Strategies used to detect and mitigate system-related errors over time: A qualitative study in an Australian health district.

BACKGROUND: Electronic medical record (EMR) systems provide timely access to clinical information and have been shown to improve medication safety. However, EMRs can also create opportunities for error, including system-related errors or errors that were unlikely or not possible with the use of paper medication charts. This study aimed to determine the detection and mitigation strategies adopted by a health district in Australia to target system-related errors and to explore stakeholder views on strategies needed to curb future system-related errors from emerging. METHODS: A qualitative descriptive study design was used comprising semi-structured interviews. Data were collected from three hospitals within a health district in Sydney, Australia, between September 2020 and May 2021. Interviews were conducted with EMR users and other key stakeholders (e.g. clinical informatics team members). Participants were asked to reflect on how system-related errors changed over time, and to describe approaches taken by their organisation to detect and mitigate these errors. Thematic analysis was conducted iteratively using a general inductive approach, where codes were assigned as themes emerged from the data. RESULTS: Interviews were conducted with 25 stakeholders. Participants reported that most system-related errors were detected by front-line clinicians. Following error detection, clinicians either reported system-related errors directly to the clinical informatics team or submitted reports to the incident information management system. System-related errors were also reported to be detected via reports run within the EMR, or during organisational processes such as incident investigations or system enhancement projects. EMR redesign was the main approach described by participants for mitigating system-related errors, however other strategies, like regular user education and minimising the use of hybrid systems, were also reported. CONCLUSIONS: Initial detection of system-related errors relies heavily on front-line clinicians, however other organisational strategies that are proactive and layered can improve the systemic detection, investigation, and management of errors. Together with EMR design changes, complementary error mitigation strategies, including targeted staff education, can support safe EMR use and development.

Erratum: iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells.

[This corrects the article DOI: 10.1016/j.isci.2023.107059.].

An Analysis of Incident Reports Related to Electronic Medication Management: How They Change Over Time.

OBJECTIVE: Electronic medication management (EMM) systems have been shown to introduce new patient safety risks that were not possible, or unlikely to occur, with the use of paper charts. Our aim was to examine the factors that contribute to EMM-related incidents and how these incidents change over time with ongoing EMM use. METHODS: Incidents reported at 3 hospitals between January 1, 2010, and December 31, 2019, were extracted using a keyword search and then screened to identify EMM-related reports. Data contained in EMM-related incident reports were then classified as unsafe acts made by users and the latent conditions contributing to each incident. RESULTS: In our sample, 444 incident reports were determined to be EMM related. Commission errors were the most frequent unsafe act reported by users (n = 298), whereas workarounds were reported in only 13 reports. User latent conditions (n = 207) were described in the highest number of incident reports, followed by conditions related to the organization (n = 200) and EMM design (n = 184). Over time, user unfamiliarity with the system remained a key contributor to reported incidents. Although fewer articles to electronic transfer errors were reported over time, incident reports related to the transfer of information between different computerized systems increased as hospitals adopted more clinical information systems. CONCLUSIONS: Electronic medication management-related incidents continue to occur years after EMM implementation and are driven by design, user, and organizational conditions. Although factors contribute to reported incidents in varying degrees over time, some factors are persistent and highlight the importance of continuously improving the EMM system and its use.

Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase.

Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N-terminal palmitoylation, making the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural data, we designed and synthesized 37 new analogues which we profiled alongside 13 previously reported analogues in enzymatic and cellular assays. Our results show that a central amide linkage, a secondary amine, and (R)-configuration at the 4-position of the core are three key factors for inhibitory potency. Several potent analogues with low- or sub-µM IC50 against purified HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and suppress the SHH signaling pathway. This work identifies IMP-1575 as the most potent cell-active chemical probe for HHAT function, alongside an inactive control enantiomer, providing tool compounds for validation of HHAT as a target in cellular assays.

Determination of Ligand-Binding Affinity (Kd) Using Transverse Relaxation Rate (R2) in the Ligand-Observed 1H NMR Experiment and Applications to Fragment-Based Drug Discovery.

