A central hurdle in developing small interfering RNAs (siRNAs) as therapeutics is the inefficiency of their delivery across the plasma and endosomal membranes to the cytosol, where they interact with the RNA interference machinery. With the aim of improving endosomal release, a poorly understood and inefficient process, we studied the uptake and cytosolic release of siRNAs, formulated in lipoplexes or lipid nanoparticles, by live-cell imaging and correlated it with knockdown of a target GFP reporter. siRNA release occurred invariably from maturing endosomes within ~5–15 min of endocytosis. Cytosolic galectins immediately recognized the damaged endosome and targeted it for autophagy. However, inhibiting autophagy did not enhance cytosolic siRNA release. Gene knockdown occurred within a few hours of release and required <2,000 copies of cytosolic siRNAs. The ability to detect cytosolic release of siRNAs and understand how it is regulated will facilitate the development of rational strategies for improving the cytosolic delivery of candidate drugs.

Objective To illustrate ways in which clinical decision support systems (CDSSs) malfunction and identify patterns of such malfunctions.Materials and Methods We identified and investigated several CDSS malfunctions at Brigham and Women’s Hospital and present them as a case series. We also conducted a preliminary survey of Chief Medical Information Officers to assess the frequency of such malfunctions.Results We identified four CDSS malfunctions at Brigham and Women’s Hospital: (1) an alert for monitoring thyroid function in patients receiving amiodarone stopped working when an internal identifier for amiodarone was changed in another system; (2) an alert for lead screening for children stopped working when the rule was inadvertently edited; (3) a software upgrade of the electronic health record software caused numerous spurious alerts to fire; and (4) a malfunction in an external drug classification system caused an alert to inappropriately suggest antiplatelet drugs, such as aspirin, for patients already taking one. We found that 93% of the Chief Medical Information Officers who responded to our survey had experienced at least one CDSS malfunction, and two-thirds experienced malfunctions at least annually.Discussion CDSS malfunctions are widespread and often persist for long periods. The failure of alerts to fire is particularly difficult to detect. A range of causes, including changes in codes and fields, software upgrades, inadvertent disabling or editing of rules, and malfunctions of external systems commonly contribute to CDSS malfunctions, and current approaches for preventing and detecting such malfunctions are inadequate.Conclusion CDSS malfunctions occur commonly and often go undetected. Better methods are needed to prevent and detect these malfunctions.

ObjectiveTo develop an empirically derived taxonomy of clinical decision support (CDS) alert malfunctions.Materials and MethodsWe identified CDS alert malfunctions using a mix of qualitative and quantitative methods: (1) site visits with interviews of chief medical informatics officers, CDS developers, clinical leaders, and CDS end users; (2) surveys of chief medical informatics officers; (3) analysis of CDS firing rates; and (4) analysis of CDS overrides. We used a multi-round, manual, iterative card sort to develop a multi-axial, empirically derived taxonomy of CDS malfunctions.ResultsWe analyzed 68 CDS alert malfunction cases from 14 sites across the United States with diverse electronic health record systems. Four primary axes emerged: the cause of the malfunction, its mode of discovery, when it began, and how it affected rule firing. Build errors, conceptualization errors, and the introduction of new concepts or terms were the most frequent causes. User reports were the predominant mode of discovery. Many malfunctions within our database caused rules to fire for patients for whom they should not have (false positives), but the reverse (false negatives) was also common.DiscussionAcross organizations and electronic health record systems, similar malfunction patterns recurred. Challenges included updates to code sets and values, software issues at the time of system upgrades, difficulties with migration of CDS content between computing environments, and the challenge of correctly conceptualizing and building CDS.ConclusionCDS alert malfunctions are frequent. The empirically derived taxonomy formalizes the common recurring issues that cause these malfunctions, helping CDS developers anticipate and prevent CDS malfunctions before they occur or detect and resolve them expediently.

Objective: The United States Office of the National Coordinator for Health Information Technology sponsored the development of a “high-priority” list of drug-drug interactions (DDIs) to be used for clinical decision support. We assessed current adoption of this list and current alerting practice for these DDIs with regard to alert implementation (presence or absence of an alert) and display (alert appearance as interruptive or passive).Materials and methods: We conducted evaluations of electronic health records (EHRs) at a convenience sample of health care organizations across the United States using a standardized testing protocol with simulated orders.Results: Evaluations of 19 systems were conducted at 13 sites using 14 different EHRs. Across systems, 69% of the high-priority DDI pairs produced alerts. Implementation and display of the DDI alerts tested varied between systems, even when the same EHR vendor was used. Across the drug pairs evaluated, implementation and display of DDI alerts differed, ranging from 27% (4/15) to 93% (14/15) implementation.Discussion: Currently, there is no standard of care covering which DDI alerts to implement or how to display them to providers. Opportunities to improve DDI alerting include using differential displays based on DDI severity, establishing improved lists of clinically significant DDIs, and thoroughly reviewing organizational implementation decisions regarding DDIs.Conclusion: DDI alerting is clinically important but not standardized. There is significant room for improvement and standardization around evidence-based DDIs.