SM-20 in either undifferentiated or NGF-differentiated cells resulted in cell death. Cell death was accompanied by an increase in caspase activity and was inhibited by the caspase inhibitor zVAD-FMK. Analysis of cytochrome c in cytosolic and mitochondria-enriched subcellular fractions revealed that induction of SM-20 led to the accumulation of cytochrome c in the cytosol. Surprisingly, SM-20 expression also resulted in a selective increase in the total amount of cytochrome c protein. Thus, induction of SM-20 expression appears to affect both the amount and subcellular localization of cytochrome c in PC12 cells. These results suggest that SM-20 promotes caspase-dependent cell death through a mechanism involving cytochrome c.