High hit rates from initial ligand-observed NMR screening can make it challenging to prioritize which hits to follow up, especially in cases where there are no available crystal structures of these hits bound to the target proteins or other strategies to provide affinity ranking. Here, we report a reproducible, accurate, and versatile quantitative ligand-observed NMR assay, which can determine Kd values of fragments in the affinity range of low µM to low mM using transverse relaxation rate R2 as the observable parameter. In this study, we examined the theory and proposed a mathematical formulation to obtain Kd values using non-linear regression analysis. We designed an assay format with automated sample preparation and simplified data analysis. Using tool compounds, we explored the assay reproducibility, accuracy, and detection limits. Finally, we used this assay to triage fragment hits, yielded from fragment screening against the CRBN/DDB1 complex.

A Degron Blocking Strategy Towards Improved CRL4CRBN Recruiting PROTAC Selectivity.

Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4CRBN recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4CRBN neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4CRBN molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC-induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.

What Goes Up, Must Come Down: A State-of-the-Art Electronic Health Record Downtime and Uptime Procedure in a Metropolitan Health Setting.

BACKGROUND: Electronic health records (EHRs) are used at most hospitals around the world, and downtime events are inevitable and common. Downtime represents a risky time for patients because patient information and critical EHR functionality are unavailable. Many institutions have used EHRs for years, with health professionals less likely to be familiar or comfortable with paper-based processes, resulting in an increased risk of errors during downtimes. There is currently limited guidance available on how to develop and operationalize downtime procedure at a local level. In this paper, we fill this gap by describing our state-of-the-art downtime and uptime procedure and its evaluation. METHOD: A district-wide downtime and uptime procedure was revised and standardized based on lessons learned from other health care organizations. The procedure outlines downtime and uptime preparations including downtime drills, downtime viewer auditing, and downtime education; downtime response including activating downtime and tracking patient changes; and uptime recovery including medication reconciliation and uptime documentation. IMPLEMENTATION: We implemented our new procedure across the district during an 8-hour planned downtime. A district downtime planning committee was formed, and a virtual command center was established to coordinate the downtime and uptime events. During downtime and uptime, onsite support was provided by the district's health informatics teams and clinicians. Data recovery was completed safely and efficiently with the revised uptime process. Following the event, we gathered staff feedback and reflections on implementing the procedure which highlighted its success but also revealed some areas for further improvement. CONCLUSION: In this paper, we describe a state-of-the-art EHR downtime and uptime procedure and lessons learned from its implementation. The implementation was successful with staff well prepared and information reconciled efficiently ensuring safe continuity of care. It was only through extensive planning, significant commitment, and engagement of all stakeholders that this outcome was possible.

iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells.

To address the limitation associated with degron based systems, we have developed iTAG, a synthetic tag based on IMiDs/CELMoDs mechanism of action that improves and addresses the limitations of both PROTAC and previous IMiDs/CeLMoDs based tags. Using structural and sequence analysis, we systematically explored native and chimeric degron containing domains (DCDs) and evaluated their ability to induce degradation. We identified the optimal chimeric iTAG(DCD23 60aa) that elicits robust degradation of targets across cell types and subcellular localizations without exhibiting the well documented "hook effect" of PROTAC-based systems. We showed that iTAG can also induce target degradation by murine CRBN and enabled the exploration of natural neo-substrates that can be degraded by murine CRBN. Hence, the iTAG system constitutes a versatile tool to degrade targets across the human and murine proteome.

Nurses' Medication Administration Workarounds when Using Electronic Systems: An Analysis of Safety Incident Reports.

Electronic medication management systems (EMMS) have been implemented in most acute care settings in Australia to reduce medication error rates. One of the key challenges related to the introduction of EMMS in hospitals is the uptake of informal "workarounds" by clinicians, including nurses. In this study, we aimed to examine one workaround in depth, nurses not documenting medication administration in the EMMS at the time of administration. We conducted a review of incident reports to identify the factors that contribute to this workaround occurring and the consequences or potential consequences of this workaround on patients. We identified a range of contributing factors, with factors relating to the user (e.g. nurses being time poor) occurring most frequently in incident reports. The most frequently seen consequence of this workaround was the patient receiving an additional dose. This research revealed that strategies to reduce the uptake of this workaround should consider user and organisational factors rather than just EMMS design alone.

Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.

Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes.

The existence of multiple centrosomes in some cancer cells can lead to cell death through the formation of multipolar mitotic spindles and consequent aberrant cell division. Many cancer cells rely on HSET (KIFC1) to cluster the extra centrosomes into two groups to mimic the bipolar spindle formation of non-centrosome-amplified cells and ensure their survival. Here, we report the discovery of a novel 2-(3-benzamidopropanamido)thiazole-5-carboxylate with micromolar in vitro inhibition of HSET (KIFC1) through high-throughput screening and its progression to ATP-competitive compounds with nanomolar biochemical potency and high selectivity against the opposing mitotic kinesin Eg5. Induction of the multipolar phenotype was shown in centrosome-amplified human cancer cells treated with these inhibitors. In addition, a suitable linker position was identified to allow the synthesis of both fluorescent- and trans-cyclooctene (TCO)-tagged probes, which demonstrated direct compound binding to the HSET protein and confirmed target engagement in cells, through a click-chemistry approach.

Accuracy of best possible medication histories by pharmacy students: an observational study.

BACKGROUND: Medication reconciliation is an effective strategy to prevent medication errors upon hospital admission and requires obtaining a patient's best possible mediation history (BPMH). However, obtaining a BPMH is time-consuming and pharmacy students may assist pharmacists in this task. AIM: To evaluate the proportion of patients who have an accurate BPMH from the pharmacy student-obtained BPMH compared to the pharmacist-obtained BPMH. METHOD: Twelve final-year pharmacy students were trained to obtain BPMHs upon admission at 2 tertiary hospitals and worked in pairs. Each student pair completed one 8-h shift each week for 8 weeks. Students obtained BPMHs for patients taking 5 or more medications. A pharmacist then independently obtained and checked the student BPMH from the same patient for accuracy. Deviations were determined between student-obtained and pharmacist-obtained BMPH. An accurate BPMH was defined as only having no-or-low risk medication deviations. RESULTS: The pharmacy students took BPMHs for 91 patients. Of these, 65 patients (71.4%) had an accurate BPMH. Of the 1170 medications included in patients' BPMH, 1118 (95.6%) were deemed accurate. For the student-obtained BPMHs, they were more likely to be accurate for patients who were older (OR 1.04; 95% CI 1.03-1.06; p < 0.001), had fewer medications (OR 0.85; 95% CI 0.75-0.97; p = 0.02), and if students used two source types (administration and supplier) to obtain the BPMH (OR 1.65; 95% CI 1.09-2.50; p = 0.02). CONCLUSION: It is suitable for final-year pharmacy students to be incorporated into the BPMHs process and for their BPMHs to be verified for accuracy by a pharmacist.

Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.

Building a pharmacy workforce from the ground up to support the COVID-19 vaccine rollout: lessons learned and recommendations.

The COVID-19 pandemic has required an unprecedented surge in the pharmacy workforce to support mass vaccination hubs. This review discusses the challenges faced while training and credentialing a surge pharmacy workforce and how these challenges were overcome. The process used for training and credentialing new employees has been described and recommendations and insights have been provided based on the lessons learned at two COVID-19 mass vaccination hubs in New South Wales. Operationalising one of the largest mass vaccination hubs in Australia required efficient training and credentialing of the pharmacy workforce. This process included the use of pharmacist-extenders such as students, assistants, and those from other healthcare and non-healthcare backgrounds. Training was optimised by using a flipped classroom model, so that the vaccine preparation process was provided via asynchronous online videos. The videos covered each step of vaccine dose preparation with visual cues to guide appropriate technique. On-site training involved use of simulation and checklists for credentialing. Many factors contributed to the success of this process, including the use of triaging and the re-allocation of personnel based on skill level, collaboration with the Sydney Pharmacy School to train and support a surge workforce involving students, initial on-site information technology support in the form of pharmacy superusers, the use of checklists and guides for troubleshooting, and assigned pharmacy educators to train new employees. The public health response to the COVID-19 pandemic forced us to rapidly adapt to build a pharmacy workforce in record time to support mass vaccination hubs. The recommendations and insights provided from our experience can guide future surges. Some of these concepts may also be applied to pharmacy practice in hospitals when resources are constrained.

Stakeholder perspectives of system-related errors: Types, contributing factors, and consequences.

BACKGROUND: Despite growing evidence of the benefits of electronic medication management systems (EMMS), research has also identified a range of new safety risks linked with their use. There is limited qualitative research focusing on system-related errors that result from use of EMMS. The aim of this study was to explore in-depth stakeholders' perceptions and experiences of system-related errors. METHODS: Semi-structured interviews were conducted with EMMS users and other relevant staff (e.g. supporting roles in EMMS) across a local health district in Sydney, Australia. Analysis was conducted iteratively using a general inductive approach, and then mapped to Reason's accident causation model, where codes were categorized as 1) unsafe acts (i.e. what error occurred), 2) latent conditions (i.e. what factors contributed to errors), and 3) consequences resulting from the error. RESULTS: Twenty-five participants were interviewed between September 2020 and May 2021. Participants most frequently described omission errors (e.g. failure to check for duplicate orders) as unsafe acts, although commission errors and workarounds were also reported. Poor EMMS design was reported to be a significant workplace factor contributing to system-related errors, however participants also described user factors, such as an overreliance on the system, and organizational factors, such as system downtime, as contributing to errors. Reported consequences of system-related errors included medication errors, but also impacts to the EMMS and on workers. CONCLUSIONS: EMMS design is a significant contributor to system-related errors, but this research showed that user and organizational factors are also at play. As these factors are not independent, minimizing system-related errors requires a multi-faceted approach, where mitigation strategies target not only the EMMS, but also the context in which the system has been implemented.

Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.

The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.

Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.

To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.

Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.

We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes.

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of 'druggable' targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1-/- tumours in subcutaneous xenograft models, with no significant effect in LIMD1+/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.

Electronic Medication Management Systems: Analysis of Enhancements to Reduce Errors and Improve Workflow.

BACKGROUND: Electronic medication management (eMM) has been shown to reduce medication errors; however, new safety risks have also been introduced that are associated with system use. No research has specifically examined the changes made to eMM systems to mitigate these risks. OBJECTIVES: To (1) identify system-related medication errors or workflow blocks that were the target of eMM system updates, including the types of medications involved, and (2) describe and classify the system enhancements made to target these risks. METHODS: In this retrospective qualitative study, documents detailing updates made from November 2014 to December 2019 to an eMM system were reviewed. Medication-related updates were classified according to "rationale for changes" and "changes made to the system." RESULTS: One hundred and seventeen updates, totaling 147 individual changes, were made to the eMM system over the 4-year period. The most frequent reasons for changes being made to the eMM were to prevent medication errors (24% of reasons), optimize workflow (22%), and support "work as done" on paper (16%). The most frequent changes made to the eMM were options added to lists (14% of all changes), extra information made available on the screen (8%), and the wording or phrasing of text modified (8%). Approximately a third of the updates (37%) related to high-risk medications. The reasons for system changes appeared to vary over time, as eMM functionality and use expanded. CONCLUSION: To our knowledge, this is the first study to systematically review and categorize system updates made to overcome new safety risks associated with eMM use. Optimization of eMM is an ongoing process, which changes over time as users become more familiar with the system and use is expanded to more sites. Continuous monitoring of the system is necessary to detect areas for improvement and capitalize on the benefits an electronic system can provide.